Labdane-Type Diterpenes, Galangalditerpenes A-C, with Melanogenesis Inhibitory Activity from the Fruit of Alpinia galanga.

In our continuing study of biologically active natural products from the fruit of Alpinia galanga (Zingiberaceae), we newly isolated three new labdane-type diterpenes, termed galangalditerpenes A-C (1-3), along with four known sesquiterpenes (4-7) and two diterpenes (8 and 9). The stereostructures of 1-3 were elucidated on the basis of their spectroscopic properties. The melanogenesis inhibitory activities in theophylline-stimulated murine B16 melanoma 4A5 cells of these isolates, including the new diterpenes (1-3, IC50 = 4.4, 8.6, and 4.6 µM, respectively), were found to be more than 6-87-fold higher than that of arbutin (174 µM), a commercially available positive control.

Melanogenesis inhibitory activity of a 7-O-9'-linked neolignan from Alpinia galanga fruit.

An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50=7.3µg/mL). Through bioassay-guided separation of the extract, a new 7-O-9'-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2-15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC50=2.5µM), 1'S-1'-acetoxychavicol acetate (2, 5.0µM), and 1'S-1'-acetoxyeugenol acetate (3, 5.6µM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1'-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9'-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1' (IC50=1.9µM) and 2' (4.5µM)] and racemic mixtures [(±)-1 (2.2µM) and (±)-2 (4.4µM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1-3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity.

Intervendor Variabilities of Left and Right Ventricular Myocardial Velocities among Three Tissue Doppler Echocardiography Systems.

BACKGROUND: Whether an intervendor discordance of myocardial velocities determined by tissue Doppler echocardiography (TDE) can be generalized remains unclear. We compared intervendor variabilities of left ventricular (LV) and right ventricular (RV) myocardial velocities among three TDE systems. METHODS: Examinations with TDE were performed in 41 healthy subjects and 11 patients with cardiovascular risk factors (CVR) using α-7 (V1, Hitachi Aloka Medical), Artida (V2, Toshiba Medical Systems), and Vivid E9 (V3, GE Healthcare) on the same day. Peak systolic (s'), early diastolic (e'), and late diastolic (a') myocardial velocities at medial and lateral sites of the mitral annulus and lateral site of the tricuspid annulus were measured using both pulsed-wave TDE and color TDE. Intra-observer and inter-observer variabilities were determined in 10 subjects and test-retest variability in 14 subjects. RESULTS: As for test-retest variability, reproducibilities of LV and RV myocardial velocities determined by pulsed-wave TDE and color TDE were relatively low but comparable between V1, V2, and V3. Myocardial velocities in healthy subjects determined by both pulsed-wave TDE and color TDE were significantly different among the three TDE systems. Myocardial velocities by pulsed-wave TDE in V3 were 2-12% lower (P < 0.05) than those by V2 and 5-14% lower (P < 0.05) than those by V1. Similar differences in myocardial velocities determined by both pulsed-wave TDE and color TDE were found in patients with CVR. CONCLUSIONS: LV and RV myocardial velocities determined by both pulsed-wave TDE and color TDE are vendor dependent, and reproducibility of the myocardial velocities determined by both TDE systems is relatively low.

Factors Related to Treatment Non-Adherence Among Caregivers of Pediatric and Adolescent Growth Hormone Deficiency Patients in Japan.

Background: About one-third of caregivers of pediatric or adolescent growth hormone deficiency (pGHD) patients in Japan have reported poor treatment adherence. However, few studies have examined factors related to adherence for that group. Objective: The aim of this study is to consider factors related to poor adherence to daily treatment among caregivers of pGHD patients in Japan. Methods: A cross-sectional survey was conducted among caregivers of pGHD patients in Japan. Caregivers were asked about demographic and treatment characteristics, health literacy, treatment satisfaction, opinions about treatment, and treatment adherence. Health literacy was assessed using the 14-item health literacy scale (HLS-14). Adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8). Statistical association with adherence was considered using Chi-square and Student's t-testing. An exploratory factor analysis (EFA) and K-means cluster analysis was conducted to consider the influence of treatment satisfaction and opinions concerning treatment on adherence. Results: Responses were collected from 112 caregivers. The caregiver's age being 30-39 years old, the primary caregiver being male, the primary caregiver being employed, and low functional health literacy for the caregiver were associated with poor adherence. Patients being pre-elementary school age was also associated with poor adherence. Low satisfaction with drug treatment and/or their device and communication with healthcare professionals (HCPs), and lack of agreement with the importance of treatment management (eg, keeping injection records, getting informed about the disease/therapy, reporting non-adherence, and sticking to an administration schedule), were also associated with poor adherence. Conclusion: Strategies to improve treatment adherence among caregivers of pGHD patients in Japan should consider the age, gender, and employment status of the caregiver - as well as their functional literacy. Improvement in satisfaction with the drug or device used, better communication with HCPs, and greater awareness of the importance of treatment management, may also lead to better adherence.

Learning Curve Effect of Combined Technique Thrombectomy as First-Line Attempt for Acute Ischemic Stroke: A Single-Center Retrospective Study.

OBJECTIVES: We retrospectively examined the initial experience and learning curve after the introduction of thrombectomy with the combined technique using an aspiration catheter and a stent retriever as first-line attempt for acute ischemic stroke. METHODS: Consecutive patients undergoing thrombectomy for acute ischemic stroke at our institution between January 2020 and December 2022 were divided into 3 groups according to the year of thrombectomy. Patient characteristics and procedural, safety, and clinical outcomes were compared between the three year periods to determine predictors of favorable clinical outcome. RESULTS: In 2020, 2021, and 2022, the numbers of patients were 74, 70, and 90, respectively, with similar patient characteristics across the three years; successful recanalization rates were 79.7%, 97.1%, and 93.3%, respectively (P < 0.01 for the first 2 years); median procedure times were 67, 43, and 32 minutes, respectively (P < 0.01 for the first 2 years and P = 0.018 for the last 2 years); first pass effect rates were 20.3%, 41.4%, and 44.4%, respectively (P < 0.01 for the first 2 years); symptomatic intracranial hemorrhage rates were 14.9%, 2.9%, and 1.1%, respectively (P = 0.018 for the first 2 years); and percentages of modified Rankin Scale score 0-2 at 90 days were 24.3%, 42.9%, and 41.1%, respectively (P = 0.022 for the first 2 years). Procedure time (P = 0.038) and successful recanalization (P = 0.041) were independent predictors of favorable clinical outcome. CONCLUSIONS: The learning curve effect of the combined technique may be associated with better clinical outcome due to increased successful recanalization rates, shortened procedure time, and reduced symptomatic intracranial hemorrhage.

Anterior condylar arteriovenous fistula mainly fed by peripheral branches of the bilateral internal maxillary arteries: illustrative case.

BACKGROUND: The main feeding artery of an anterior condylar arteriovenous fistula (AC-AVF) is the ascending pharyngeal artery and rarely the internal maxillary artery. OBSERVATIONS: A 58-year-old male with a history of sinusitis since adolescence presented with a 5-year history of bilateral pulsatile tinnitus and a 2-month history of right ocular symptoms. Angiography showed that the peripheral branches of the bilateral internal maxillary arteries were the main feeding arteries of the AC-AVF and that they gathered in the clivus with a relatively large shunted pouch in the left jugular tubercle. Shunt flow drained to the right external jugular vein via the right superior ophthalmic vein. A sheath was placed in the right external jugular vein, and a small distal access catheter was guided to the right superior ophthalmic vein to allow the microcatheter to reach the shunted pouch. Selective angiography of the contralateral sphenopalatine artery allowed us to confirm the gathering site of the feeding arteries and the shunted pouch and archive the complete occlusion. LESSONS: Selective angiography of the contralateral sphenopalatine artery may be useful to confirm the gathering site of the peripheral branches of the bilateral internal maxillary arteries in an AC-AVF.

Perception of Adherence to Daily Human Growth Hormone Treatments Among Pediatric and Adolescent Patients in Japan: A Cross-Sectional Survey of Physicians and Caregivers.

Background: Poor adherence to daily human growth hormone (hGH) treatment has been shown to be associated with poor clinical outcomes for growth hormone deficiency (GHD) patients. However, few studies have examined the perception of adherence to hGH treatment among both physicians and caregivers in Japan. Objective: The aim of this study is to examine the perception of adherence for daily hGH treatment among physicians and caregivers of pediatric and adolescent patients treated with GH in Japan. Moreover, we explore reasons for skipping treatment and the potential impact of a once-weekly treatment on adherence. Methods: A cross-sectional survey was conducted in Japan among physicians that prescribe daily hGH treatment and caregivers that have administered daily hGH treatment to children/adolescents for 3 months or longer. The Morisky Medication Adherence Scale (MMAS-8) was used to gauge perceived adherence for both physician and caregiver groups. Caregivers were also questioned regarding reasons for missing injections. Moreover, both groups were asked about the impact of a once-weekly treatment on adherence. Results: Responses were collected from 123 physicians and 112 caregivers. Physicians reported that 18.1% of patients have poor adherence based on the MMAS-8 instrument. In contrast, 32.1% of the caregivers reported poor adherence. "Simply forgetting", "Patient refused/resisted", and being "Busy with school activities, etc" were the most commonly selected reasons by caregivers for missing an injection. Physicians felt that a once-weekly injection could improve adherence for 64.5% of patients with poor adherence. Moreover, 56.9% of the caregivers that reported an experience of missed injections felt that a once-weekly injection would improve their adherence. Conclusion: Approaches to improve adherence to hGH treatment in Japan are continuously needed. While further research is needed to understand factors most likely to improve adherence, availability of a once-weekly treatment is expected to help improve adherence.

A Staged Operation as a Surgical Strategy for a Patient with Type VI Isolated Superior Mesenteric Artery Dissection.

An isolated superior mesenteric artery (SMA) dissection (ISMAD) is extremely rare among visceral artery dissections. Its diagnosis is made by abdominal contrast CT scan which shows SMA occlusion partially or completely. The ISMAD is classified into 6 types: type I-V has partial occlusion and treated medically using antiplatelets or anticoagulants. On the other hand, type VI has complete occlusion and must be treated by urgent surgical operation. We present a 67-year-old female who presented with sudden onset abdominal pain and melena. An urgent contrast CT revealed type VI ISMAD. She underwent 3 staged operations as follows: (1) first, as laparotomy showed pale color in almost the extensive length of the small intestine, arterial bypassing of SMA was undertaken using SMA to the right common iliac artery bypass; (2) as the second-look operation on the next day, the terminal ileum was resected, and the remaining small intestine was able to be preserved. However, when the abdomen was tried to be closed, systemic blood pressure decreased to pre-shock condition, so the abdominal wall was closed at skin level with silastic sheet. (3) As the third-look operation on the 7th day, ileostomy was created, and the abdominal wall was safely closed. The postoperative course was uneventful. This case study shows that SMA grafting and staged operations might be an option to preserve the length of the small intestine when ISMAD is diagnosed as type VI.

Achievement of alternative configurations of vehicles on multiple lanes.

Heavy traffic congestion occurs daily at merging sections on a highway. For relieving this congestion, possibility of alternative configuration of vehicles on multiple-lane road at a merging area is discussed in this paper. This is the configuration where no vehicles move aside on the other lane. It has merit in making a smooth merging at an intersection or a junction due to the so-called "zipper effect." We show, by developing a cellular automaton model for multiple lanes, that this configuration is achieved by simple local interactions between vehicles neighboring each other. The degree of the alternative configuration in terms of the spatial increase in parallel driving length is studied by using both numerical simulations and mean-field theory. We successfully construct a theoretical method for calculating this degree of the alternative configuration by using cluster approximation. It is shown that the theoretical results coincide with those of the simulations very well.

Collective opinion formation model under Bayesian updating and confirmation bias.

We propose a collective opinion formation model with a so-called confirmation bias. The confirmation bias is a psychological effect with which, in the context of opinion formation, an individual in favor of an opinion is prone to misperceive new incoming information as supporting the current belief of the individual. Our model modifies a Bayesian decision-making model for single individuals [M. Rabin and J. L. Schrag, Q. J. Econ. 114, 37 (1999)] for the case of a well-mixed population of interacting individuals in the absence of the external input. We numerically simulate the model to show that all the agents eventually agree on one of the two opinions only when the confirmation bias is weak. Otherwise, the stochastic population dynamics ends up creating a disagreement configuration (also called polarization), particularly for large system sizes. A strong confirmation bias allows various final disagreement configurations with different fractions of the individuals in favor of the opposite opinions.

Collective motion of oscillatory walkers.

We study a system of interacting self-propelled particles whose walking velocity depends on the stage of the locomotion cycle. The model introduces a phase equation in the optimal velocity model for vehicular traffic. We find that the system exhibits novel types of flow: synchronized free flow, phase-anchoring free flow, orderly jam flow, and disordered jam flow. The first two flows are characterized by synchronization of the phase, while the others do not have the global synchronization. Among these, the disordered jam flow is very complex, although the underlying model is simple. This phenomenon implies that the crowd behavior of moving particles can be destabilized by coupling their velocity to the phase of their motion. We also focus on "phase-anchoring" phenomena. They strongly affect particle flow in the system, especially when the density of particles is high.

Car-following model with relative-velocity effect and its experimental verification.

In driving a vehicle, drivers respond to the changes of both the headway and the relative velocity to the vehicle in front. In this paper a new car-following model including these maneuvers is proposed. The acceleration of the model becomes infinite (has a singularity) when the distance between two vehicles is zero, and the asymmetry between the acceleration and the deceleration is incorporated in a nonlinear way. The model is simple but contains enough features of driving for reproducing real vehicle traffic. From the linear stability analysis, we confirm that the model shows the metastable homogeneous flow around the critical density, beyond which a traffic jam emerges. Moreover, we perform experiments to verify this model. From the data it is shown that the acceleration of a vehicle has a positive correlation with the relative velocity.

Introduction of frictional and turning function for pedestrian outflow with an obstacle.

In this paper, two important factors which affect the pedestrian outflow at a bottleneck significantly are studied in detail to analyze the effect of an obstacle setup in front of an exit. One is a conflict at an exit when pedestrians evacuate from a room. We use floor field model for simulating such behavior, which is a well-studied pedestrian model using cellular automata. The conflicts have been taken into account by the friction parameter. However, the friction parameter so far is a constant and does not depend on the number of the pedestrians conflicting at the same time. Thus, we have improved the friction parameter by the frictional function, which is a function of the number of the pedestrians involved in the conflict. Second, we have presented the cost of turning of pedestrians at the exit. Since pedestrians have inertia, their walking speeds decrease when they turn and the pedestrian outflow decreases. The validity of the extended model, which includes the frictional function and the turning function, is supported by the comparison of a mean-field theory and real experiments. We have observed that the pedestrian flow increases when we put an obstacle in front of an exit in our real experiments. The analytical results clearly explains the mechanism of the effect of the obstacle, i.e., the obstacle blocks pedestrians moving to the exit and decreases the average number of pedestrians involved in the conflict. We have also found that an obstacle works more effectively when we shift it from the center since pedestrians go through the exit with less turning.