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Jing Lin,* Chaoyue Zhao,* Cuijuan Liu, Shiyao Fu, Luying Han, Xinping Lu, Chunrong Yang College of Pharmacy, Jiamusi University, Jiamusi, Heilongjiang, China *These authors contributed equally to this work Introduction: The development of nanodrug carriers utilizing tumor microenvironment has become a hotspot in reversing multidrug resistance (MDR). Materials and methods: This study synthesized a redox-sensitive copolymer, Pluronic F127-disulfide bond-D-α-tocopheryl polyethylene glycol 1000 succinate (FSST), through the connection of the reduction-sensitive disulfide bond between F127 and D-α-tocopheryl polyethylene glycol 1000 succinate. This polymer could induce the elevation of reactive oxygen species (ROS) levels, ultimately resulting in cytotoxicity. Moreover, the redox-responsive mixed micelles, F127-folate (FA)/FSST/P123 (FFSSTP), based on FSST, Pluronic F127-FA, and Pluronic P123, were prepared to load paclitaxel (PTX). Results: The in vitro release study demonstrated that FFSSTP/PTX accelerated the PTX release through the breakage of disulfide bond in reductive environment. In cellular experiment, FFSSTP/PTX induced significant apoptosis in PTX-resistant MCF-7/PTX cells through inhibiting adenosine triphosphate (ATP)-binding cassette proteins from pumping out PTX by interfering with the mitochondrial function and ATP synthesis. Furthermore, FFSSTP/PTX induced apoptosis through elevating the intracellular levels of ROS. Conclusion: FFSSTP could become a potential carrier for the treatment of MDR tumors. Keywords: redox responsive, mixed micelles, multidrug resistance, paclitaxel, tumor microenvironment

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy., Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response., Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis., Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose ( C 0 /D) ratio and efficacy outcomes were compared., Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p  = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C 0 /D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C 0 /D ratio when patients were concomitant with sodium channel blockers (SCBs)., Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration., (© The Author(s), 2024.)

Objective: To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies. Methods: This was a retrospective case analysis of the phenotypes, genotypes and prognoses of adolescence-onset MMA patients. There were 55 patients diagnosed in Peking University First Hospital from January 2002 to June 2023, the data of symptoms, signs, laboratory results, gene variations, and outcomes was collected. The follow-ups were done through WeChat, telephone, or clinic visits every 3 to 6 months. Results: Among the 55 patients, 31 were males and 24 were females. The age of onset was 12 years old (range 10-18 years old). They visited clinics at Tanner stages 2 to 5 with typical secondary sexual characteristics. Nine cases (16%) were trigged by infection and 5 cases (9%) were triggered by insidious exercises. The period from onset to diagnosis was between 2 months and 6 years. Forty-five cases (82%) had neuropsychiatric symptoms as the main symptoms, followed by cardiovascular symptoms in 12 cases (22%), kidney damage in 7 cases (13%), and eye disease in 12 cases (22%). Fifty-four cases (98%) had the biochemical characteristics of methylmalonic acidemia combined with homocysteinemia, and 1 case (2%) had the isolated methylmalonic acidemia. Genetic diagnosis was obtained in 54 cases, with 20 variants identified in MMACHC gene and 2 in MMUT gene. In 53 children with MMACHC gene mutation,1 case had dual gene variants of PRDX1 and MMACHC, with 105 alleles. The top 5 frequent variants in MMACHC were c.482G>A in 39 alleles (37%), c.609G>A in 17 alleles (16%), c.658_660delAAG in 11 alleles (10%), c.80A>G in 10 alleles (10%), c.567dupT and c.394C>T both are 4 alleles (4%). All patients recovered using cobalamin, L-carnitine, betaine, and symptomatic therapy, and 54 patients (98%) returned to school or work. Conclusions: Patients with adolescence-onset MMA may triggered by fatigue or infection. The diagnosis is often delayed due to non-specific symptoms. Metabolic and genetic tests are crucial for a definite diagnosis. Treatment with cobalamin, L-carnitine, and betaine can effectively reverse the prognosis of MMA in adolescence-onset patients.

Pesticides remain a cornerstone in pest control, yet their extensive and irrational use also fuel the evolution of resistance. This review analyzes globally published experimental data spanning from the 1970s to 2023 to focus on how phenotypic and underlying genotypic variations are shaped during the selective response. The discussion commences with an examination of sex-linked/maternal resistance. Observations related to maternal inheritance have enriched our understanding of pesticide mode of action, notably exemplified by bifenazate. However, the predominant control of the resistant phenotype is attributed to autosomal traits, with a high prevalence of dominance and monogenic inheritance observed, also evident in field strains. This observation raises concerns regarding resistance management strategies due to their potential to accelerate the spread of resistance. The interplay between dominance levels and monogenic inheritance is further explored, with dominant traits being significantly more prevalent in polygenic inheritance. This observation may be attributed to the accumulation of enhanced metabolism. Notably, further analysis indicated that field strains exhibit a higher incidence of monogenic inheritance compared to other selected strains, aligning with established theoretical frameworks. In conclusion, the genetic architecture of resistance warrants increased research focus for its pivotal role in guiding resistance management strategies and advancing fundamental research., Competing Interests: Declaration of competing interest The authors declare no competing of interests., (Copyright © 2023. Published by Elsevier Inc.)

Histone deacetylase (HDAC) serves as a critical molecular regulator in the pathobiology of various malignancies and have garnered attention as a viable target for therapeutic intervention. A variety of HDAC inhibitors (HDACis) have been developed to target HDACs. Many preclinical studies have conclusively demonstrated the antitumor effects of HDACis, whether used as monotherapy or in combination treatments. On this basis, researchers have conducted various clinical studies to evaluate the potential of selective and pan-HDACis in clinical settings. In our work, we extensively summarized and organized current clinical trials, providing a comprehensive overview of the current clinical advancements in targeting HDAC therapy. Furthermore, we engaged in discussions about several clinical trials that did not yield positive outcomes, analyzing the factors that led to their lack of anticipated therapeutic effectiveness. Apart from the experimental design factors, issues such as toxicological side effects, tumor heterogeneity, and unexpected off-target effects also contributed to these less-than-expected results. These challenges have naturally become significant barriers to the application of HDACis. Despite these challenges, we believe that advancements in HDACi research and improvements in combination therapies will pave the way or lead to a broad and hopeful future in the treatment of solid tumors., (© 2024. The Author(s).)

Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

Objective: To evaluate the effectiveness and safety of perampanel (PER) monotherapy (MT) or add-on therapy (AT) in Chinese children with epilepsy, as well as to evaluate the data from routine therapeutic drug monitoring (TDM) of PER for these pediatric patients., Methods: This retrospective and observational study was carried out on children with epilepsy (n = 340) from 2020 to 2022 at the Children's Hospital of Nanjing Medical University. Outcome measures were the responder rate (50% or greater seizure reduction), long-term efficacy, and tolerability (number and types of adverse events) in MT and AT groups. Concentrations of plasma PER obtained from these patients, if available, were analyzed too., Results: A total of 279 patients achieved at least 3 months of therapy, and 58.1% responded to PER therapy. 53 of the responders were seizure-free (32.7%). The retention rate dropped from 88.0% at 3 months to 40.6% at 12 months after treatment. Patients with MT achieved better seizure control than those with AT (P < 0.001). Intriguingly, PER exerted a very weak effect on patients who took more than 2 ASMs or were diagnosed with drug-resistant epilepsy. There were no significant differences in tolerability between the two groups. In addition, 179 patients were routinely monitored for PER, and the trough concentrations (C 0 ) for these patients ranged from 30.0 to 992.0 ng/mL. However, no significant difference in C 0 was observed between responders and nonresponders (333 ng/mL vs 325.5 ng/mL, P = 0.264)., Significance: This study provides effectiveness and safety data on Chinese children with epilepsy treated with PER either as MT or as AT. The efficacy of patients receiving MT was much better than cases administered with more than 2 ASMs or diagnosed with drug-resistant epilepsy. In addition, no association was found between the plasma PER concentration and efficacy or safety., Plain Language Summary: The study reports the effects of perampanel on seizures and adverse effects in Chinese patients with epilepsy younger than 18 years. Seizures decreased in 58.1% of patients (responders); in a third of these responders, seizures stopped. After treatment was started, 88% of patients were still on perampanel at 3 months and 40.6% at 12 months. People who were treated with perampanel only were more likely to respond than those who received perampanel and other antiseizure treatments, although perampanel was tolerated equally well in these groups. Plasma perampanel concentration did not predict seizure response or adverse effects., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Abstract: A 79-year-old man with nasopharyngeal cancer (NPC) presented with diplopia symptom and a history of diabetes mellitus was referred for an FDG PET/CT scan to determine the pretreatment staging. The FDG PET/CT scan revealed NPC with skull base invasion and decreased FDG uptake at the left striatum. A review of his clinical history and a brain MRI conducted 5 months ago confirmed a previous diagnosis of left hyperglycemic hemichorea. In this NPC patient with inadequate blood sugar control, unilateral striatum hypometabolism may persist for up to 5 months after the initial clinical symptoms., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: A 58-year-old man with lung cancer was referred for an 18 F-FDG PET/CT scan for pretreatment staging. The FDG PET/CT scan revealed focal uptakes in the lower abdomen. We differentiated the etiology of the lesions by performing a delayed scan with urine retention and bladder distension. The delayed scan demonstrated a tubular, radioactivity-filled structure arising above the urinary bladder. Combining the FDG PET/CT scan, clinical findings, and ultrasonography, we made the diagnosis of vesicourachal diverticulum., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The drug-refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy., Methods: This single-center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non-responders with VPA polytherapy (NR group) were collected. Non-targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p-value <0.05 were regarded as statistically different substances., Results: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well-established partial least squares-discriminant analysis (PLS-DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L-thyroxine, but with an increased level of glucose and 2-oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism., Significance: The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high-priority strategies for DRE management., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective To evaluate the impact of deep learning reconstruction algorithm on the image quality of head and neck CT angiography (CTA) at 100 kVp. Methods CT scanning was performed at 100 kVp for the 37 patients who underwent head and neck CTA in PUMC Hospital from March to April in 2021.Four sets of images were reconstructed by three-dimensional adaptive iterative dose reduction (AIDR 3D) and advanced intelligent Clear-IQ engine (AiCE) (low,medium,and high intensity algorithms),respectively.The average CT value,standard deviation (SD),signal-to-noise ratio (SNR),and contrast-to-noise ratio (CNR) of the region of interest in the transverse section image were calculated.Furthermore,the four sets of sagittal maximum intensity projection images of the anterior cerebral artery were scored (1 point:poor,5 points:excellent). Results The SNR and CNR showed differences in the images reconstructed by AiCE (low,medium,and high intensity) and AIDR 3D (all P <0.01).The quality scores of the image reconstructed by AiCE (low,medium,and high intensity) and AIDR 3D were 4.78±0.41,4.92±0.27,4.97±0.16,and 3.92±0.27,respectively,which showed statistically significant differences (all P <0.001). Conclusion AiCE outperformed AIDR 3D in reconstructing the images of head and neck CTA at 100 kVp,being capable of improving image quality and applicable in clinical examinations.

Vigabatrin is one of the second-generation anti-seizure medications (ASMs) designated orphan drugs by the FDA for monotherapy for pediatric patients with infantile spasms from 1 month to 2 years of age. Vigabatrin is also indicated as the adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures. Ideally, the vigabatrin treatment entails achieving complete seizure freedom without significant adverse effects, and the therapeutic drug monitoring (TDM) will make a significant contribution to this aim, which provides a pragmatic approach to such epilepsy care in that the dose tailoring can be undertaken for uncontrollable seizures and in cases of clinical toxicity guided by the drug concentrations. Thus, reliable assays are mandatory for TDM to be valuable, and blood, plasma, or serum are the matrixes of choice. In this study, a simple, rapid, and sensitive LC-ESI-MS/MS method for the measurement of plasma vigabatrin was developed and validated. The sample clean-up was performed by an easy-to-use method, i.e. , protein precipitation using acetonitrile (ACN). Chromatographic separation of vigabatrin and vigabatrin- 13 C,d 2 (internal standard) was achieved on the Waters symmetry C18 column (4.6 mm × 50 mm, 3.5 μm) with isocratic elution at a flow rate of 0.35 mL min -1 . The target analyte was completely separated by elution with a highly aqueous mobile phase for 5 min, without any endogenous interference. The method showed good linearity over the 0.010-50.0 μg mL -1 concentration range with a correlation coefficient r 2 = 0.9982. The intra-batch and inter-batch precision and accuracy, recovery, and stability of the method were all within the acceptable parameters. Moreover, the method was successfully used in pediatric patients treated with vigabatrin and also provided valuable information for clinicians by monitoring plasma vigabatrin levels in our hospital.

Objective: To compare the effects of human menopausal gonadotropin (HMG) combined with letrozole (LE) to HMG only for ovarian stimulation on pregnancy outcome of infertile patients undergoing artificial insemination by husband (AIH) due to unexplained or mild male factors., Materials and Methods: Infertile patients with unexplained or mild male factors treated from July 2015 to December 2021 were selected as subjects. The patients were divided into two groups according to the ovarian stimulation schemes they received, namely HMG combined with LE or HMG only. We analyzed the laboratory examination results before drug treatment (baseline) and during ovarian stimulation and compared the pregnancy outcomes of the two groups using univariable analysis and multivariable logistic regression analysis., Results: In total, 526 cycles of 372 couples were included. The univariate analysis showed that the clinical pregnancy rate of the HMG combined with LE group was 24.8%, significantly higher than that of the HMG group (14.8%, P = 0.007). The live birth rate (19.9%) of the HMG combined with LE group were also significantly higher than those of the HMG group (11.2%, respectively). In multivariate logistic analysis, the age of males was negatively associated with the clinical pregnancy rate (OR 0.874, 95% CI 0.793~0.963, P=0.006) and live birth (OR0.875, 95% CI 0.783~0.977, P=0.018). Moreover, ovarian stimulation with HMG+LE was the only beneficial factor significantly associated with clinical pregnancy (OR 1.929, 95% CI 1.068~3.485, P=0.029) and live birth (OR 2.255, 95% CI 1.188~4.282, P=0.013)., Conclusion: Ovarian stimulation using HMG combined with LE can increase the clinical outcomes (live birth and clinical pregnancy) among infertile patients undergoing AIH due to explained or mild male factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Pan, Su, Lu, Chen and Chen.)

Objective: This study aimed to investigate the efficacy and tolerability of perampanel (PER) therapy and to optimize a specific plasma reference range for PER in children. Another major aim was to evaluate the potential determinators of PER concentration., Methods: Concentrations obtained from 80 children were analyzed for routine therapeutic drug monitoring (TDM) between 2021 and 2022. We retrospectively reviewed the clinical data of these patients and assessed the efficacy at 3 months after treatment initiation. Trough concentration-to-dose ratio (C 0 /Dose ratio) of PER was compared among patients on various potential influencing factors., Results: A 3-month PER therapy produced a ≥50% reduction in seizure frequency in 58.8% of patients. Twelve patients reported at least one adverse effect (AE), mainly dizziness. The monitoring data showed that the median C 0 was 325.5 ng/mL. Under maintenance dosages, approximately 75% of the C 0 values were 180.0-610.0 ng/mL. The C 0 /Dose ratio in patients aged 1 to <4 was significantly lower by twofold than in those aged 4 to ≤12 years (P = 0.001). Enzyme-inducing ASMs (EIASMs) decreased the C 0 /Dose ratio of PER by 25.9% (P = 0.165). In addition, seizure frequency reduction in responders was achieved at a median PER C 0 value of 357 ng/mL, which was similar to the value of 314 ng/mL found in nonresponders (P = 0.288). No significant difference was found in PER C 0 values between patients with and without AEs (P = 0.082)., Significance: In this study, PER treatment showed acceptable efficacy and tolerance in Chinese children with epilepsy. Contributing factors like age to variable C 0 /Dose ratios were identified, and complex PER-ASMs interactions were observed. Notably, the reference range, that is, 180.0-610.0 ng/mL, for routine PER monitoring may be more applicable for them. Routine TDM should be considered a positive attempt to manage the effectiveness and safety of PER., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Context: Shen-Shi-Jiang-Zhuo formula (SSJZF) exhibits a definite curative effect in the clinical treatment of non-alcoholic fatty liver disease (NAFLD)., Objective: To explore the therapeutic effect and mechanism of SSJZF on NAFLD., Materials and Methods: Sprague Dawley rats were randomly divided into control, NAFLD, positive drug (12 mg/kg/day), SSJZF high-dose (200 mg/kg/day), SSJZF middle-dose (100 mg/kg/day), and SSJZF low-dose (50 mg/kg/day) groups. After daily intragastric administration of NAFLD rats for 8 weeks, lipid metabolism and hepatic fibrosis were evaluated by biochemical indices and histopathology. Then we uncovered the main active compounds and mechanism of SSJZF against NAFLD by integrating RNA-sequencing and network pharmacology, and PI3K/AKT pathway activity was verified by western blot., Results: High dose SSJZF had the best inhibitory effect on hepatic lipid accumulation and fibrosis in rats with NAFLD, which significantly down-regulated t otal triglycerides (58%), cholesterol (62%), aspartate aminotransferase (57%), alanine aminotransferase (41%) andγ-glutamyl transpeptidase (36%), as well as the expression of ACC (5.3-fold), FAS (12.1-fold), SREBP1C (2.3-fold), and CD36 (4.4-fold), and significantly reduced collagen deposition (67%). Then we identified 23 compounds of SSJZF that acted on 25 key therapeutic targets of NAFLD by integrating RNA-sequencing and network pharmacology. Finally, we also confirmed that high dose SSJZF increased p-PI3K/PI3K (1.6-fold) and p-AKT/AKT (1.6-fold) in NAFLD rats., Discussion and Conclusion: We found for first time that SSJZF improved NAFLD in rats by activating the PI3K/Akt pathway. These findings provide scientific support for SSJZF in the clinical treatment of NAFLD and contribute to the development of new NAFLD drugs.

Oral antiseizure medications are the preferred option for the clinical treatment of epilepsy. Therapeutic drug monitoring has become an important means of achieving individualized treatment of epilepsy. A sensitive, accurate and rapid LC-ESI-MS/MS method was developed and validated for the simultaneous determination of 15 antiseizure medications in human plasma (carbamazepine, gabapentin, pregabalin, phenytoin, zonisamide, oxcarbazepine, tiagabine, lamotrigine, topiramate, phenobarbital, lacosamide, primidone, 10,11-Dihydro-10-hydroxy carbamazepine, ethosuximide, and levetiracetam). The sample preparation procedure was an one-step protein precipitation with methanol. Mass detection was performed in ionization polarity switching mode (positive-negative-positive) using multiple reaction monitoring mode. A "boot-shaped" gradient elution program was applied to separate and concentrate those target analytes, resulting in symmetrical peak shapes within 10 min, without endogenous interference. The method showed great linearity over the concentration ranges with acceptable correlation coefficients (0.9966-0.9996). The precision and accuracy values for intra- and inter-assays were within ±15%. Consequently, the method was successfully implemented on pediatric patients undergoing mono- or polytherapy for epilepsy and provided timely concentration results to ordering clinicians., (© 2022 John Wiley & Sons Ltd.)

Introduction: Bullous systemic lupus erythematosus (BSLE) is a rare form of subcutaneous blistering lupus erythematosus (SLE). There is currently no effective treatment for BSLE. However, here, we present the first report of the successful treatment of refractory BSLE with belimumab in a 16-year-old girl., Case Presentation: A 16-year-old girl with BSLE had undergone different treatment options, with no significant improvement. Since B-lymphocyte stimulator plays an important role in the pathophysiology of SLE, belimumab was administered and showed remarkable effects for the first time in this patient with both SLE and BSLE. The patient's skin lesions improved steadily over the course of three weeks and completely disappeared in 30 days. In addition, no sign of recurrence of BSLE was observed over the 9-month follow-up period., Conclusions: To our knowledge, this is the first report of the successful short-term therapy of refractory BSLE/SLE overlap syndrome with belimumab in a pediatric patient. Although the use of belimumab resulted in excellent.

Objective: Despite the potential role of valproic acid (VPA) in weight gain, the effects of VPA therapy on lipid profiles remain unclear. This study aimed to review the influence of VPA therapy on serum lipid profiles in children with epilepsy., Methods: This meta-analysis was conducted on data from PubMed, Web of Science, Cochrane Library, and Embase databases. Case-controlled studies, which assessed the effects of VPA therapy on lipid profiles, were included. All outcomes were recorded as continuous variables, and the effect size was measured., Results: VPA therapy was associated with a significant reduction in total cholesterol (mean difference [MD]=-6.34, 95% confidence interval [CI]: -12.30, -0.37, p=0.04) and low-density lipoprotein cholesterol levels (MD = -7.75, 95% CI: -13.48, -2.0, p=0.008). No significant effects were observed regarding the levels of high-density lipoprotein cholesterol and triglycerides., Significance: In conclusion, this meta-analysis indicates that VPA therapy causes a decrease in the levels of total cholesterol and low-density lipoprotein cholesterol.

Objective: The specific objective of this study was to evaluate the effects of atmospheric pressure plasma (APP) in the treatment of experimental periodontitis in Beagle dogs., Methods: The APP jet was diagnosed using optical emission spectroscopy and laser-induced fluorescence spectroscopy. Six Beagles received stainless steel ligatures to establish experimental periodontitis model. The teeth in the control group were subjected to conventional root surface debridement (RSD) and chlorhexidine irrigation. The APP group also started with RSD and was then subjected to plasma irradiation. Clinical analyses including plaque index, modified sulcus bleeding index, pocket depth and attachment loss (AL), as well as cone-beam computed tomography (CBCT) analysis, were performed at baseline, 4th week, 8th week and 12th week after treatment., Results: The results showed that typical reactive oxygen and nitrogen species were found in the full spectrum and the gas temperature of APP was close to room temperature. The highest concentrations of hydroxide and oxygen were obtained at 5 mm away from the nozzle. In both groups, all values in clinical examinations were significantly lower (P<0.05) at 12th week after treatment than those at baseline. At the 12th week, the AL in clinical examinations and the bone loss in CBCT images in the APP group were significantly lower than those in the control group (P<0.05). The hematoxylin-eosin staining showed more renascent alveolar bone in the APP group than in the control group., Conclusion: These findings suggested that APP has profound potential for use as an adjunct approach for periodontitis treatment., (© 2022. Huazhong University of Science and Technology.)

Background: Lacosamide (LCM) is a newer anti-seizure medication (ASM) that was approved in China in 2018, but its real-world clinical data and plasma concentrations in Chinese children with epilepsy are very limited. Of note, the reference range for routine LCM therapeutic drug monitoring is still unknown. The purpose of this study was to investigate the efficacy and safety of LCM as a monotherapy or an adjunctive treatment with other ASMs and to evaluate the potential factors affecting its efficacy and variable LCM plasma concentrations in Chinese children with epilepsy., Methods: Children with epilepsy (<18 years) with routine plasma LCM monitoring from March 2019 to December 2021 at the Department of Pharmacy, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system., Results: 76 pediatric patients (52 males) were finally enrolled. Mean age was 7.9 years (1.3-17.3 years) with a mean dose of LCM 6.3 mg/kg/day (2.0-11.3 mg/kg/day). The TDM data as a whole showed that the median plasma trough concentration ( C 0 ) was 3.42 μg/mL (1.25-8.31 μg/mL). A 6-month LCM add-on therapy produced 70% of patients achieving ≥50% seizure frequency reductions, and the number was 81% for the one-year follow-up findings. Interestingly, more patients who took LCM monotherapy achieved seizure freedom over the same periods of follow-up observations. Under maintenance dosages, approximately 92.1% of the C 0 values were 2.0-7.0 μg/mL. The plasma- C 0 -to-daily dose ( C 0 /Dose) ratio was significantly associated with age and body weight (BW). The C 0 /Dose ratio in patients aged 1- ≤ 6 and 6- ≤ 12 years was significantly higher by 81% and 29% than those aged 12- ≤ 18 years, respectively. The C 0 /Dose ratio in patients with a BW of ≥40 kg was 1.7-fold lower than in patients with a BW of ≤ 20 kg. In addition, complex LCM-ASMs interactions were observed. Oxcarbazepine significantly decreased the C 0 /Dose ratio of LCM by 28%., Conclusion: This retrospective study confirmed the effectiveness and tolerability of the LCM treatment used alone or with other ASMs in children with focal epilepsy. Children with higher BW and older age have lower C 0 /Dose ratio. Complex drug interactions between LCM and other concomitant ASMs were revealed. Notably, based on the data in our hands, the reference range, i.e ., 2.0-7.0 μg/mL, for routine LCM monitoring may be feasible. The real-world evidence of this study supports LCM as a promising option in children with focal epilepsy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Guo, Zhang, Dong, Hu, chen, Lu and Chen.)

Objective: To compare the serum 25-OH-VitD levels, the major marker of vitamin D (VitD) status, between healthy children and children with epilepsy before initiation of and during anti-seizure medications (ASMs) treatment and to evaluate the potential influence factors on 25-OH-VitD levels. Another major aim was to assess the potential role of VitD supplementation., Methods: For comparison, we finally enrolled and collected data from 6,338 healthy children presenting to Health Care Department and 648 children visiting primary care pediatricians with symptoms of epilepsy in Children's Hospital of Nanjing Medical University from January 2019 to June 2021. The demographic and biochemical characteristics of each child were extracted from the hospital information system., Results: Serum 25-OH-VitD levels in 648 children with epilepsy were significantly lower than those of 6,338 healthy children ( P < 0.0001), and the percentage of VitD insufficiency and deficiency status in pediatric patients was 49.19%. Of note, the serum 25-OH-VitD levels in children with newly diagnosed epilepsy before receiving any ASMs treatment were also significantly lower than those in healthy controls. Interestingly, ASMs therapy, alone or in combination, did not consistently reduce baseline serum VitD levels in children with epilepsy. The lower serum VitD levels in pediatric patients than those in healthy children might be related to the disease itself, rather than the ASMs treatment. As expected, VitD supplementation substantially increased the serum 25-OH-VitD levels ( P < 0.0001). More critically, children with epilepsy receiving VitD supplementation achieved good seizure control in our study., Significance: In this retrospective study, the childhood epilepsy before initiation of and during ASMs treatment decreased the serum 25-OH-VitD concentrations, suggesting a clear association between epileptic disease and the risk of VitD deficiency. ASMs coadministration and long-term valproic acid treatment did not worse VitD-deficiency status, but in the small group receiving VitD supplementation, there was a significant improvement in reduction of seizure frequency. Therefore, pediatric clinicians are urged to raise public awareness of epilepsy-associated VitD deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dong, Guo, Hu, Yang, Xu, Ding, Qiu, Jiang, Chen, Lu and Li.)

Vibrational properties associated with the intra- and intermolecular bonding of the crystalline Dibenz[a,h]anthracene at low temperatures are investigated by Raman scattering. A complete characterization of phonon spectra is given for this material. In the 120-150 K temperature region, several lattice modes show abrupt changes of splitting and the discontinuities in the temperature shift, but no emergence of new modes. Moreover, the intensity ratio of I 68 / 38 is greater than 1 below 130 K. Meanwhile, the aromatic C-C stretching modes exhibit anomalous behaviors in frequencies, widths, and intensities at about 130 K. These spectroscopic results demonstrate a disorder-order transition occurred at about 130 K. However, the modes, corresponding to C-H out-of-plane bending, C-H in-plane bending, and/or C-H rocking, have no significant change in the whole temperature range. It indicates that the transition mainly results from the change of the tilt angle between the molecules. Our work is of great significance to understand the internal vibrational properties of Dibenz[a,h]anthracene, and it also provides considerable supports for the further study of this material., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to evaluate the long-term sequelae and cognitive profiles resulting from severe hand, foot, and mouth disease (HFMD) with central nervous system (CNS) involvement., Methods: 294 HFMD cases were included in a retrospective follow-up study. Physical examinations were conducted. The Chinese Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was used to assess intelligence., Results: 58 mild HFMD cases and 99 severe HFMD cases with mild CNS involvement did not present any neurological sequelae. In comparison, the sequelae incidence for severe HFMD with more severe CNS complications was 50.0%. The proportion of full-scale intelligence quotient (FSIQ) impairment was 45.0%. In the 2:6-3:11 age group, severe HFMD with more severe CNS complications and lower maternal education level were risk factors for verbal comprehension disorder. Urban-rural residence and lower paternal education level were risk factors for FSIQ disorder. Furthermore, in the 4:0-6:11 age group, severe HFMD with more severe CNS complication was a risk factor for visual spatial disorder and fluid reasoning disorder. Lower paternal education level was a risk factor for FSIQ disorder., Conclusion: Early assessment and intervention among severe HFMD patients with more severe CNS involvement at a very young age will prove beneficial for their future performance., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Wilforine, a compound of sesquiterpene alkaloids isolated from Tripterygium wilfordii, exhibits excellent insecticidal activity against Mythimna separata. In order to clarify the action mechanism of wilforine, the plasma membrane calcium transporting ATPase (PMCA) and inositol 1,4,5-trisphosphate receptor (IP 3 R) from M. separata were studied. Results showed that the open reading frame of MsIP 3 R and MsPMCA were 8118 bp and 3438 bp in length, as well as encoded 2706 and 1146 amino acids, respectively. Multiple sequence alignment and phylogenetic analysis revealed that the MsIP 3 R and MsPMCA had high homology with the IP 3 R and PMCA of other insects, but had low similarity with those of mammals, which means the IP 3 R and PMCA have potential to be the novel targets of insecticides with high selectivity between mammals and insects. Both MsIP 3 R and MsPMCA genes existed throughout the life cycle of M. separata, and were all predominantly expressed in somatic muscle of fifth-instar larvae and the adults. The susceptibilities of PMCA-silenced M. separata to wilforine were significantly lower than that of the normal M. separata, which illustrates that PMCA could be one of the targets of wilforine. However, the susceptibilities of IP 3 R-silenced M. separata to wilforine did not change significantly compared with the susceptibilities of normal M. separata, which shows that wilforine may not interact with the IP 3 R protein. These findings provide clues for elucidating the insecticidal mechanism of wilforine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Valproic acid (VPA) is a widely used antiseizure medication and its dosing needs to be tailored individually through therapeutic drug monitoring (TDM) to avoid or prevent toxicity. Currently, immune-enzymatic assays such as Enzyme Multiplied Immunoassay Technique (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS), resulting a potential lack of concordance between laboratories. Methods: In this study, plasma VPA concentrations were determined for 711 pediatric patients with epilepsy by a routine EMIT assay and by a validated in-house LC-ESI-MS/MS method on the same group of samples, aimed to address the aforementioned concern. Consistency between two assays was evaluated using linear regression and Bland-Altman analysis. Results: The calibration curve was linear in the range of 5.00-300 μg/ml for LC-ESI-MS/MS method and 1.00-150 μg/ml for EMIT assay, respectively. The two methods were proven to be accurate with quality control samples. As a result, a significant correlation between two methods was obtained with a regression equation described as [ EMIT ] = 1.214 × [ LC - ESI - MS / MS ] + 3.054 ( r 2 = 0.9281). Bland-Altman plot showed a mean bias of 14.5 μg/ml (95% confidence interval (CI) (-0.2, 29.2) and a mean increase of 27.8% (95% CI (3.3, 52.4) measured by EMIT assay more than that measured by LC-ESI-MS/MS method. Conclusion: In conclusion, two methods were closely correlated, but EMIT assay overestimate VPA levels in human plasma compared with LC-ESI-MS/MS method. Due to the observed significant discordance between the tested methods, switching from immunoassays to LC-based techniques for TDM of VPA deserves close attention and therapeutic range of 35.0-75.0 μg/ml may be feasible. However, further studies are needed to evaluate the eligibility of this alternative range in the clinical practice. Clinicians should be informed when switching the VPA quantitation methods during the clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xia, Long, Shen, Dong, Guo, Hu, Lu, Ding, Chen and Qiu.)

Background: Persistent liver inflammatory damage is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. Thus, accurate prediction of the degree of liver inflammation is a high priority and a growing medical need., Aim: To build an effective and robust non-invasive model for predicting hepatitis B-related hepatic inflammation., Methods: A total of 650 treatment-naïve CHB (402 HBeAg-positive and 248 HBeAg-negative) patients who underwent liver biopsy were enrolled in this study. Histological inflammation grading was assessed by the Ishak scoring system. Serum quantitative hepatitis B core antibody (qAnti-HBc) levels and 21 immune-related inflammatory factors were measured quantitatively using a chemiluminescent microparticle immunoassay. A backward feature elimination (BFE) algorithm utilizing random forest (RF) was used to select optional features and construct a combined model. The diagnostic abilities of the model or variables were evaluated based on the estimated area under the receiver operating characteristics curve (AUROC) and compared using the DeLong test., Results: Four features were selected to predict moderate-to-severe inflammation in CHB patients using the RF-BFE method. These predictive features included qAnti-HBc, ALT, AST, and CXCL11. Spearman's correlation analysis indicated that serum qAnti-HBc, ALT, AST, and CXCL11 levels were positively correlated with the histology activity index (HAI) score. These selected features were incorporated into the model to establish a novel model named I-3A index. The AUROC [0.822; 95% confidence interval (CI): 0.790-0.851] of the I-3A index was significantly increased compared with qAnti-HBc alone (0.760, 95%CI: 0.724-0.792, P < 0.0001) in all CHB patients. The use of an I-3A index cutoff value of 0.41 produced a sensitivity of 69.17%, specificity of 81.44%, and accuracy of 73.8%. Additionally, the I-3A index showed significantly improved diagnostic performance for predicting moderate-to-severe inflammation in HBeAg-positive and HBeAg-negative CHB patients (0.829, 95%CI: 0.789-0.865 and 0.810, 95%CI: 0.755-0.857, respectively)., Conclusion: The selected features of the I-3A index constructed using the RF-BFE algorithm can effectively predict moderate-to-severe liver inflammation in CHB patients., Competing Interests: Conflict-of-interest statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: This study was conducted to evaluate the potential genetic and non-genetic factors contributing to plasma trough concentration-to-dose ( C 0 / D ) ratio of valproic acid (VPA) in pediatric patients with epilepsy. Study Design: A single-center, retrospective cohort study was performed by collecting data from 194 children aged 1-14 years between May 2018 and November 2018. The oral solution ( n = 135) group and the sustained-release (SR) tablet group ( n = 59) were defined, and the plasma VPA C 0 was measured. Twenty-six single-nucleotide polymorphisms (SNPs) were chosen for genotyping with the MassARRAY system. A multiple logistic regression model was used for data analysis. Results: Body weight (BW) and age were positively correlated with the C 0 / D ratio in 194 patients, but the positive correlation disappeared after the patients were divided into oral solution and SR tablet subgroups. The average C 0 / D ratio was significantly increased by 2.11-fold ( P = 0.000) in children who took VPA SR tablets compared with children who were administered VPA oral solutions. No significant association between genetic variants and the C 0 / D ratio was found, even for the five well-studied SNPs, namely UGT2B7 G211T, C802T, C161T, T125C, and CYP2C9 * 3 A1075C. However, a significant association between the C 0 / D ratio and UGT1A6/9 Del>A (rs144486213) was observed in the VPA oral solution group, but not in the VPA SR tablet group. Conclusions: The dosage forms of sodium valproate, rather than BW, age, or genetic polymorphisms, significantly affected the VPA C 0 / D ratios in pediatric patients with epilepsy. Based on our findings, switching the dosage form between solution and SR tablet should be performed cautiously. Total daily dose adjustment should be considered, and the plasma concentration, seizure-control effect, and adverse drug reaction should also be monitored very closely., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xu, Guo, Li, Zhang, Jing, Xu, Qiu, Lu, Ding, Chen and Xu.)

Objective: To explore the clinical characteristics of pediatric glucose transporter type 1 deficiency syndrome (GLUT1 DS), evaluate the efficacy and safety of ketogenic diet therapy (KDT). Methods: Clinical data of 19 children with GLUT1 DS admitted to Children's Hospital of Fudan University, Tianjin Children's Hospital, Shenzhen Children's Hospital, Children's Hospital of Nanjing Medical University and Jiangxi Provincial Children's Hospital between 2015 and 2019 were collected retrospectively. The first onset symptom, main clinical manifestations, cerebrospinal fluid features and genetic testing results of patients were summarized, the efficacy and safety of ketogenic diet treatment were analyzed. Results: Among the 19 cases, 13 were males and 6 females. The age of onset was 11.0 (1.5-45.0) months,the age of diagnosis was 54.0 (2.8-132.0) months. Epilepsy was the first onset symptom of 13 cases. Different forms of tonic-clonic seizures were the most common types of epilepsy (7 cases with generalized tonic-clonic seizures, 5 cases with focal tonic or clonic seizures, 4 cases with generalized tonic seizures). Antiepileptic drugs were effective in 4 cases. Paroxysmal motor dysfunction was present in 12 cases and ataxia was the most common one. All patients had different degrees of psychomotor retardation. Among 17 patients received cerebrospinal fluid examination, cerebrospinal fluid (CSF) glucose level was lower than 2.2 mmol/L and CSF glucose/glycemic index was<0.45 in 16 cases, only 1 case presented normal CSF glucose level (2.3 mmol/L) and normal CSF glucose/glycemic index(0.47). SLC2A1 gene mutations were found in 16 patients, missense, frameshift and nonsense mutations were the common types with 5 cases, 5 cases and 3 cases respectively. All 19 patients were treated with ketogenic diet, which was effective in 18 cases in seizure control, 11 cases in dyskinesia improvement and 18 cases in cognitive function improvement. No serious side effects were reported in any stage of KDT. Conclusions: The diagnosis of GLUT1 DS is often late. It is necessary to improve the early recognition of the disease and perform CSF glucose detection and genetic testing as early as possible. The KDT is an effective and safe treatment for GLUT1 DS, but a small number of patients have not response to diet therapy.

Sirtuin 7 (SIRT7), an NAD + -dependent deacetylase, plays vital roles in energy sensing, but the underlying mechanisms of action remain less clear. Here, we report that SIRT7 is required for p53-dependent cell-cycle arrest during glucose deprivation. We show that SIRT7 directly interacts with p300/CBP-associated factor (PCAF) and the affinity for this interaction increases during glucose deprivation. Upon binding, SIRT7 deacetylates PCAF at lysine 720 (K720), which augments PCAF binding to murine double minute (MDM2), the p53 E3 ubiquitin ligase, leading to accelerated MDM2 degradation. This effect results in upregulated expression of the cell-cycle inhibitor, p21 Waf1/Cip1 , which further leads to cell-cycle arrest and decreased cell viability. These data highlight the importance of the SIRT7-PCAF interaction in regulating p53 activity and cell-cycle progression during conditions of glucose deprivation. This axis may represent a new avenue to design effective therapeutics based on tumor starvation.

Insect glutathione S-transferases (GSTs) are important in insecticide detoxification and Insect-specific GSTs, Epsilon and Delta, have largely expanded in insects. In this study, we functionally expressed and characterized an epsilon class GST gene (BdGSTe8), predominant in the adult Malpighian tubules of Bactrocera dorsalis. This gene may be associated with malathion resistance based on transcriptional studies of resistant and susceptible strains. RNA interference-mediated knockdown of this gene significantly recovered malathion susceptibility in the adults of a malathion-resistant strain, and overexpression of BdGSTe8 enhanced resistance in transgenic Drosophila. Analysis of BdGSTe8 polymorphism showed that several point mutations may be associated with metabolic resistance to malathion. A cytotoxicity assay in Escherichia coli indicated that both of the recombinant BdGSTe8 proteins may play a functional role in protecting cells from toxicity. The allele of BdGSTe8-B conferred higher levels of malathion detoxification capability. Liquid chromatography and ultra-performance liquid chromatography-tandem mass spectrometry analysis showed that the BdGSTe8-A allele did not metabolize malathion directly. However, the BdGSTe8-B allele was involved in the direct metabolism of malathion, which was caused by a mutation in V128A. Further analysis of the sequence suggests that BdGSTe8 evolved rapidly. It maybe play the role of a backup gene and could become a new gene in the future in order to retain the ability of detoxification of malathion, which was driven by positive selection. These results suggest that divergent molecular evolution in BdGSTe8 has played a role in metabolic resistance to malathion in B. dorsalis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Thrips Anaphothrips obscurus are one of the cosmopolitan major pests feeding on cereals and other grasses. In order to develop alternatives of chemical insecticides for thrips control, based on fumigant activity screening and evaluation of 22 essential oil (EO) compounds against the thrips, the binary interactions of methyl salicylate and carvacrol (MS-C) with high fumigant toxicity were studied systematically by bioassay and field trials., Results: The bioassay results showed that six in 22 EO compounds had high fumigant toxicity against both the second-instar nymphs and adults of A. obscurus, including methyl salicylate, carvacrol, thymol, trans-cinnamaldehyde, diallyl trisulfide, and L-perillaldehyde. Furthermore, the combination of methyl salicylate mixed with carvacrol at a volume ratio of 5:5 exhibited the most significant synergism against A. obscurus, with a poison ratio value of 1.32 and a co-toxicity coefficient of 151.15. The optimal formulation of microemulsion (ME) was composed of 5% methyl salicylate, 5% carvacrol, 46% adjuvant and 44% deionized water. The result of dynamic light scattering and stability showed that MS-C 10% ME was a transparent, single-phase and homogeneous liquid system. Field trials indicated that the ME displayed a significant control efficacy of about 89.17% on thrips in peppers, and 82.59% in broad bean on the seventh day post application with a dosage of 600.0 g A.I hm -2 , respectively., Conclusion: The binary combination of MS-C possesses strikingly synergistic action against thrips A. obscurus, and the MS-C 10% ME has the potential to be developed as a botanical pesticide product for thrips control. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

Purpose: To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls., Methods: A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed., Results: Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses., Conclusion: This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient., (Copyright © 2019 British Epilepsy Association. All rights reserved.)

Background: The oriental fruit fly Bactrocera dorsalis (Hendel), a widespread agricultural pest, has evolved resistance to many insecticides, including organophosphorus compounds. Glutathione S-transferases (GSTs) are involved in xenobiotic detoxification and insecticide resistance in many insects. However, the role of delta class GSTs in detoxifying malathion in B. dorsalis is unknown. Here, we evaluated the roles of two delta class GSTs in malathion detoxification in this species., Results: Two delta class GSTs genes, BdGSTd1 and BdGSTd10, were characterized in B. dorsalis. They were highly expressed in 5-day-old adults, as well as in midgut and Malpighian tubules. Upon malathion exposure, the two genes were upregulated by 2.63- and 2.85-fold, respectively. Injection of double-stranded RNA targeting BdGSTd1 or BdGSTd10 significantly reduced their mRNA levels in adults and also significantly increased adult susceptibility to malathion. The expression of these two GSTs in Escherichia coli helped the host to endure malathion stress at a concentration of 10 µg mL -1 according to a Cell Counting Kit-8 assay. High-performance liquid chromatography analyses indicated that malathion could be significantly depleted by the two delta GSTs. The role of BdGSTd10 in malathion sequestration was also discussed., Conclusion: BdGSTd1 and BdGSTd10 play important roles in the detoxification of malathion in B. dorsalis. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

Resistance to pyrethroid and organophosphate insecticides has been a growing problem in the management of cotton bollworm Helicoverpa armigera (Hübner) populations in the Yangtze River and Yellow River valleys of China, but resistance status and mechanisms of H. armigera populations from northeast China are less documented. In this study, a field strain collected from Shenyang in northeast China (SYR) is up to 16-fold more resistant than a susceptible strain (SS) to λ-cyhalothrin, while the resistance level to phoxim remained low (2.6-fold). Synergist tests and enzymatic assays show that increased cytochrome P450 monooxygenase (P450) activity is the main mechanism for λ-cyhalothrin resistance. Eight out of 10 genes from CYP6 and CYP9 subfamilies were significantly overexpressed in the SYR strain, and CYP6AE11 was the mostly overexpressed P450 (59-fold). These results suggest that overexpression of multiple P450 enzymes contributes to λ-cyhalothrin resistance in the SYR strain of H. armigera from northeast China.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC., (© 2019 Wiley Periodicals, Inc.)

Background: To investigate the roles of microembolus and plasma D-dimer in evaluating the warfarin anticoagulant therapy efficacies for patients with atrial fibrillation (AF)., Methods: Fifty-six AF patients were treated with aspirin antiplatelet therapy (Group ASP) and forty AF patients were treated with warfarin anticoagulant therapy (Group WAR). The microemboli and plasma D-dimer in these two groups were monitored and compared before and after treatment., Results: Group ASP had 21 and 17 cases with positive microemboli before and after treatment, respectively, and there was no significant difference in the detection rate of microemboli before and after treatment; Group WAR had 14 and 5 cases with positive microemboli before and after treatment, respectively, and the detection rate of microemboli was significantly reduced after treatment. The levels of plasma D-dimer in the two groups were significantly reduced after treatment (327±73 µg/L vs 235±61 µg/L and 313±81 µg/L vs 170±67 µg/L, respectively, P<0.05), among which the reduction level in Group WAR was more significant., Conclusions: Microemboli and D-dimer can be used as the indicators for evaluating the embolism risk and therapeutic efficacies in AF patients.

Background: Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed., Methods: We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized., Results: The formation of VPA reactive metabolites, inhibition of fatty acid β-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity., Conclusion: Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Biogenic amines perform many kinds of important physiological functions in the central nervous system (CNS) of insects, acting as neuromodulators, neurotransmitters, and neurohormones. The five most abundant types of biogenic amines in invertebrates are dopamine, histamine, serotonin, tyramine, and octopamine (OA). However, in beetles, an important group of model and pest insects, the role of tyramine β-hydroxylase (TβH) in the OA biosynthesis pathway and the regulation of behavior remains unknown so far. We therefore investigated the molecular characterization and spatiotemporal expression profiles of TβH in red flour beetles ( Triboliun castaneum ). Most importantly, we detected the production of OA and measured the crawling speed of beetles after ds TcTβH injection. We concluded that TcTβH controls the biosynthesis amount of OA in the CNS, and this in turn modulates the mobility of the beetles. Our new results provided basic information about the key genes in the OA biosynthesis pathway of the beetles, and expanded our knowledge on the physiological functions of OA in insects., Competing Interests: The authors declare no conflict of interest.

Roughing disorder (RD) is a significant quality barrier in citrus fruit, prevalent on easy-peeling mandarins. As RD is not yet well-understood, this study aimed to examine the changes and synergic molecular processes involved in peel RD. Peel with RD was induced by severely defruiting Satsuma mandarin trees. Morphology observations, RNA-sequencing, and targeted and untargeted metabolic analyses were conducted. The results showed that the primary metabolites of sugars, organic acids and amino acids are dramatically changed in RD peel. The RD peel was always characterized by higher magnesium content during development. Comparative transcriptome profiling was performed for CK and RD peels at 30, 80, and 170 days after full bloom (DAFB) which represented fruit at cell division stage, cell enlargement stage and fruit maturity stage, respectively. Physiological and molecular biological evidence suggested that the month after full bloom is a crucial stage for RD initiation. A total of 4,855 differentially expressed genes (DEGs) in RD peel, relative to CK peel were detected at cell division stage, about 2 to 4-fold more than other stages had. Among the differentially expressed transcription factors, the bHLH family were affected most by RD, and six bHLH transcription factors functionally involved in GA metabolism were assessed to associate with RD occurrence. Gene set enrichment analysis suggested that RD significantly altered starch and GA metabolism in peel. Higher starch content and hydrolysed chain status were found in RD peel at cell division stage. RD occurrence on the peel was influenced significantly by GA, especially abundant GA before July. These changes may mean a significant alteration in sink strength of RD peel. The findings of this study provide insights into the emergence, development and molecular mechanisms of RD.

There are many evidences that insect carboxylesterase possess important physiological roles in xenobiotic metabolism and are implicated in the detoxification of organophosphate (OP) insecticides. Despite the ongoing resistance development in the oriental fruit fly, Bactrocera dorsalis (Hendel), the molecular basis of carboxylesterase and its ability to confer OP resistance remain largely obscure. This study was initiated to provide a better understanding of carboxylesterase-mediated resistance mechanism in a tephritid pest fly. Here, we narrow this research gap by demonstrating a well-conserved esterase B1 gene, BdB1, mediates malathion resistance development via gene upregulation with the use of a laboratory selected malathion-resistant strain (MR) of B. dorsalis. No sequence mutation of BdB1 was detected between MR and the susceptible strain (MS) of B. dorsalis. BdB1 is predominantly expressed in the midgut, a key insect tissue for detoxification. As compared with transcripts in MS, BdB1 was significantly more abundant in multiple tissues in the MR. RNA interference (RNAi)-mediated knockdown of BdB1 significantly increased malathion susceptibility. Furthermore, heterologous expression along with cytotoxicity assay revealed BdB1 could probably have the function of malathion detoxification., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The fruiting body formation mechanisms of Cordyceps sinensis are still unclear. To explore the mechanisms, proteins potentially related to the fruiting body formation, proteins from fruiting bodies, and mycelia of  Cordyceps  species were assessed by using two-dimensional fluorescence difference gel electrophoresis, and the differential expression proteins were identified by matrix-assisted laser desorption/ionisation tandem time of flight mass spectrometry. The results showed that 198 differential expression proteins (252 protein spots) were identified during the fruiting body formation of  Cordyceps  species, and 24 of them involved in fruiting body development in both  C. sinensis  and other microorganisms. Especially, enolase and malate dehydrogenase were first found to play an important role in fruiting body development in macro-fungus. The results implied that cAMP signal pathway involved in fruiting body development of  C. sinensis , meanwhile glycometabolism, protein metabolism, energy metabolism, and cell reconstruction were more active during fruiting body development. It has become evident that fruiting body formation of  C. sinensis  is a highly complex differentiation process and requires precise integration of a number of fundamental biological processes. Although the fruiting body formation mechanisms for all these activities remain to be further elucidated, the possible mechanism provides insights into the culture of  C. sinensis .

This work illustrates an accurate method for determination of Se by electrolytic hydride generation technique based on a novel carbon paste electrode for sample introduction combined with atomic fluorescence spectral analysis. The studies show that Se(IV) can be converted efficiently to SeH 2 on an L -cysteine modified carbon paste electrode (CMCPE), which has never been reported before. Significantly, generation from Se(IV) implies that the use of carbon paste electrode-based electron-induced hydride generation system to achieve efficiency is almost 90% to that obtained by chemical hydride generation, and the response obtained from CMCPE is 2 and 3 times of that from the Pb and graphite electrode, respectively. Results also display that the lifetime and the stability of the CMCPE is superior to that of L -cysteine ornamented graphite electrode fabricated by covalently bonding. Under the optimal conditions, a low concentration limit of detection 0.065µgL -1 of Se(IV) is achieved. The repeatability denoted as % RSD is 2.2% for 1.0μgL -1 Se(IV). The utility of the studied method is compared with certified reference materials as well as several edible samples. The advantages and limitations of this method, compared with existing techniques, are also discussed., (Copyright © 2017 Elsevier B.V. All rights reserved.)