Brain MRI radiomics analysis may predict poor psychomotor outcome in preterm neonates.

OBJECTIVES: This study aimed to apply a radiomics approach to predict poor psychomotor development in preterm neonates using brain MRI. METHODS: Prospectively enrolled preterm neonates underwent brain MRI near or at term-equivalent age and neurodevelopment was assessed at a corrected age of 12 months. Two radiologists visually assessed the degree of white matter injury. The radiomics analysis on white matter was performed using T1-weighted images (T1WI) and T2-weighted images (T2WI). A total of 1906 features were extracted from the images and the minimum redundancy maximum relevance algorithm was used to select features. A prediction model for the binary classification of the psychomotor developmental index was developed and eightfold cross-validation was performed. The diagnostic performance of the model was evaluated using the AUC with and without including significant clinical and DTI parameters. RESULTS: A total of 46 preterm neonates (median gestational age, 29 weeks; 26 males) underwent brain MRI (median corrected gestational age, 37 weeks). Thirteen of 46 (28.3%) neonates showed poor psychomotor outcomes. There was one neonate among 46 with moderate to severe white matter injury on visual assessment. For the radiomics analysis, twenty features were selected for each analysis. The AUCs of prediction models based on T1WI, T2WI, and both T1WI and T2WI were 0.925, 0.834, and 0.902. Including gestational age or DTI parameters did not improve the prediction performance of T1WI. CONCLUSIONS: A radiomics analysis of white matter using early T1WI or T2WI could predict poor psychomotor outcomes in preterm neonates. KEY POINTS: • Radiomics analysis on T1-weighted images of preterm neonates showed the highest diagnostic performance (AUC, 0.925) for predicting poor psychomotor outcomes. • In spite of 45 of 46 neonates having no significant white matter injury on visual assessment, the radiomics analysis of early brain MRI showed good diagnostic performance (sensitivity, 84.6%; specificity, 78.8%) for predicting poor psychomotor outcomes. • Radiomics analysis on early brain MRI can help to predict poor neurodevelopmental outcomes in preterm neonates.

Maternal, neonatal, and child health systems under rapid urbanization: a qualitative study in a suburban district in Vietnam.

BACKGROUND: Vietnam has been successful in increasing access to maternal, neonatal, and child health (MNCH) services during last decades; however, little is known about whether the primary MNCH service utilization has been properly utilized under the recent rapid urbanization. We aimed to examine current MNCH service utilization patterns at a district level. METHODS: The study was conducted qualitatively in a rural district named Quoc Oai. Women who gave a birth within a year and medical staff at various levels participated through 43 individual in-depth interviews and 3 focus group interviews. RESULTS: Primary MNCH services were underutilized due to a failure to meet increased quality needs. Most of the mothers preferred private clinics for antenatal care and the district hospital for delivery due to the better service quality of these facilities compared to that of the commune health stations (CHSs). Mothers had few sociocultural barriers to acquiring service information or utilizing services based on their improved standard of living. A financial burden for some services, including caesarian section, still existed for uninsured mothers, while their insured counterparts had relatively few difficulties. CONCLUSIONS: For the improved macro-efficiency of MNCH systems, the government needs to rearrange human resources and/or merge some CHSs to achieve economies of scale and align with service volume distribution across the different levels.

The First Reported Case of Infant Botulism in Korea: Treatable Infantile Neuromuscular Disease.

Botulism is a rare neuromuscular disorder caused by neurotoxins produced by Clostridium botulinum. The diagnosis of infant botulism may be obscured or delayed, as its presentation is similar to that of infantile neuromuscular disorders. We report the first Korean case of infant botulism in an acute progressive floppy infant with poor sucking and a weak cry. No abnormalities were found in all blood, cerebrospinal fluid, genetic test, nerve conduction study, and imaging studies. A stool-toxin test was finally performed under suspicion of infant botulism, and the result was positive. The patient was immediately treated with heptavalent botulism antitoxin. Follow-up after 3 months showed normal development with a complete resolution of all symptoms. Therefore, clinical suspicion of infant botulism, which is a treatable infantile neuromuscular disease, is essential for early diagnosis and prompt treatment in the differential diagnosis of a floppy infant.

Effect of the application of local vibration in scaption on joint stability.

[Purpose] The aim of this study was to determine the initial effect of local vibration on the stability of the shoulder joints by applying local vibration to the shoulder joints. [Subjects and Methods] For the test, the subjects held a FlexBar with one hand, at about 10 cm from one end, and performed the oscillation movement with the shoulder at 90° flexion and the elbow in the full-extension position in scaption; the vibration stimulus was set to 5 Hz. Then, the subjects underwent the Upper Quarter Y Balance Test to evaluate the stability of the shoulder joints. [Results] The moving distances in the left, right, and upper directions after the oscillation movement were increased significantly compared with the results before the oscillation movement. [Conclusion] A vibration stimulus is effective as an exercise method to increase the stability of the shoulder joints.

The effects of shoulder joint abduction angles on the muscle activity of the serratus anterior muscle and the upper trapezius muscle while vibrations are applied.

[Purpose] The purpose of this study was to examine the ratio between the upper trapezius and the serratus anterior muscles during diverse shoulder abduction exercises applied with vibrations in order to determine the appropriate exercise methods for recovery of scapular muscle balance. [Subjects and Methods] Twenty-four subjects voluntarily participated in this study. The subjects performed shoulder abduction at various shoulder joint abduction angles (90°, 120°, 150°, 180°) with oscillation movements. [Results] At 120°, all the subjects showed significant increases in the muscle activity of the serratus anterior muscle in comparison with the upper trapezius muscle. However, no significant difference was found at angles other than 120°. [Conclusion] To selectively strengthen the serratus anterior, applying vibration stimuli at the 120° shoulder abduction position is considered to be appropriate.

The effects of ankle loads on balance ability during one-leg stance.

[Purpose] The purpose of this study was to evaluate the effects of ankle loads on balance ability and to suggest an appropriate load amount. [Subjects and Methods] The 31 healthy subjects randomly put 0%, 1%, and 2% body weight loads on their ankles using a strap, and limit of stability was measured using a Biorescue system. Limits of stability were measured for 10 seconds using their dominant leg in the left, right, forward, and backward directions. [Results] All values for limit of stability increased significantly with the 1% load compared with the 0% load during a one-leg stance. However, all values except for the backward limit of stability showed a significant decrease with the 2% load compared with the 1% load. There was a significant difference between the 0% and 2% loads. [Conclusion] Application of loads on the ankles can be used as a training method for improving balance ability, and to increase efficiency, it is appropriate to apply 1% of the subject's body weight.

Genetic influences on hallux valgus in Koreans: the healthy twin study.

Hallux valgus (HV) is a common foot deformity of multifactorial etiology, but knowledge about the relative importance of genetics and environments on HV has been limited. In order to estimate genetic influences on HV, 1,265 adults, including 175 monozygotic twin (MZ) pairs, 31 dizygotic twin (DZ) pairs, and 853 first-degree singleton family members of the twins were included from the Healthy Twin study, a population-based twin-family cohort in Korea. All participants underwent foot examination and weight-bearing radiographic assessment (anterior-posterior and lateral) in addition to a general health survey. Of the subjects, 208 (16.4%) were classified as HV (as HV angle >20°). The genetic influence on HV was estimated to be substantial; the heritability of HV was 0.51 (95% CI 0.42-0.59) and the heritability of HV angle was 0.47 (0.38-0.56), while contributions from shared environmental effects were negligible. These findings suggest that genetic factors play an important role in determining HV deformity.

Tract-based spatial statistics of diffusion tensor imaging after corpus callosotomy in relation to seizure recurrence.

PURPOSE: To delineate microstructural changes in transected white matter tracts after corpus callosotomy in relation to seizure recurrence using tract-based spatial statistics of diffusion tensor imaging (DTI-TBSS). METHODS: We retrospectively included 12 total corpus callosotomy patients who had undergone serial pre- and postoperative DTI studies. The first postoperative DTI was performed within 6 months after callosotomy. The second postoperative DTI was performed in five patients with seizure recurrence (symptomatic group) and in seven patients without seizure recurrence (asymptomatic group) after 1 year following surgery. Group comparisons of fractional anisotropy (FA) with age- and sex-matched controls were performed in a whole brain voxel-wise manner using DTI-TBSS. RESULTS: The first postoperative DTI-TBSS showed a significant FA decrease in the entire corpus callosum in all patients. The second postoperative DTI-TBSS showed that a significant FA decrease remained in the entire corpus callosum in the asymptomatic group. However, in the symptomatic group, no significant decrease of FA was observed in some parts of the posterior body and splenium of the corpus callosum, although there was still a significant FA decrease in the genu of the corpus callosum. CONCLUSIONS: Using DTI-TBSS analysis, we characterized and visualized microstructural white matter changes over time in relation to seizure recurrence in callosotomy patients, suggesting that reorganization of some transected white matter tracts may be related to seizure recurrence. DTI-TBSS analysis can provide reliable and useful information about the state of white matter bundles affected by corpus callosotomy in a noninvasive manner.

Comparison of Muscle Activities Using a Pressure Biofeedback Unit during Abdominal Muscle Training Performed by Normal Adults in the Standing and Supine Positions.

[Purpose] The purpose of this study was to assess the effects of draw-in exercise on abdominal muscle activity in the standing and supine positions. [Methods] Twenty healthy women participated in this study. The subjects were required to complete two draw-in exercises (standing and supine positions) using a biofeedback pressure unit. The root mean square (RMS) values of the EMG data were expressed as a percentage of the resting contraction. The data were analyzed using the independent t-test. [Results] According to the changes in the activities of the abdominal muscles, the draw-in exercise in the standing position produced the most significant increase in the activities of the rectus abdominis, the transverse abdominis, the internal oblique, and the external oblique muscles. [Conclusion] The activities of the trunk stability muscles (rectus abdominis, transverse abdominis, internal oblique, and external oblique) increased more in the standing than in the supine position, enabling the subjects to overcome gravity. Therefore, to strengthen the activation of the abdominal muscles, a standing position seems to be more effective than a supine position for draw-in exercises.

Risk factors for neurologic complications of hand, foot and mouth disease in the Republic of Korea, 2009.

In 2009, the first outbreak of hand, foot and mouth disease (HFMD) or herpangina (HP) caused by enterovirus 71 occurred in the Republic of Korea. This study inquired into risk factors associated with complications of HFMD or HP. A retrospective medical records review was conducted on HFMD or HP patients for whom etiologic viruses had been verified in 2009. One hundred sixty-eight patients were examined for this investigation. Eighty patients were without complications while 88 were accompanied by complications, and 2 had expired. Enterovirus 71 subgenotype C4a was the most prevalent in number with 67 cases (54.9%). In the univariate analysis, the disease patterns of HFMD rather than HP, fever longer than 4 days, peak body temperature over 39℃, vomiting, headache, neurologic signs, serum glucose over 100 mg/dL, and having an enterovirus 71 as a causative virus were significant risk factors of the complications. After multiple logistic analysis, headache (Odds ratio [OR], 10.75; P < 0.001) and neurologic signs (OR, 42.76; P < 0.001) were found to be the most significant factors. Early detection and proper management of patients with aforementioned risk factors would be necessary in order to attain a better clinical outcome.

Targeting IKKß Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice.

The kinase activity of inhibitory κB kinase ß (IKKß) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKß activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKß, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKß activity. To understand the importance of IKKß activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKß activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKß inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKß, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKß activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses.

Assessing Health and Economic Benefits of Omega-3 Fatty Acid Supplementation on Cardiovascular Disease in the Republic of Korea.

BACKGROUND: Cardiovascular disease (CVD) is the primary cause of mortality worldwide and imposes a significant social burden on many countries. METHODS: This study assessed the health and economic benefits of omega-3 associated with CVD. The meta-analysis estimated the risk ratio (RR) and absolute risk reduction (ARR), and the economic impact was calculated using direct and indirect costs related to CVD treatments in Korean adults. RESULTS: A total of 33 studies were included in the meta-analysis on CVD outcomes, with 80,426 participants in the intervention group and 80,251 participants in the control group. The meta-analysis determined a significant reduction in omega-3 in CVD (RR = 0.92, 95% CI: 0.86~0.97) and ARR (1.48%). Additionally, the subgroup analysis indicated that higher doses and the long-term consumption of omega-3 could further enhance these effects. After applying ARR from meta-analysis to the target population of about 1,167,370 in 2021, the Republic of Korea, it was estimated that omega-3 consumption could result in an economic benefit of KRW 300 billion by subtracting the purchase expenses of omega-3 supplements from the total social cost savings. CONCLUSION: Omega-3 supplements can help to reduce the risk of CVD and subsequent economic benefits in the Republic of Korea.

Association of Cerebral Blood Flow and Brain Tissue Relaxation Time With Neurodevelopmental Outcomes of Preterm Neonates: Multidelay Arterial Spin Labeling and Synthetic MRI Study.

OBJECTIVES: Both cerebral blood flow (CBF) and brain tissue relaxation times are known to reflect maturation in the neonatal brain. However, we do not yet know if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire CBF and relaxation time in preterm neonates, using multidelay arterial spin labeling and synthetic magnetic resonance imaging (MRI), and show their association with later neurodevelopmental outcomes. MATERIALS AND METHODS: In this prospective study, preterm neonates were recruited, and multidelay arterial spin labeling and synthetic MRI were performed between September 2017 and December 2018. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age, and both cognitive and motor outcome scores were measured. Transit time-corrected CBF and T1 and T2 relaxation time values were measured for different brain regions. The measured values were correlated with gestational age (GA) at birth and corrected GA at the MRI scan. Simple and multiple linear regression analyses were performed for the measured values and neurodevelopmental outcome scores. RESULTS: Forty-nine neonates (median [interquartile range] GA, 30 [2] weeks, 209 [17] days; 28 boys) underwent MRI scans at or near term-equivalent age (median [interquartile range] corrected GA, 37 [2] weeks, 258 [14] days). Transit time-corrected CBF (coefficient, 0.31-0.59) and relaxation time (coefficient, -0.39 to -0.86) values showed significant correlation with corrected GA but not with GA. After controlling for GA, the frontal white matter CBF in preterm neonates showed a negative relationship with cognitive outcome scores (ß = -0.97; P = 0.029). Frontal white matter T1 relaxation times showed a positive relationship with cognitive outcome scores (ß = 0.03; P = 0.025) after controlling for GA. CONCLUSIONS: Higher CBF values and lower T1 relaxation times in frontal white matter were associated with poorer cognitive outcomes. As quantitative neuroimaging markers, CBF and relaxation times may help predict neurodevelopmental outcomes in preterm neonates.

Treatment strategies for Lennox-Gastaut syndrome: outcomes of multimodal treatment approaches.

Background: Multimodal treatment approaches are often considered for patients with Lennox-Gastaut syndrome (LGS). Creating an algorithm that can guide healthcare providers in selecting treatment options for patients with LGS remains a challenge. Herein, we assessed the long-term seizure-free and neurodevelopmental outcomes of stepwise multimodal treatment in patients with LGS. Objective: Herein, we assess the long-term seizure-free and neurodevelopmental outcomes of stepwise multimodal treatment in patients with LGS. Methods: We retrospectively examined the data of 371 patients with LGS who underwent stepwise multimodal treatment, including antiseizure medication (ASM) therapy, dietary therapy (DT), resective epilepsy surgery (R-ES), and palliative epilepsy surgery (P-ES). The seizure-free outcome was considered to be the effect of the final treatment according to the treatment algorithm, and the percentage of patients who remained seizure-free in each treatment group was calculated. ASM treatment, DT, R-ES, and P-ES were applied to 371 (100%), 201 (54.2%), 112 (30.2%), and 115 (31.0%) patients with LGS, respectively. We evaluated the stepwise multimodal treatment outcomes in these patients. Results: One hundred sixty-eight patients (45.3%) remained seizure-free for at least 1 year (seizure-free-for-1-year group), 61 of whom (16.5%) remained seizure-free for more than 5 years (remained-seizure-free group). Among the patients treated with ASM therapy, DT, R-ES, and P-ES, 41 (11.1%), 53 (14.3%), 56 (15.1%), and 29 (7.8%), respectively, remained seizure-free for 1 year. In addition, 15 (4.1%), 15 (4.1%), 19 (5.1%), and 12 (3.2%) patients in the ASM, DT, R-ES, and P-ES treatment groups, respectively, remained seizure-free for more than 5 years. Both the seizure-free-for-1-year and remained-seizure-free groups showed significant improvement in electroencephalography findings and neurodevelopmental status following treatment. Conclusion: This study provides an update on the long-term seizure outcomes and neurodevelopmental improvements in a large cohort of patients with LGS following comprehensive multimodal treatment. We emphasize that the active combination of multiple ASMs, DT, and surgical treatment could provide long-term seizure-free outcomes and significant neurological benefits to patients with LGS.

Long-term results of vagus nerve stimulation in children with Dravet syndrome: Time-dependent, delayed antiepileptic effect.

OBJECTIVE: This study aimed to assess the long-term outcomes of vagus nerve stimulation (VNS) in children with pharmaco-resistant Dravet syndrome (DS). METHODS: We enrolled 22 patients with pharmaco-resistant DS who underwent VNS implantation at Severance Children's Hospital from March 2005 to October 2020. Efficacy and tolerability were assessed at 3, 6, 12, 18, 24, 30, and 36 months after VNS implantation. Efficacy was measured as the percentage reduction in seizure frequency at each follow-up compared with the baseline (pre-implantation) values. RESULTS: Median patient age at VNS implantation was 10.0 years (interquartile range 7.7-13.3). The median follow-up period was 4.3 years (interquartile range 3.0-6.5) after VNS implantation. All cases were followed up for ≥2 years after VNS implantation. Three (13.6 %) patients maintained seizure freedom for ≥1 year. Among them, one achieved seizure freedom after 30 months of VNS. More than 50 % reduction in seizure frequency was observed in 36.4 % (8/22), 54.5 % (12/22), and 63.2 % (12/19) of the patients at 12, 24, and 36 months, respectively. The median percent reduction in seizure frequency was 18.8 %, 50.6 %, and 60.0 % at 12, 24, and 36 months, respectively. Compared with the baseline value, the seizure frequency was significantly lower at 24, 30, and 36 months, as well as at the longest follow-up period (p < 0.05, Wilcoxon signed-rank test). The symptom that was mostly associated with adverse events was hoarseness (4/22, 18.2 %); however, they had temporary or minimal effects on activities of daily living. CONCLUSIONS: Our findings demonstrate that VNS therapy allows long-term, progressive, and time-dependent improvement in seizure control for pharmaco-resistant DS. Clinicians should be aware of the delayed VNS efficacy over the years and should encourage long-term VNS maintenance by patients.

Utility of 7 Tesla Magnetic Resonance Imaging in Patients With Epilepsy: A Systematic Review and Meta-Analysis.

Objective: 7 Tesla magnetic resonance imaging (MRI) enables high resolution imaging and potentially improves the detection of morphologic abnormalities in patients with epilepsy. However, its added value compared with conventional 1.5T and 3.0T MRI is unclear. We reviewed the evidence for the use of 7 Tesla MRI in patients with epilepsy and compared the detection rate of focal lesions with clinical MRI. Methods: Clinical retrospective case studies were identified using the indexed text terms "epilepsy" AND "magnetic resonance imaging" OR "MR imaging" AND "7T" OR "7 Tesla" OR "7T" in Medline (2002-September 1, 2020) and Embase (1999-September 1, 2020). The study setting, MRI protocols, qualitative, and quantitative assessment were systematically reviewed. The detection rate of morphologic abnormalities on MRI was reported in each study in which surgery was used as the reference standard. Meta-analyses were performed using a univariate random-effects model in diagnostic performance studies with patients that underwent both 7T MRI and conventional MRI. Results: Twenty-five articles were included (467 patients and 167 healthy controls) consisting of 10 case studies, 10 case-control studies, 4 case series, and 1 cohort study. All studies included focal epilepsy; 12 studies (12/25, 48%) specified the disease etiology and 4 studies reported focal but non-lesional (MRI-negative on 1.5/3.0T) epilepsy. 7T MRI showed superior detection and delineation of morphologic abnormalities in all studies. In nine comparative studies, 7T MRI had a superior detection rate of 65% compared with the 22% detection rate of 1.5T or 3.0T. Significance: 7T MRI is useful for delineating morphologic abnormalities with a higher detection rate compared with conventional clinical MRI. Most studies were conducted using a case series or case study; therefore, a cohort study design with clinical outcomes is necessary. Classification of Evidence: Class IV Criteria for Rating Diagnostic Accuracy Studies.

Extrahippocampal Radiomics Analysis Can Potentially Identify Laterality in Patients With MRI-Negative Temporal Lobe Epilepsy.

Objective: The objective of the study was to investigate whether radiomics features of extrahippocampal regions differ between patients with epilepsy and healthy controls, and whether any differences can identify patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE). Methods: Data from 36 patients with hippocampal sclerosis (HS) and 50 healthy controls were used to construct a radiomics model. A total of 1,618 radiomics features from the affected hippocampal and extrahippocampal regions were compared with features from healthy controls and the unaffected side of patients. Using a stepwise selection method with a univariate t-test and elastic net penalization, significant predictors for identifying TLE were separately selected for the hippocampus (H+) and extrahippocampal region (H-). Each model was independently validated with an internal set of MRI-negative adult TLE patients (n = 22) and pediatric validation cohort with MRI-negative TLE (n = 20) from another tertiary center; diagnostic performance was calculated using area under the curve (AUC) of the receiver-operating-characteristic curve analysis. Results: Forty-eight significant H+ radiomic features and 99 significant H- radiomic features were selected from the affected side of patients and used to create a hippocampus model and an extrahippocampal model, respectively. Texture features were the most frequently selected feature. Training set showed slightly higher accuracy between hippocampal (AUC = 0.99) and extrahippocampal model (AUC = 0.97). In the internal validation and external validation sets, the extrahippocampal model (AUC = 0.80 and 0.92, respectively) showed higher diagnostic performance for identifying the affected side of patients than the hippocampus model (AUC = 0.67 and 0.69). Significance: Radiomics revealed extrahippocampal abnormality in the affected side of patients with TLE and could potentially help to identify MRI-negative TLE. Classification of Evidence: Class IV Criteria for Rating Diagnostic Accuracy Studies.

18F-FDG PET and MRS of the early stages of subacute sclerosing panencephalitis in a child with a normal initial MRI.

In subacute sclerosing panencephalitis (SSPE), conventional MRI findings have been reported. However, in the early clinical stages, imaging studies can appear normal. Moreover, with no history of infant measles infection, the diagnosis of SSPE can only be arrived at after extensive investigation that must eliminate a number of neurodegenerative diseases. We report here on (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) and magnetic resonance spectroscopy (MRS) findings in a 14-year-old girl with a normal initial MRI who had not contracted measles. Although (18)F-FDG PET and MRS are not specific or diagnostic for SSPE, these techniques can demonstrate substantial metabolic impairments when MRI findings show no obvious abnormalities, as is often the case in the early stages of this disease.

Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation.

Rationale: Microphthalmia-associated transcription factor M (MITF-M) plays important roles in the pigment production, differentiation and survival of melanocytes. Stem cell factor (SCF) and its receptor KIT stimulate MITF-M activity via phosphorylation at the post-translation level. However, the phosphorylation shortens half-life of MITF-M protein over the course of minutes. Here, we investigated novel hypotheses of (i) whether SCF/KIT can regulate MITF-M activity through gene expression as the alternative process, and (ii) whether chemical inhibition of KIT activity can mitigate the acquired pigmentation in skin by targeting the expression of MITF-M. Methods: We employed melanocyte cultures in vitro and pigmented skin samples in vivo, and applied immunoblotting, RT-PCR, siRNA-based gene knockdown and confocal microscopy. Results: The protein and mRNA levels of MITF-M in epidermal melanocytes and the promoter activity of MITF-M in B16-F0 melanoma cells demonstrated that SCF/KIT could trigger the expression of MITF-M de novo, following the phosphorylation-dependent proteolysis of pre-existing MITF-M protein. SCF/KIT regulated the transcription abilities of cAMP-responsive element-binding protein (CREB), CREB-regulated co-activator 1 (CRTC1) and SRY-related HMG-box 10 (SOX10) but not ß-catenin at the MITF-M promoter. Meanwhile, chemical inhibition of KIT activity abolished SCF-induced melanin production in epidermal melanocyte cultures, as well as protected the skin from UV-B-induced hyperpigmentation in HRM2 mice or brownish guinea pigs, in which it down-regulated the expression of MITF-M de novo at the promoter level. Conclusion: We propose the targeting of SCF/KIT-inducible MITF-M expression as a strategy in the therapeutics for acquired pigmentary disorders.