Brain-age estimation with a low-cost EEG-headset: effectiveness and implications for large-scale screening and brain optimization.

Over time, pathological, genetic, environmental, and lifestyle factors can age the brain and diminish its functional capabilities. While these factors can lead to disorders that can be diagnosed and treated once they become symptomatic, often treatment is difficult or ineffective by the time significant overt symptoms appear. One approach to this problem is to develop a method for assessing general age-related brain health and function that can be implemented widely and inexpensively. To this end, we trained a machine-learning algorithm on resting-state EEG (RS-EEG) recordings obtained from healthy individuals as the core of a brain-age estimation technique that takes an individual's RS-EEG recorded with the low-cost, user-friendly EMOTIV EPOC X headset and returns that person's estimated brain age. We tested the current version of our machine-learning model against an independent test-set of healthy participants and obtained a correlation coefficient of 0.582 between the chronological and estimated brain ages (r = 0.963 after statistical bias-correction). The test-retest correlation was 0.750 (0.939 after bias-correction) over a period of 1 week. Given these strong results and the ease and low cost of implementation, this technique has the potential for widespread adoption in the clinic, workplace, and home as a method for assessing general brain health and function and for testing the impact of interventions over time.

Electroencephalography Spectral-power Volatility Predicts Problem-solving Outcomes.

Temporal variability is a fundamental property of brain processes and is functionally important to human cognition. This study examined how fluctuations in neural oscillatory activity are related to problem-solving performance as one example of how temporal variability affects high-level cognition. We used volatility to assess step-by-step fluctuations of EEG spectral power while individuals attempted to solve word-association puzzles. Inspired by recent results with hidden-state modeling, we tested the hypothesis that spectral-power volatility is directly associated with problem-solving outcomes. As predicted, volatility was lower during trials solved with insight compared with those solved analytically. Moreover, volatility during prestimulus preparation for problem-solving predicted solving outcomes, including solving success and solving time. These novel findings were replicated in a separate data set from an anagram-solving task, suggesting that less-rapid transitions between neural oscillatory synchronization and desynchronization predict better solving performance and are conducive to solving with insight for these types of problems. Thus, volatility can be a valuable index of cognition-related brain dynamics.

Creative flow as optimized processing: Evidence from brain oscillations during jazz improvisations by expert and non-expert musicians.

Using a creative production task, jazz improvisation, we tested alternative hypotheses about the flow experience: (A) that it is a state of domain-specific processing optimized by experience and characterized by minimal interference from task-negative default-mode network (DMN) activity versus (B) that it recruits domain-general task-positive DMN activity supervised by the fronto-parietal control network (FPCN) to support ideation. We recorded jazz guitarists' electroencephalograms (EEGs) while they improvised to provided chord sequences. Their flow-states were measured with the Core Flow State Scale. Flow-related neural sources were reconstructed using SPM12. Over all musicians, high-flow (relative to low-flow) improvisations were associated with transient hypofrontality. High-experience musicians' high-flow improvisations showed reduced activity in posterior DMN nodes. Low-experience musicians showed no flow-related DMN or FPCN modulation. High-experience musicians also showed modality-specific left-hemisphere flow-related activity while low-experience musicians showed modality-specific right-hemisphere flow-related deactivations. These results are consistent with the idea that creative flow represents optimized domain-specific processing enabled by extensive practice paired with reduced cognitive control.

Uncovering the Interplay of Oscillatory Processes During Creative Problem Solving: A Dynamic Modeling Approach.

To solve a new problem, people spontaneously engage multiple cognitive processes. Previous work has identified a diverse set of oscillatory components critical at different stages of creative problem solving. In this project, we use hidden state modeling to untangle the roles of oscillation processes over time as people solve puzzles. Building on earlier work, we further developed analytical methods, such as incorporating source separating techniques and identifying the optimal number of states using cross-validation. We extracted brain states characterized by spatio-spectral topographies from time-resolved EEG spectral powers. The data driven approach allowed us to infer the dynamic, trial-by-trial, state sequences, and provided a comprehensive depiction of how various oscillation components interact recurrently throughout the trial. The properties of the states suggest their dissociable cognitive functions. For example, we identified three states with dominant activation in alpha bands but having distinct spatial distributions. People were differentially engaged in these states depending on the stages (e.g., onset or response) and outcomes of the trials (solved with insight or analysis). The current approach, applicable to many tasks requiring extended trial duration, can potentially reconcile findings from previous EEG studies and drive new hypotheses to further our understanding of the complex creative process.

Effectiveness of Chickpeas on Blood Sugar: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Diabetes affects one in eleven adults globally, with rising cases in the past 30 years. Type 1 and type 2 cause blood sugar problems, increasing cardiovascular risks. Dietary control, including chickpeas, is suggested but needs more research. Comprehensive searches were conducted across multiple databases for the randomized controlled trial efficacy of chickpea consumption to lower blood sugar levels to a healthy range, with data extraction and risk of bias assessment performed independently by two researchers. Statistical analysis was performed using RevMan 5.4, expressing continuous data as mean differences and risk ratios with 95% confidence intervals, and a summary of the findings is provided considering the variations in study characteristics. A total of 118 articles were initially identified from seven databases, primarily from Anglo-American countries, resulting in 12 selected studies after the identification and screening processes. These studies involved 182 participants, focusing on healthy or normoglycemic adults, and assessed the effects of chickpeas compared to various foods such as wheat, potatoes, pasta, sauce, cheese, rice, and corn. A meta-analysis involving a subset of studies demonstrated that chickpeas were more effective in reducing blood glucose iAUC compared to potatoes and wheat. Chickpeas offer the potential for blood sugar control through low starch digestibility, high fiber, protein, and hormonal effects. Although insulin benefits are seen, statistical significance varies, supporting their role in diabetic diets focusing on nutrient-rich foods over processed carbs.

An examination of frontal asymmetry in relation to eating in the absence of hunger and loss-of-control eating.

Loss-of-control (LOC) eating involves a subjective feeling that one cannot stop eating or control one's eating. Individuals with LOC eating may exhibit strong appetitive drives and weak inhibitory control, and these two opposing motivations have been related to EEG measurements of frontal asymmetry or lateralized frontal activation. The present study investigated whether frontal asymmetry is related to hedonic hunger, LOC eating severity and frequency, and eating in the absence of hunger (EAH) in the laboratory. Fifty-nine individuals participated in an ostensible taste study after resting-state electroencephalogram (EEG) recordings. After the EEGs, they were provided a meal to eat until fullness, followed by an array of snacks and instructions to eat as much as they would like. The results indicated that several measures of right-frontal asymmetry were related to greater EAH and greater self-reported LOC eating severity. Although right-frontal asymmetry has been theorized to reflect avoidance motivation, recent evidence suggests it may indicate effortful control during approach-avoidance conflicts. Because individuals with LOC eating presumably experience heightened conflict between drives to eat beyond energy needs and to minimize such eating, those experiencing greater LOC may exert greater effort to manage these conflicting motivations. An integration of these neurobiological correlates of LOC eating may help provide a more comprehensive understanding of LOC eating and inform treatments.

Asterias pectinifera-Derived Collagen Peptides Mixed with Halocynthia roretzi Extracts Exhibit Anti-Photoaging Activities during Exposure to UV Irradiation, and Antibacterial Properties.

Asterias pectinifera, a species of starfish and cause of concern in the aquaculture industry, was recently identified as a source of non-toxic and highly water-soluble collagen peptides. In this study, we investigated the antioxidant and anti-photoaging functions of compounds formulated using collagen peptides from extracts of Asterias pectinifera and Halocynthia roretzi (AH). Our results showed that AH compounds have various skin protective functions, including antioxidant effects, determined by measuring the scavenging activity of 2,2-diphenyl-1-picrylhydrazyl radicals, as well as anti-melanogenic effects, determined by measuring tyrosinase inhibition activity. To determine whether ethosome-encapsulated AH compounds (E(AH)) exert ultraviolet (UV)-protective effects, human dermal fibroblasts or keratinocytes were incubated with E(AH) before and after exposure to UVA or UVB. E(AH) treatment led to inhibition of photoaging-induced secretion of matrix metalloproteinase-1 and interleukin-6 and -8, which are associated with inflammatory responses during UV irradiation. Finally, the antibacterial effects of AH and E(AH) were confirmed against both gram-negative and gram-positive bacteria. Our results indicate that E(AH) has the potential for use in the development of cosmetics with a range of skin protective functions.

Dynamics of hidden brain states when people solve verbal puzzles.

When people try to solve a problem, they go through distinct steps (encoding, ideation, evaluation, etc.) recurrently and spontaneously. To disentangle different cognitive processes that unfold throughout a trial, we applied an unsupervised machine learning method to electroencephalogram (EEG) data continuously recorded while 39 participants attempted 153 Compound Remote Associates problems (CRA). CRA problems are verbal puzzles that can be solved in either insight-leaning or analysis-leaning manner. We fitted a Hidden Markov Model to the time-frequency transformed EEG signals and decoded each trial as a time-resolved state sequence. The model characterizes hidden brain states with spectrally resolved power topography. Seven states were identified with distinct activation patterns in the theta (4-7 Hz), alpha (8-9 Hz and 10-13 Hz), and gamma (25-50 Hz) bands. Notably, a state featuring widespread activation only in alpha-band frequency emerged, from this data-driven approach, which exhibited dynamic characteristics associated with specific temporal stages and outcomes (whether solved with insight or analysis) of the trials. The state dynamics derived from the model overlap and extend previous literature on the cognitive function of alpha oscillation: the "alpha-state" probability peaks before stimulus onset and decreases before response. In trials solved with insight, relative to solved with analysis, the alpha-state is more likely to be visited and maintained during preparation and solving periods, and its probability declines more sharply immediately preceding a response. This novel paradigm provides a way to extract dynamic features that characterize problem-solving stages and potentially provide a novel window into the nature of the underlying cognitive processes.

Pre-stimulus brain oscillations predict insight versus analytic problem-solving in an anagram task.

There are two general strategies for solving a problem. Insight is the sudden realization of a novel idea or problem solution accompanied by an "aha" experience. Analysis occurs in a conscious, deliberate fashion without an "aha" experience. Previous research has shown that brain activity during a preparatory period immediately before a problem is presented can predict whether the subsequently presented problem will be solved by insight or by analysis. Those prior studies used a type of brief verbal problem called compound remote associates (CRA). To determine whether prestimulus activity predicts subsequent insight versus analytic solving for other types of problems, the present study used an anagram task. We examined high-density electroencephalograms (EEGs) immediately preceding the presentation of anagrams and found that during the 2-s prestimulus interval there was greater beta-band activity recorded over right central-parietal cortex prior to analytic solving compared with insightful solving. EEG source reconstruction showed that this activity originated in left mid-cingulate cortex (MCC) and the right postcentral gyrus. In contrast to prior work, we found no evidence of a significant interaction between insight-related prestimulus brain activity and positive mood, although positive mood was associated with greater activity in anterior cingulate cortex and with a larger number of insight solutions. The present MCC results suggest that participants' anagram-solving strategies may be influenced by allostasis, that is, the estimation and marshalling of neurocognitive resources required to cope with an expected task. Specifically, when a participant adequately prepares for an upcoming problem, then MCC activity is high, enabling solution by resource-intensive analytic processing. Alternatively, when preparation is insufficient for analytic processing, then MCC activity is low and subsequent solving occurs by low-demand insight processing. The current findings and explanatory model differ from those of previous studies that used a CRA task, suggesting the possibility of complex interactions between task-type and procedure-type in determining the nature of prestimulus preparation. Future research examining such interactions may yield results that benefit educators who teach students problem-solving strategies.

Network Analysis on Herbal Formulas from Wenrejingwei and Shang Han Lun.

OBJECTIVES: This study aims to describe the utilization of herbal formulas from Wenrejingwei by using network analysis and understand the treatment of acute exogenous febrile diseases. METHODS: We constructed a matrix of high-frequency herbal combinations (HCs) from Wenrejingwei and Shang Han Lun and cluster networks based on cohesive analysis. Network analysis was performed to compare the results. RESULTS: The results of the high-frequency HC network in Wenrejingwei showed cohesive patterns in three categories corresponding to dampness-heat and warm-fever treatment. Compared to the Shang Han Lun network, the Wenrejingwei network indicated a careful approach in the use of pungent and warm herbs such as Guizhitang. Moreover, the combination of Scutellaria baicalensis and Coptis chinensis along with the use of herbs strengthening yin, such as Ginseng Radix and Liriopes Radix, provide evidence of a holistic approach in the treatment of exogenous febrile diseases by considering the balance of the human body damaged by heat. CONCLUSION: The results of this study could help select appropriate herbal formulas and treatment methods for treating Onbyeong and modern acute febrile infectious diseases.

An insight-related neural reward signal.

Moments of insight, a phenomenon of creative cognition in which an idea suddenly emerges into awareness as an "Aha!" are often reported to be affectively positive experiences. We tested the hypothesis that problem-solving by insight is accompanied by neural reward processing. We recorded high-density EEGs while participants solved a series of anagrams. For each solution, they reported whether the answer had occurred to them as a sudden insight or whether they had derived it deliberately and incrementally (i.e., "analytically'). Afterwards, they filled out a questionnaire that measures general dispositional reward sensitivity. We computed the time-frequency representations of the EEGs for trials with insight (I) solutions and trials with analytic (A) solutions and subtracted them to obtain an I-A time-frequency representation for each electrode. Statistical Parametric Mapping (SPM) analyses tested for significant I-A and reward-sensitivity effects. SPM revealed the time, frequency, and scalp locations of several I â€‹> â€‹A effects. No A â€‹> â€‹I effect was observed. The primary neural correlate of insight was a burst of (I â€‹> â€‹A) gamma-band oscillatory activity over prefrontal cortex approximately 500 â€‹ms before participants pressed a button to indicate that they had solved the problem. We correlated the I-A time-frequency representation with reward sensitivity to discover insight-related effects that were modulated by reward sensitivity. This revealed a separate anterior prefrontal burst of gamma-band activity, approximately 100 â€‹ms after the primary I-A insight effect, which we interpreted to be an insight-related reward signal. This interpretation was supported by source reconstruction showing that this signal was generated in part by orbitofrontal cortex, a region associated with reward learning and hedonically pleasurable experiences such as food, positive social experiences, addictive drugs, and orgasm. These findings support the notion that for many people insight is rewarding. Additionally, these results may explain why many people choose to engage in insight-generating recreational and vocational activities such as solving puzzles, reading murder mysteries, creating inventions, or doing research. This insight-related reward signal may be a manifestation of an evolutionarily adaptive mechanism for the reinforcement of exploration, problem solving, and creative cognition.

Dual-process contributions to creativity in jazz improvisations: An SPM-EEG study.

Conflicting theories identify creativity either with frontal-lobe mediated (Type-2) executive control processes or (Type-1) associative processes that are disinhibited when executive control is relaxed. Musical (jazz) improvisation is an ecologically valid test-case to distinguish between these views because relatively slow, deliberate, executive-control processes should not dominate during high-quality, real-time improvisation. In the present study, jazz guitarists (n â€‹= â€‹32) improvised to novel chord sequences while 64-channel EEGs were recorded. Jazz experts rated each improvisation for creativity, technical proficiency and aesthetic appeal. Surface-Laplacian-transformed EEGs recorded during the performances were analyzed in the scalp-frequency domain using SPM12. Significant clusters of high-frequency (beta-band and gamma-band) activity were observed when higher-quality versus lower-quality improvisations were compared. Higher-quality improvisations were associated with predominantly posterior left-hemisphere activity; lower-quality improvisations were associated with right temporo-parietal and fronto-polar activity. However, after statistically controlling for experience (defined as the number of public performances previously given), performance quality was a function of right-hemisphere, largely right-frontal, activity. These results support the notion that superior creative production is associated with hypofrontality and right-hemisphere activity thereby supporting a dual-process model of creativity in which experience influences the balance between executive and associative processes. This study also highlights the idea that the functional neuroanatomy of creative production depends on whether creativity is defined in terms of the quality of products or the type of cognitive processes involved.

Research trends in Korean medicine based on temporal and network analysis.

BACKGROUND: Much research on Korean medicine has been recently published in Korea. The aim of this study was to determine the research trends in Korean medicine by performing a comprehensive analysis of articles that have been published in Korea using temporal and network analysis methods. METHODS: A total of 29,876 articles from 1963 to 2018 were prepared from OASIS (Oriental Medicine Advanced Searching Integrated System), the largest portal for Korean medicine. After the keywords and years were extracted from the metadata of the articles, an annual frequency matrix was obtained for the keywords. By using the matrix, the temporal trends of the keywords were analyzed by comparing the changes in similarity between the lists of keywords by year. Moreover, to analyze the relationship among research topics, a clustered network was constructed in which a node was a keyword and an edge was a similarity between two keywords. RESULTS: The temporal trend of the keywords was classified into six chronological phases. The appearance frequency of most keywords tended to increase gradually, but only the keywords "mibyeong," "systems biology" and "korean medicine hospital" appeared in the most recent phase. The network of keywords was clustered and visualized into thirteen groups with the Gephi software. The main keywords in each group were related to effects such as "anti-inflammation" and "antioxidant," to diseases such as "allergic rhinitis" and "diabetes" and to therapies such as "herbal acupuncture" and "herbal formula." CONCLUSIONS: The analysis of the trends determined in this study provides a systematic understanding as well as future research directions in Korean medicine to researchers. In the future, an overall analysis of the research trends in Korean medicine will be done by analyzing articles published in Korea and other countries.

Dihydrocapsaicin Inhibits Epithelial Cell Transformation through Targeting Amino Acid Signaling and c-Fos Expression.

Chili peppers are one of the most widely consumed spices worldwide. However, research on the health benefits of chili peppers and some of its constituents has raised controversy as to whether chili pepper compounds possess cancer-promoting or cancer-preventive effects. While ample studies have been carried out to examine the effect of capsaicin in carcinogenesis, the chemopreventive effect of other major components in chili pepper, including dihydrocapsaicin, capsiate, and capsanthin, is relatively unclear. Herein, we investigated the inhibitory effect of chili pepper components on malignant cell transformation. Among the tested chili pepper compounds, dihydrocapsaicin displayed the strongest inhibitory activity against epidermal growth factor (EGF)-induced neoplastic transformation. Dihydrocapsaicin specifically suppressed EGF-induced phosphorylations of the p70S6K1-S6 pathway and the expression of c-Fos. A reduction in c-Fos levels by dihydrocapsaicin led to a concomitant downregulation of AP-1 activation. Further analysis of the molecular mechanism responsible for the dihydrocapsaicin-mediated decrease in phospho-p70S6K1, revealed that dihydrocapsaicin can block amino acid-dependent mechanistic targets of rapamycin complex 1 (mTORC1)-p70S6K1-S6 signal activation. Additionally, dihydrocapsaicin was able to selectively augment amino acid deprivation-induced cell death in mTORC1-hyperactive cells. Collectively, dihydrocapsaicin exerted chemopreventive effects through inhibiting amino acid signaling and c-Fos pathways and, thus, might be a promising cancer preventive natural agent.

Resting-state brain oscillations predict trait-like cognitive styles.

Anecdotal reports suggest the existence of individual differences in peoples' cognitive styles for solving problems, in particular, the tendency to rely on insight (the "aha" phenomenon) versus deliberate analytical thought. We hypothesized that such stable individual differences exist and are associated with trait-like individual differences in resting-state brain activity. We tested this idea by recording participants' resting-state electroencephalograms (RS-EEGs) on 4 occasions over approximately 7 weeks and then tasking them with solving anagrams and compound remote associates problems that are solvable by either strategy. We found that peoples' tendency to solve problems consistently by insight or by analysis spans both tasks and time. Moreover, we discovered trait-like individual differences in the balance between frontal and posterior resting-state brain activity and in temporal-lobe hemispheric asymmetries that predict, at least weeks in advance, the tendency to solve by insight versus analysis. The discovery of an insight-analytic dimension of cognitive style and its neural basis in resting state brain activity suggests new avenues for the development of neuroscience-based methods for intellectual, educational, and vocational assessment.

Authenticity testing of environment-friendly Korean rice (Oryza sativa L.) using carbon and nitrogen stable isotope ratio analysis.

The increasing demand for organic foods creates, in turn, a pressing need for the development of more accurate tools for the authentication of organic food in order to ensure both fair trade and food safety. This study examines the feasibility of δ13C and δ15N analyses as potential tools for authentication of environment-friendly rice sold in Korea. δ13C and δ15N examination in different rice grains showed that environment-friendly rice can be successfully distinguished from conventional rice. No multi-residue pesticides were detected in the examined rice samples, including conventional rice. This study demonstrates the complementary feasibility of δ13C and δ15N analyses for the authentication of environment-friendly rice sold in Korea in cases where pesticide residue analysis alone is insufficient for discrimination of organic and conventional rice. In future, complementary analyses including compound-specific isotope ratio analysis might be employed for improving the reliability of organic authentication.

Ginseng authenticity testing by measuring carbon, nitrogen, and sulfur stable isotope compositions that differ based on cultivation land and organic fertilizer type.

BACKGROUND: The natural ratios of carbon (C), nitrogen (N), and sulfur (S) stable isotopes can be varied in some specific living organisms owing to various isotopic fractionation processes in nature. Therefore, the analysis of C, N, and S stable isotope ratios in ginseng can provide a feasible method for determining ginseng authenticity depending on the cultivation land and type of fertilizer. METHODS: C, N, and S stable isotope composition in 6-yr-old ginseng roots (Jagyeongjong variety) was measured by isotope ratio mass spectrometry. RESULTS: The type of cultivation land and organic fertilizers affected the C, N, and S stable isotope ratio in ginseng (p < 0.05). The δ15NAIR and δ34SVCDT values in ginseng roots more significantly discriminated the cultivation land and type of organic fertilizers in ginseng cultivation than the δ13CVPDB value. The combination of δ13CVPDB, δ15NAIR, or δ34SVCDT in ginseng, except the combination δ13CVPDB-34SVCDT, showed a better discrimination depending on soil type or fertilizer type. CONCLUSION: This case study provides preliminary results about the variation of C, N, and S isotope composition in ginseng according to the cultivation soil type and organic fertilizer type. Hence, our findings are potentially applicable to evaluate ginseng authenticity depending on cultivation conditions.

Discriminative study of a potato (Solanum tuberosum L.) cultivation region by measuring the stable isotope ratios of bio-elements.

Compared to other foods, the use of common bio-elements to identify the geographical origin of potato remains limited. Thus, this study aimed to verify whether the cultivation regions of raw potato tubers could be determined by the stable isotope composition analysis of bio-elements. δ(13)CVPDB and δ(15)NAIR in potato were influenced by region and cultivar, whereas δ(18)OVSMOW and δ(34)SVCDT were only influenced by region (p<0.0001). A two-dimensional plot of δ(18)OVSMOW and δ(34)SVCDT effectively distinguished between high and low altitude regions, and also reliably discriminated Wanju, Haenam, and Boseong cultivars in low altitude regions. δ(34)SVCDT was the main component that was responsible for the separation of samples in the principal component analysis (eigenvector of -0.6209) and orthogonal projection to latent structure-discriminant analysis (VIP value of 1.0566). In conclusion, this study improves our understanding of how the isotope composition of potato tubers varies with respect to cultivation regions and cultivars.

Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism.

Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations.