Risk adjustment model for tuberculosis compared to non-tuberculosis mycobacterium or latent tuberculosis infection: Center for Personalized Precision Medicine of Tuberculosis (cPMTb) cohort database.

BACKGROUND: The Center for Personalized Precision Medicine of Tuberculosis (cPMTb) was constructed to develop personalized pharmacotherapeutic systems for tuberculosis (TB). This study aimed to introduce the cPMTb cohort and compare the distinct characteristics of patients with TB, non-tuberculosis mycobacterium (NTM) infection, or latent TB infection (LTBI). We also determined the prevalence and specific traits of polymorphisms in N-acetyltransferase-2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) phenotypes using this prospective multinational cohort. METHODS: Until August 2021, 964, 167, and 95 patients with TB, NTM infection, and LTBI, respectively, were included. Clinical, laboratory, and radiographic data were collected. NAT2 and SLCO1B1 phenotypes were classified by genomic DNA analysis. RESULTS: Patients with TB were older, had lower body mass index (BMI), higher diabetes rate, and higher male proportion than patients with LTBI. Patients with NTM infection were older, had lower BMI, lower diabetes rate, higher previous TB history, and higher female proportion than patients with TB. Patients with TB had the lowest albumin levels, and the prevalence of the rapid, intermediate, and slow/ultra-slow acetylator phenotypes were 39.2%, 48.1%, and 12.7%, respectively. The prevalence of rapid, intermediate, and slow/ultra-slow acetylator phenotypes were 42.0%, 44.6%, and 13.3% for NTM infection, and 42.5%, 48.3%, and 9.1% for LTBI, respectively, which did not differ significantly from TB. The prevalence of the normal, intermediate, and lower transporter SLCO1B1 phenotypes in TB, NTM, and LTBI did not differ significantly; 74.9%, 22.7%, and 2.4% in TB; 72.0%, 26.1%, and 1.9% in NTM; and 80.7%, 19.3%, and 0% in LTBI, respectively. CONCLUSIONS: Understanding disease characteristics and identifying pharmacokinetic traits are fundamental steps in optimizing treatment. Further longitudinal data are required for personalized precision medicine. TRIAL REGISTRATION: This study registered ClinicalTrials.gov NO. NCT05280886.

iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs.

Mesenchymal stromal cells derived from induced pluripotent stem cells (iMSCs) have been proposed as alternative sources of primary MSCs with various advantages for cell therapeutic trials. However, precise evaluation of the differences between iMSCs and primary MSCs is lacking due to individual variations in the donor cells, which obscure direct comparisons between the two. In this study, we generated donor-matched iMSCs from individual bone marrow-derived MSCs and directly compared their cell-autonomous and paracrine therapeutic effects. We found that the transition from primary MSCs to iMSCs is accompanied by a functional shift towards higher proliferative activity, with variations in differentiation potential in a donor cell-dependent manner. The transition from MSCs to iMSCs was associated with common changes in transcriptomic and proteomic profiles beyond the variations of their individual donors, revealing expression patterns unique for the iMSCs. These iMSC-specific patterns were characterized by a shift in cell fate towards a pericyte-like state and enhanced secretion of paracrine cytokine/growth factors. Accordingly, iMSCs exhibited higher support for the self-renewing expansion of primitive hematopoietic progenitors and more potent immune suppression of allogenic immune responses than MSCs. Our study suggests that iMSCs represent a separate entity of MSCs with unique therapeutic potential distinct from their parental MSCs, but points to the need for iMSC characterization in the individual basis.

Pregnancy loss and Income in the Republic of Korea using National Health Insurance Service Data, 2008-2014.

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.

Prediction models for early diagnosis of actinomycotic osteomyelitis of the jaw using machine learning techniques: a preliminary study.

BACKGROUND: This study aimed to develop and validate five machine learning models designed to predict actinomycotic osteomyelitis of the jaw. Furthermore, this study determined the relative importance of the predictive variables for actinomycotic osteomyelitis of the jaw, which are crucial for clinical decision-making. METHODS: A total of 222 patients with osteomyelitis of the jaw were analyzed, and Actinomyces were identified in 70 cases (31.5%). Logistic regression, random forest, support vector machine, artificial neural network, and extreme gradient boosting machine learning methods were used to train the models. The models were subsequently validated using testing datasets. These models were compared with each other and also with single predictors, such as age, using area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: The AUC of the machine learning models ranged from 0.81 to 0.88. The performance of the machine learning models, such as random forest, support vector machine and extreme gradient boosting was significantly superior to that of single predictors. Presumed causes, antiresorptive agents, age, malignancy, hypertension, and rheumatoid arthritis were the six features that were identified as relevant predictors. CONCLUSIONS: This prediction model would improve the overall patient care by enhancing prognosis counseling and informing treatment decisions for high-risk groups of actinomycotic osteomyelitis of the jaw.

Transabdominal fetal reduction: a report of 124 cases.

To prevent fetal loss, preterm delivery, and perinatal morbidity of multifetal pregnancies (MPs), fetal reduction (FR) is offered to some patients. We retrospectively analysed the data of 124 MPs that underwent transabdominal FR to twin (n = 63) and singleton (n = 61) pregnancies at a mean gestational age of 12 + 6 weeks between December 2006 and January 2018. FR was performed transabdominally with the injection of potassium chloride into the intracardiac or intrathoracic space of the fetus or fetuses after ultrasound screening for nuchal translucency and anatomical defects. The initial number of embryos were 48 twins, 63 triplets, 11 quadruplets, and 2 quintuplets. The procedure-related pregnancy loss rate was 0.8% (1/124), the overall pregnancy loss rate was 2.4% (3/124), the fetal loss rate was 1.6% (2/124), and the neonatal death rate was 0.8% (1/124). The baby take-home rates were 96% for twin pregnancies and 96.7% for singletons. This study shows that transabdominal FR is an effective and safe procedure with a pregnancy loss rate of 2.4%.Impact statementWhat is already known on this subject? The incidence of multifetal pregnancies has increased over the years. Because multifetal pregnancies increase perinatal morbidity and mortality due to prematurity, fetal reduction is offed to some patients.What the results of this study add? The results of this study add to the growing body of research on fetal reduction. The study showed that transabdominal fetal reduction is a safe procedure with a pregnancy loss rate of 2.4%.What the implications are of these findings for clinical practice and/or further research? The results of this study can be used in counselling couples with multifetal pregnancies who are considering fetal reduction. Further research is needed to confirm the current findings.

Regioselectivity significantly impacts microsomal glucuronidation efficiency of R/S-6, 7-, and 8-hydroxywarfarin.

Coumadin (R/S-warfarin) metabolism plays a critical role in patient response to anticoagulant therapy. Several cytochrome P450s oxidize warfarin into R/S-6-, 7-, 8-, 10, and 4'-hydroxywarfarin that can undergo subsequent glucuronidation by UDP-glucuronosyltransferases (UGTs); however, current studies on recombinant UGTs cannot be adequately extrapolated to microsomal glucuronidation capacities for the liver. Herein, we estimated the capacity of the average human liver to glucuronidate hydroxywarfarin and identified UGTs responsible for those metabolic reactions through inhibitor phenotyping. There was no observable activity toward R/S-warfarin, R/S-10-hydroxywarfarin or R/S-4'-hydroxywarfarin. The observed metabolic efficiencies (Vmax/Km) toward R/S-6-, 7-, and especially 8-hydroxywarfarin indicated a high glucuronidation capacity to metabolize these compounds. UGTs demonstrated strong regioselectivity toward the hydroxywarfarins. UGT1A6 and UGT1A1 played a major role in R/S-6- and 7-hydroxywarfarin glucuronidation, respectively, whereas UGT1A9 accounted for almost all of the generation of the R/S-8-hydroxywarfarin glucuronide. In summary, these studies expanded insights to glucuronidation of hydroxywarfarins by pooled human liver microsomes, novel roles for UGT1A6 and 1A9, and the overall degree of regioselectivity for the UGT reactions.

Abolishment of N-glycan mannosylphosphorylation in glyco-engineered Saccharomyces cerevisiae by double disruption of MNN4 and MNN14 genes.

Mannosylphosphorylated glycans are found only in fungi, including yeast, and the elimination of mannosylphosphates from glycans is a prerequisite for yeast glyco-engineering to produce human-compatible glycoproteins. In Saccharomyces cerevisiae, MNN4 and MNN6 genes are known to play roles in mannosylphosphorylation, but disruption of these genes does not completely remove the mannosylphosphates in N-glycans. This study was performed to find unknown key gene(s) involved in N-glycan mannosylphosphorylation in S. cerevisiae. For this purpose, each of one MNN4 and five MNN6 homologous genes were deleted from the och1Δmnn1Δmnn4Δmnn6Δ strain, which lacks yeast-specific hyper-mannosylation and the immunogenic α(1,3)-mannose structure. N-glycan profile analysis of cell wall mannoproteins and a secretory recombinant protein produced in mutants showed that the MNN14 gene, an MNN4 paralog with unknown function, is essential for N-glycan mannosylphosphorylation. Double disruption of MNN4 and MNN14 genes was enough to eliminate N-glycan mannosylphosphorylation. Our results suggest that the S. cerevisiae och1Δmnn1Δmnn4Δmnn14Δ strain, in which all yeast-specific N-glycan structures including mannosylphosphorylation are abolished, may have promise as a useful platform for glyco-engineering to produce therapeutic glycoproteins with human-compatible N-glycans.

Comparison of fluorescent tags for analysis of mannose-6-phosphate glycans.

Mannose-6-phosphate (M-6-P) glycan analysis is important for quality control of therapeutic enzymes for lysosomal storage diseases. Here, we found that the analysis of glycans containing two M-6-Ps was highly affected by the hydrophilicity of the elution solvent used in high-performance liquid chromatography (HPLC). In addition, the performances of three fluorescent tags--2-aminobenzoic acid (2-AA), 2-aminobenzamide (2-AB), and 3-(acetyl-amino)-6-aminoacridine (AA-Ac)--were compared with each other for M-6-P glycan analysis using HPLC and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The best performance for analyzing M-6-P glycans was shown by 2-AA labeling in both analyses.

Chimeric cytochromes P450 engineered by domain swapping and random mutagenesis for producing human metabolites of drugs.

Human drug metabolites produced by cytochrome P450 enzymes are critical for safety testing and may themselves act as drugs or leads in the drug discovery and development process. Here, highly active chimeric fusion proteins (chimeras) were obtained by reductase domain swapping of mutants at key catalytic residues of the heme domain with that of a natural variant (CYP102A1.2) of P450 BM3 (CYP102A1.1) from Bacillus megaterium. Random mutagenesis at the heme domain of the chimera was also used to generate chimeric mutants that were more active and diverse than the chimeras themselves. To determine whether the chimeras and several mutants of the highly active chimera displayed enhanced catalytic activity and, more importantly, whether they acquired activities of biotechnological importance, we measured the oxidation activities of the chimeras and chimeric mutants toward human P450 substrates, mainly drugs. Some of the chimeric mutants showed high activity toward typical human P450 substrates including drugs. Statin leads, especially chiral products, with inhibitory effects toward HMG-CoA reductase could be obtained from metabolites of statin drugs generated using these chimeric mutants. This study reveals the critical role of the reductase domain for the activity of P450 BM3 and shows that chimeras generated by domain swapping can be used to develop industrial enzymes for the synthesis of human metabolites from drugs and drug leads.

Impact of ENPP1 K121Q on change of insulin resistance after web-based intervention in Korean men with diabetes and impaired fasting glucose.

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to type 2 diabetes mellitus (T2DM) and insulin resistance (IR). We hypothesized that the difference in genotype may be one of the factors that affect the outcome of intervention. We genotyped 448 men with fasting glucose≥5.6 mM/L, including 371 in subjects with K allele (KK) (69 control group [CG]; and 302 intervention group [IG]) and 77 in subjects with Q allele (KQ+QQ) (13 CG and 64 IG). The web-based intervention based on a lifestyle modification was delivered by e-mail once a month for 10 months. In the KK, IG demonstrated significantly decreased levels of fasting serum insulin (FSI) as compared to CG and homeostasis model of assessment of insulin resistance (HOMA-IR). In the KQ+QQ IG group, hemoglobin A1c (HbA1c), FSI and HOMA-IR were significantly decreased, and showed further reduction in the HOMA-IR than KQ+QQ CG. After analysis of covariance, K121Q did significantly influence the change of HbA1c in CG after appropriate adjustment. In a multivariate model, BMI change predicted HOMA-IR change (adjusted ß=0.801; P=0.022) in KK IG subjects with T2DM. ENPP1 K121Q did not influence the change in IR. However, individuals with T2DM carrying the K121 variant are very responsive to the effect of BMI reduction on HOMA-IR.

Recovery time of platelet function after aspirin withdrawal.

INTRODUCTION: Inappropriate antiplatelet therapy discontinuation increases the risk of thrombotic complications and bleeding after dental procedures. To determine the platelet reactivity recovery time after aspirin withdrawal in vivo, our study was conducted in patients with low-risk cardiovascular disease who can stop aspirin administration following the guidelines stipulated by the American College of Chest Physicians. The time it takes for platelet activity to normalize and the diagnostic accuracy of testing methods were assessed for a residual antiplatelet activity with multiple electrode aggregometry. Our study included patients with clinically indicated hypertension preparing for a dental extraction procedure. MATERIALS AND METHODS: A total of 212 patients not taking aspirin (control group) and 248 patients with hypertension receiving long-time aspirin treatment at a 100-mg daily dose were prospectively included in the study, which involved stopping aspirin intake before dental extraction. The residual platelet activity and dental bleeding in patients who stopped aspirin intake were analyzed and compared with those of the control group. In addition, platelet reactivity recovery time and bleeding risk in patients who stopped taking aspirin every 24 hours for 0 to 5 days (0-143 hours) before dental extraction was also assessed. RESULTS: Platelet reactivity normalized 96 hours after aspirin withdrawal. The cut-off value of 49 arbitrary units in the arachidonic acid platelet aggregation test excluded the effect of aspirin with 91% sensitivity and 66% specificity. AUC showed 0.86 (P < 0.001) diagnostic accuracy. The immediate bleeding complications in all treatment groups were similar to those seen in the control group and were successfully managed with local hemostatic measures. CONCLUSIONS: The antiplatelet effects of aspirin disappeared 96 hours after aspirin withdrawal in our study, and dental extractions may be safely performed in this period when appropriate local hemostatic measures are taken. Based on these results, a shorter aspirin intake cessation period may be allowable in complex dental procedures and surgery for which a longer aspirin intake cessation period (7-10 days) is recommended based on the American College of Chest Physicians guidelines.

Application of sequential multimodal analgesia before and after impacted mandibular third molar extraction: Protocol for a randomized controlled trial.

Background: Several analgesics have been applied under various protocols to control the moderate-to-severe postoperative pain caused by the surgical extraction of an impacted mandibular third molar. However, a consensus on optimal pain management while minimizing side effects is yet to be reached. Methods: This multi-center, prospective, double-blind, randomized controlled trial aims to evaluate the efficacy and safety of sequential multimodal analgesia combined with postoperative zaltoprofen along with multiple preemptive analgesics. A total of 80 participants with bilateral impacted mandibular third molar from two hospitals were randomized into two groups. Two surgical extractions were performed at one-month intervals, and in a crossover design, celecoxib or tramadol/acetaminophen was administered before one extraction and placebo before the other extraction. Following extraction, all subjects took zaltoprofen for 5 days. The outcome measures included pain at specific times, time and intensity of the first pain onset after extraction, need of rescue drugs, and occurrence and frequency of side effects. Conclusions: This ongoing clinical trial was designed to provide evidence regarding a new protocol for effective postoperative pain management of a commonly performed surgical extraction. The results of this study will provide guidance to clinicians regarding the timing and combination of oral analgesics in various oral surgeries performed under local anesthesia. Trial registration: KCT0005450, registered on October 7, 2020.

Denosumab-associated jaw bone necrosis in cancer patients: retrospective descriptive case series study.

BACKGROUND: Denosumab (DMB) is a bone antiresorptive agent used to treat osteoporosis or metastatic cancer of the bones. However, denosumab-associated osteonecrosis of the jaw (DRONJ) has become a common complication in cancer patients. The prevalence of osteonecrosis of the jaw (ONJ) in cancer patients is estimated to be similar for both bisphosphonate-related cases (1.1 to 1.4%) and denosumab-related cases (0.8 to 2%), with the addition of adjunctive therapy with anti-angiogenic agents reportedly increasing its prevalence to 3%. (Spec Care Dentist 36(4):231-236, 2016). The aim of this study is to report on DRONJ in cancer patients treated with DMB (Xgeva®, 120mg). CASE PRESENTATION: In this study, we identified four cases of ONJ among 74 patients receiving DMB therapy for metastatic cancer. Of the four patients, three had prostate cancer and one had breast cancer. Preceding tooth extraction within 2 months of the last DMB injection was found to be a risk factor for DRONJ. Pathological examination revealed that three patients had acute and chronic inflammation, including actinomycosis colonies. Among the four patients with DRONJ referred to us, three were successfully treated without complications and had no recurrence following surgical treatment, while one did not follow up. After healing, one patient experienced a recurrence at a different site. Sequestrectomy in conjunction with antibiotic therapy and cessation of DMB use proved to be effective in managing the condition, and the ONJ site healed after an average 5-month follow-up period. CONCLUSION: Conservative surgery, along with antibiotic therapy and discontinuation of DMB, was found to be effective in managing the condition. Additional studies are needed to investigate the contribution of steroids and anticancer drugs to jaw bone necrosis, the prevalence of multicenter cases, and whether there is any drug interaction with DMB.

Effects of a 12-week lifestyle intervention on health outcome and serum adipokines in middle-aged Korean men with borderline high blood pressure.

BACKGROUND: High blood pressure, in relation to blood levels of adipokines such as adiponectin and leptin, is highly associated with an unhealthy lifestyle including sedentary behaviors, poor dietary habits such as excess sodium intake, and heavy drinking. Strategies to reduce blood pressure may benefit the levels of adipokines. OBJECTIVE: Thus, we aimed to investigate the effects of lifestyle intervention on blood pressure and serum adipokines in middle-aged Korean men with borderline high blood pressure (systolic blood pressure [SBP] ≥ 130 mm Hg or diastolic blood pressure [DBP] ≥ 85 mm Hg). METHODS: Fifty-two men (aged 42.5 ± 8.5 years) with normal weight (body mass index [BMI] < 25 kg/m(2)) and high BP (NH group) and 40 men (age 42.0 ± 8.4 years) who were obese (BMI ≥ 25 kg/m(2)) with high BP (OH group) underwent 5 sessions of one-on-one intensive counseling including instruction on a nutritionally balanced diet, a low-sodium diet, how to understand calorie requirements, and strategies to implement regular exercise for blood pressure regulation over 12 weeks. In order to increase the awareness of sodium education, a salt sensory test using an unseasoned soup was performed. Anthropometrics, blood pressure measurements, 24-hour recalls were performed, and blood levels of lipids, fasting plasma glucose, C-reactive protein (CRP), leptin, and adiponectin were analyzed at week 0 and at week 12. Sodium consumption was roughly estimated using the Dish-based Frequency Questionnaire-15. RESULTS: Weight, BMI, body fat (kg and %), waist circumference, hip circumference, and blood pressure were significantly decreased after 12 weeks (p < 0.05) in all subjects. Similarly, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and CRP were decreased (p < 0.05), but LDL-C/HDL-C was significantly decreased (p < 0.01) only in the obese subjects. At baseline, blood levels of leptin were significantly higher in the obese subjects than in the normal weight subjects. In the obese subjects, a significantly negative correlation was found between leptin levels at baseline and percentage change in DBP (r = -0.338, p < 0.05). After 12 weeks, blood levels of adipokines did not show significant changes. CONCLUSIONS: These results suggest that a short-term (12 weeks) lifestyle intervention had positive effects on blood pressure control and weight reduction in the subjects, but not on their blood levels of adipokines. It is interesting that blood level of baseline leptin was negatively associated with the changes in blood pressure after this short-term intervention.

Regional cerebral blood flow abnormalities associated with apathy and depression in Alzheimer disease.

The aim of this study was to identify brain areas related to apathy or depression in patients with Alzheimer disease (AD). Eighty-one AD patients were enrolled in this prospective study. (99m)Tc-HMPAO single photon emission computed tomography was performed to evaluate regional cerebral blood flow (rCBF). According to the Neuropsychiatric Inventory subscores of apathy and depression, 9 patients were classified as clinically significant (cs) depressed and non-cs-apathetic (D+) groups and 9 were classified as cs-apathetic and non-cs-depressed (A+) groups. In addition, 18 patients were classified as age-matched and Mini-Mental State Examination-matched disease control groups (D-, A-). The significance of rCBF differences between groups and the correlation between rCBF and subscores in 81 AD patients were estimated by SPM (uncorrected P < 0.005) analysis. D+ patients had significantly lower perfusion in the right orbitofrontal and inferior frontal gyri than D- patients, whereas A+ patients had this in the right amygdala, temporal, posterior cingulate, right superior frontal, postcentral, and left superior temporal gyri than A- patients. The negatively correlated areas with depression subscores included the left inferior frontal and the right middle frontal gyri and those with apathy subscores included the right temporal and right medial frontal gyri. We suggest that this finding may indicate that apathy and depression in AD patients involve distinct functional circuits.

Use of serum homocysteine to predict cardiovascular disease in Korean men with or without metabolic syndrome.

The aim of this study was to examine whether serum homocysteine (Hcy) levels correlated with cardiovascular disease (CVD) depending on the presence or absence of metabolic syndrome (MetS) in Korean men. We conducted a case-control study, including 138 CVD and 290 non-CVD age-matched control subjects. The subjects were divided into four subgroups: 34 CVD/MetS, 104 CVD, 77 MetS, and 213 normal subgroups. The mean Hcy was significantly higher, whereas HDL and intake of vitamin B(1) and B(2) were lower in the CVD group (P < 0.05) than non-CVD group. When compared to the control group, subjects with CVD/MetS, CVD and MetS exhibited high Hcy levels, with the highest observed in the CVD/MetS subgroup (P < 0.001). Multivariate stepwise linear regression between CVD and markers of CVD showed Hcy significantly correlated with CVD (P < 0.05). To predict CVD based on Hcy, Hcy threshold of 11.72 µM in non-MetS subjects had an area under the curve (AUC) of 0.664 (95% CI 0.598-0.731). In MetS subjects, the AUC was 0.618 and Hcy threshold was 13.32 µM (95% CI 0.509-0.726). The results of our study show that the presence of MetS needs to be considered when using Hcy levels for predicting CVD.

Bilateral cleft lip repair by new trending method: a case report.

BACKGROUND: Bilateral cleft lip repair is one of the most difficult surgeries, and many techniques have been modified and developed to improve surgical outcomes. The current trend is toward preserving tissue as much as possible. When the reconstruction is based on the shape of the patient's own tissue, the most natural appearance is produced, and the relaxed remaining tissue can be benefitted from reducing tension and minimizing scarring. CASE PRESENTATION: In the conventional surgical method, the rest of the prolabium is sacrificed, except for the tissue used to make the philtrum. We used all tissues for surgery and did not discard any. The tubercle of the median vermilion was used in its original form. CONCLUSIONS: It is fundamental to restore function in cleft lip surgery. Both patients and surgeons have a desire for esthetic outcomes that go beyond function. In addition, the measure of the success of the surgery is the postoperative resemblance to normal midfacial features. Unlike the conventional method of making tubercles by collecting lateral vermilion flaps, we preserved the tissue of the prolabium. Rather than using an artificial tubercle, we were able to create a more natural shape of the upper lip using the patient's own anatomical structure. In addition, the remaining tissues of the discarded prolabium were used to make the oral mucosa, which may help to reduce tension compared to the conventional method. The modified repair method is expected to gradually become the mainstream method owing to its superior esthetic outcome and less surgical difficulty compared with traditional methods.

Preliminary Report of Validity for the Infant Comprehensive Evaluation for Neurodevelopmental Delay, a Newly Developed Inventory for Children Aged 12 to 71 Months.

OBJECTIVES: Early detection of developmental issues in infants and necessary intervention are important. To identify the comorbid conditions, a comprehensive evaluation is required. The study's objectives were to 1) generate scale items by identifying and eliciting concepts relevant to young children (12-71 months) with developmental delays, 2) develop a comprehensive screening tool for developmental delay and comorbid conditions, and 3) assess the tool's validity and cut-off. METHODS: Multidisciplinary experts devised the "Infant Comprehensive Evaluation for Neurodevelopmental Delay (ICEND)," an assessment method that comes in two versions depending on the age of the child: 12-36 months and 37-71 months, through monthly seminars and focused group interviews. The ICEND is composed of three parts: risk factors, resilience factors, and clinical scales. In parts 1 and 2, there were 41 caretakers responded to the questionnaires. Part 3 involved clinicians evaluating ten subscales using 98 and 114 questionnaires for younger and older versions, respectively. The Child Behavior Checklist, Strengths and Difficulties Questionnaire, Infant- Toddler Social Emotional Assessment, and Korean Developmental Screening Test for Infants and Children were employed to analyze concurrent validity with the ICEND. The analyses were performed on both typical and high-risk infants to identify concurrent validity, reliability, and cut-off scores. RESULTS: A total of 296 people participated in the study, with 57 of them being high-risk (19.2%). The Cronbach's alpha was positive (0.533-0.928). In the majority of domains, the ICEND demonstrated a fair discriminatory ability, with a sensitivity of 0.5-0.7 and specificity 0.7-0.9. CONCLUSION: The ICEND is reliable and valid, indicating its potential as an auxiliary tool for assessing neurodevelopmental delay and comorbid conditions in children aged 12-36 months and 37-71 months.

Diesel Exhaust Particles Impair Therapeutic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis through ROS/ERK/cFos Signaling Pathway.

Background and Objectives: Epidemiological investigations have shown positive correlations between increased diesel exhaust particles (DEP) in ambient air and adverse health outcomes. DEP are the major constituent of particulate atmospheric pollution and have been shown to induce proinflammatory responses both in the lung and systemically. Here, we report the effects of DEP exposure on the properties of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs), including stemness, regeneration, and immunomodulation. Methods and Results: Non-apoptotic concentrations of DEP (10 µg/ml) inhibited the migration and osteogenic differentiation capacity of WJ-MSCs. Gene expression profiling showed that DEP increased intracellular reactive oxygen species (ROS) and expression of pro-inflammatory and metabolic-process-related genes including cFos. Furthermore, WJ-MSCs cultured with DEP showed impaired suppression of T cell proliferation that was reversed by inhibition of ROS or knockdown of cFos. ERK inhibition assay revealed that DEP-induced ROS regulated cFos through activation of ERK but not NF-κB signaling. Overall, low concentrations of DEP (10 µg/ml) significantly suppressed the stemness and immunomodulatory properties of WJ-MSCs through ROS/ERK/cFos signaling pathways. Furthermore, WJ-MSCs cultured with DEP impaired the therapeutic effect of WJ-MSCs in experimental colitis mice, but was partly reversed by inhibition of ROS. Conclusions: Taken together, these results indicate that exposure to DEP enhances the expression of pro-inflammatory cytokines and immune responses through a mechanism involving the ROS/ERK/cFos pathway in WJ-MSCs, and that DEP-induced ROS damage impairs the therapeutic effect of WJ-MSCs in colitis. Our results suggest that modulation of ROS/ERK/cFos signaling pathways in WJ-MSCs might be a novel therapeutic strategy for DEP-induced diseases.

Generation of human chiral metabolites of simvastatin and lovastatin by bacterial CYP102A1 mutants.

Recently, the wild-type and mutant forms of cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium were found to oxidize various xenobiotic substrates, including pharmaceuticals, of human P450 enzymes. Simvastatin and lovastatin, which are used to treat hyperlipidemia and hypercholesterolemia, are oxidized by human CYP3A4/5 to produce several metabolites, including 6'ß-hydroxy (OH), 3″-OH, and exomethylene products. In this report, we show that the oxidation of simvastatin and lovastatin was catalyzed by wild-type CYP102A1 and a set of its mutants, which were generated by site-directed and random mutagenesis. One major hydroxylated product (6'ß-OH) and one minor product (6'-exomethylene), but not other products, were produced by CYP102A1 mutants. Formation of the metabolites was confirmed by high-performance liquid chromatography, liquid chromatography-mass spectroscopy, and NMR. Chemical methods to synthesize the metabolites of simvastatin and lovastatin have not been reported. These results demonstrate that CYP102A1 mutants can be used to produce human metabolites, especially chiral metabolites, of simvastatin and lovastatin. Our computational findings suggest that a conformational change in the cavity of the mutant active sites is related to the activity change. The modeling results also suggest that the activity change results from the movement of several specific residues in the active sites of the mutants. Furthermore, our computational findings suggest a correlation between the stabilization of the binding site and the catalytic efficiency of CYP102A1 mutants toward simvastatin and lovastatin.