Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together.

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

Transvaginal ultrasound parameters to evaluate cervical favorability and predict the outcome of induction of labor.

OBJECTIVE: To compare the values of transvaginal ultrasound (TVU) and Bishop score (BS) for predicting outcomes of induction of labor (IOL). METHODS: The BS and TVU were assessed before IOL. TVU parameters included cervical length (CL) and E-Cervix comprising the cervical hard ratio (HR) and the mean strain level of internal os (IOS). Study end-points included the duration of the latent phase within 15 or 18 h and delivery within 24 h. RESULTS: In multivariable logistic regression models, at the first two end-points, the areas under the curve (AUCs) for CL with HR were 0.733 and 0.777, and the AUCs for CL with IOS were 0.754 and 0.787, respectively, The AUC for HR was 0.750 at the third end-point. With receiver operating characteristic (ROC) analysis, the best cut-off value for CL was ≤1.38 cm and that for IOS was ≥0.35. The AUCs of the TVU scoring system by the cut-off values for CL and IOS for the three end-points were 0.784, 0.833, and 0.855, respectively. The predicting values of both methods were better than those of the BS (AUC = 0.672, 0.694, and 0.687, respectively). CONCLUSION: Cervical length along with E-Cervix showed better predictive values for successful induction compared with the BS.

Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence.

PURPOSE: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. METHODS: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. RESULTS: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine ß hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient. CONCLUSION: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.

The lymphatic system: a therapeutic target for central nervous system disorders.

The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis, metabolite clearance, and immune surveillance. The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology. They emerge as major pathways for fluid exchange. The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity. The lymphatic system, through its role in the clearance of neurotoxic proteins, autoimmune cell infiltration, and the transmission of pro-inflammatory signals, participates in the pathogenesis of a variety of neurological disorders, including neurodegenerative and neuroinflammatory diseases and traumatic injury. Vascular endothelial growth factor C is the master regulator of lymphangiogenesis, a process that is critical for the maintenance of central nervous system homeostasis. In this review, we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.

High Intensity Interval Training: A Potential Method for Treating Sarcopenia.

Sarcopenia, an age-related disease characterized by loss of muscle strength and muscle mass, has attracted the attention of medical experts due to its severe morbidity, low living quality, high expenditure of health care, and mortality. Traditionally, persistent aerobic exercise (PAE) is considered as a valid way to attenuate muscular atrophy. However, nowadays, high intensity interval training (HIIT) has emerged as a more effective and time-efficient method to replace traditional exercise modes. HIIT displays comprehensive effects on exercise capacity and skeletal muscle metabolism, and it provides a time-out for the recovery of cardiopulmonary and muscular functions without causing severe adverse effects. Studies demonstrated that compared with PAE, HIIT showed similar or even higher effects in improving muscle strength, enhancing physical performances and increasing muscle mass of elder people. Therefore, HIIT might become a promising way to cope with the age-related loss of muscle mass and muscle function. However, it is worth mentioning that no study of HIIT was conducted directly on sarcopenia patients, which is attributed to the suspicious of safety and validity. In this review, we will assess the effects of different training parameters on muscle and sarcopenia, summarize previous papers which compared the effects of HIIT and PAE in improving muscle quality and function, and evaluate the potential of HIIT to replace the status of PAE in treating old people with muscle atrophy and low modality; and point out drawbacks of temporary experiments. Our aim is to discuss the feasibility of HIIT to treat sarcopenia and provide a reference for clinical scientists who want to utilize HIIT as a new way to cope with sarcopenia.

Diagnosis and genetic analysis of a case with mandibuloacral dysplasia type B due to compound heterozygous mutations of the ZMPSTE24 gene.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, mainly caused by pathogenic variants of the LMNA and ZMPSTE24 genes. In this study, we reported the first case of a patient with type B cranial and mandibular dysplasia in China. The patient presented with distinctive facial features, feeding difficulties, significant physical retardation, and overall developmental delay with abnormal tooth and bone development. Trio-whole exome sequencing analysis showed that the patient carried compound heterozygous mutations of c.743C>T (p.Pro248Leu) (dbSNP: rs121908095) and the loss of exons 1-10 of the ZMPSTE24 gene. Sanger sequencing and real-time quantitative PCR (RT-qPCR) showed that these two mutations were inherited from the patient's phenotypically normal mother and father, respectively. By summarizing and analyzing the characteristics of this case and the pedigree of the family, we suggested that trio-whole-exome sequencing could be performed to assist in the diagnosis of diseases that are difficult to be diagnosed definitively based on clinical phenotypes. The publication of this case has improved clinicians' understanding of MAD disease and provide new clinical information for the subsequent genetic study of this disease.

Correlation between mild fetal ventriculomegaly, chromosomal abnormalities, and copy number variations.

BACKGROUND: Lateral ventriculomegaly is the most common abnormality of the fetal nervous system. This study investigated the incidence of chromosomal abnormalities and copy number variations (CNVs) in fetuses with mild ventriculomegaly (MV) based on various ultrasonic manifestations, identifying their corresponding features via ultrasound examination. METHODS: A retrospective analysis was performed on ultrasound and neurosonogram (NSG) manifestations and genetic profiles of 334 cases with MV and invasive prenatal diagnosis. RESULTS: Three hundred thirty-four cases with fetal MV were assessed via karyotyping. Further chromosomal microarray analysis (CMA) was performed in 182 cases with normal chromosome karyotypes; pathogenic chromosomal copy number variations (CNVs) were found in eight cases with a prevalence of 4.4% (8/182). In this study, the incidence rate of pathogenic abnormalities of chromosomes and CNVs was 5.7% (19/334). Based on whether lateral ventriculomegaly was complicated with other ultrasonic features, the 334 patients were divided into two groups: (1) 175 cases exhibited isolated ventriculomegaly (IVM; 52.4%, 175/334 group A) including two (1.1%, 2/175) with pathogenic chromosomal karyotype abnormalities-both trisomy 21; (2) 159 cases exhibited non-isolated ventriculomegaly (N-IVM; 47.6%, 159/334) with pathogenic chromosomal abnormalities and CNVs detected in17 cases (10.7%, 17/159). The N-IVM group was further divided into two groups: 105 cases exhibited MV with undetermined ultrasonic abnormalities (31.4%, 105/334, group B) with pathogenic chromosomal abnormalities and CNVs detected in eight cases (7.6%, 8/105); 54 cases exhibited MV with structural malformations (16.2%, 54/334, group C) of which nine cases (16.7%, 9/54) presented both pathogenic chromosomal abnormalities and CNVs, and five cases (55.6%, 5/9) were diagnosed with various cortical malformations. The pathogenicity rates of the IVM and N-IVM groups were statistically different (χ2=14.159, p = 0.000). There were significant differences (χ2=7.992, p = 0.005) among groups A, B, and C. CONCLUSIONS: Combinations of various ultrasonic abnormalities significantly affect the risk of pathogenic chromosomal abnormalities and CNVs in fetuses with MV. Cases involving cortical malformations require particular attention to the occurrence of pathogenic genetic abnormalities. When fetal MV is detected, a comprehensive ultrasound examination focusing on undetermined ultrasonic abnormalities is critical. Fetal NSG should be conducted to detect potential cerebral cortical malformation easily missed by routine ultrasound.

Antibodies against thyroid-stimulating hormone receptor cause maternal-neonatal transmission of Graves' Disease.

The present study aimed to investigate whether the thyroid-stimulating hormone receptor (TSHR) autoantibodies (Ab) from mothers with Graves' disease (GD) could cause neonatal thyroid disease and the underlying mechanisms of this. An adenovirus expressing the TSHR A-subunit and a control adenovirus expressing ß-galactosidase was constructed by Beijing Sino Geno Max Co., Ltd. The sequences were subsequently verified and amplified via PCR. A GD model was established in female BALB/c mice (n=90) by three intramuscular injections of a TSHR-expressing adenovirus (Ad-TSHR). Mice injected with Ad-ß-galactosidase served as a sham immunization group. The immunized females were paired with unimmunized males to generate offspring. The serum levels of TSHR-Ab and thyroxine (T4) of mothers and neonates were measured after delivery. Breast milk was collected from the stomachs of neonatal mice to determine the TSHR-Ab levels. The positive rate of serum TSHR-Ab (>0.3 IU/l) in the TSHR group was 99% (89/90) and 0% in the sham group. The mother mice in the TSHR group had elevated serum T4 levels and the thyroid pathological features of Graves' hyperthyroidism.GD mice gave birth to smaller newborns with thyroid pathological changes and higher serum levels of TSHR-Ab and T4, compared to the offspring in the sham group. The TSHR-Ab levels in breast milk from the GD mice declined with time. Mice immunized with Ad-TSHR exhibited the clinicopathological features of human GD and give birth to neonates with thyroid disease at birth.

The Mechanism, Clinical Efficacy, Safety, and Dosage Regimen of Atomoxetine for ADHD Therapy in Children: A Narrative Review.

Atomoxetine, a selective norepinephrine (NE) reuptake inhibitor, was approved for attention deficit/hyperactivity disorder (ADHD) treatment in children, adolescents and adults. We searched the database PubMed/MEDLINE (2000 to October 1, 2021). Only publications in English were considered. Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of NE throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex (PFC). The novel mechanism of atomoxetine also includes several new brain imaging studies and animal model studies. It is mainly metabolized by the highly polymorphic drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Atomoxetine is effective and generally well tolerated. ADHD is often accompanied by multiple comorbidities. A series of studies have been published suggesting that atomoxetine is effective in the treatment of ADHD symptoms for children with various types of comorbidity. In some cases, it is possible that atomoxetine may have a positive influence on the symptoms of comorbidities. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, and has a negligible risk of abuse or misuse. The latest guideline updated that clinical dose selection of atomoxetine was recommended based on both CYP2D6 genotype and the peak concentration. To have a more comprehensive understanding of atomoxetine, this review sets the focus on the mechanism, clinical efficacy and dosage regimen in detail, and also touches on those studies regarding adverse reactions of atomoxetine.

A Retrospective Analysis of Patients with Short Stature in the South of China between 2007 and 2015.

OBJECTIVE: To describe the demographic features of children with short stature and poor growth in the south of China and provide better guidance on clinical strategy and decisions. STUDY DESIGN: This retrospective, chart review study analyzed children with short stature and poor growth admitted to the Department of Endocrinology of Children's Hospital of Nanjing Medical University from Jan 2007 to Dec 2015. RESULTS: The chart review yielded 4142 patients, including 2546 boys and 1596 girls (P < 0.001); the number of patients gradually increased per year from 2007 to 2015. There was an upward trend in the average levels of height standard deviations (SDs) during the study period (P < 0.001), both in males (P < 0.001) and females (P < 0.001). Mean height SDs were smaller in females (-2.42±1.09) than males (-2.33±1.03; P = 0.01). The percentage of females admitted at normal height (33.83%) was lower than that of males (37.20%; P = 0.028). The peak age range of hospitalization in males was 10-12 years of age, while females were generally admitted earlier-8-10 years. CONCLUSIONS: There was an increasing tendency to focus on children's height. Parents and pediatricians were recommended to pay more attention to the treatment needs of girls while avoiding excessive treatment of those who merely appear not to be tall enough without a clear medical issue related to growth, especially for boys.

Effect of bisphenol A on SOCS-3 and insulin signaling transduction in 3T3-L1 adipocytes.

The aim of the present study was to investigate whether environmental endocrine disrupting chemical, bisphenol A (BPA), affects secretion of suppressor of cytokine signaling 3 (SOCS-3) and insulin signaling transduction in 3T3-L1 adipocytes. 3T3-L1 adipocytes were treated for 0, 2, 6, 12 and 24 h with BPA at 80 µM in serum­deprived medium. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the mRNA expression levels of SOCS­3 and protein expression levels of SOCS­3, insulin receptor substrate 1 (IRS­1), phosphorylated (p)­IRS­1, Akt and p­Akt. The levels of p­IRS­1, Akt and p­Akt in cultures treated for 6 h with BPA were also analyzed by immunofluorescence. The SOCS­3 mRNA and protein expression levels were decreased in the 6, 12 and 24 h groups. The levels of p­IRS­1 and p­Akt protein were markedly downregulated, while the level of IRS­1 and Akt protein remained unaltered among these groups, which was consistent with the results observed using immunofluorescence. BPA may inhibit insulin signal transduction and result in the occurrence of insulin resistance via promoting the expression of SOCS-3.

4-phenylbutyric acid attenuates endoplasmic reticulum stress-mediated pancreatic ß-cell apoptosis in rats with streptozotocin-induced diabetes.

Endoplasmic reticulum stress (ERS) plays an important role in diabetes mellitus (DM), but the association between DM and ERS is unknown. We have previously shown that streptozotocin (STZ)-induced diabetes in rats is characterized by increased levels of ERS markers. Here, we tested whether the chemical chaperone 4-phenylbutyric acid (4-PBA) ameliorated ERS-associated apoptosis in pancreatic ß-cells in rats with STZ-induced diabetes. Male Sprague-Dawley rats were divided into 3 groups: control group, DM group, and DM model plus 4-PBA treatment group (4-PBA group). DM model rats were induced by injection of STZ (60 mg/kg) intraperitoneally, and 4-PBA was administered daily by gavage at a dose of 500 mg/kg body weight for 20 days. ß-cell apoptosis was higher in the DM group than in the control group. Moreover, the expression of caspase-3, Bax, and the ERS indicators Bip and CHOP was markedly elevated in the pancreas of rats in the DM group, whereas the expression of Bcl-2 was lower in these rats (P < 0.05). Blood glucose concentration in diabetic rats gradually decreased with 4-PBA treatment but remained higher at the end of the experiment compared to the concentration in control rats. Consistent with this, 4-PBA raised the fasting insulin level in diabetic rats; it also suppressed the expression of caspase-3, Bax, and ERS indicators but enhanced the expression of Bcl-2. In conclusion, 4-PBA protects pancreatic ß-cells from apoptosis in STZ-induced diabetes by attenuating the severity of ERS.

Lipolysis and apoptosis of adipocytes induced by neuropeptide Y-Y5 receptor antisense oligodeoxynucleotides in obese rats.

AIM: To investigate the influence of central administration of neuropeptide Y-Y5 receptor antisense oligodeoxynucleotides (ODN) on the body weight and fat pads of high-energy diet-induced obese rats, and the effects on white adipocyte lipolysis and apoptosis. METHODS: Y5 receptor antisense, sense, mismatched oligodeoxynucleotides (ODN) or vehicle were intracerebroventricularly injected, and average adipocyte area was calculated. DNA ladders were measured to evaluate adipocyte apoptosis, and RT-PCR was used to analyze the expression of bcl-2 and bax gene. RESULTS: (1) Central administration of Y5 receptor antisense ODN significantly decreased body weight, fat pads, and average adipocyte area. (2) DNA fragmentation was presented after electrophoresis at both epididymal and retroperitoneal adipose tissue. (3) The expression of bcl-2 gene was downregulated, while the expression of bax was upregulated. CONCLUSION: Lipolysis and adipocyte apoptosis may be important reasons for Y5 receptor antisense therapy.