Assessment of body fat mass, anthropometric measurement and cardiometabolic risk in children and adolescents with achondroplasia and hypochondroplasia.

Achondroplasia is a rare skeletal dysplasia characterized by rhizomelic short stature, whose prevalence is about 1 per 25,000 births. For some patients with achondroplasia, excess body weight is one of the major concerns due to an impaired linear growth. Epidemiological studies revealed a premature onset of cardiovascular or cerebrovascular events in achondroplasia. An association between obesity and cardiometabolic risk factors related to cardiovascular events remains unknown in patients with achondroplasia/hypochondroplasia. This cross-sectional study investigated anthropometric measurements, body compositions and cardiometabolic risk factors in pediatric patients with achondroplasia/hypochondroplasia. Thirty-two patients with achondroplasia and ten with hypochondroplasia aged between 1.9 and 18.7 years were enrolled in this study. Half of the participants presented at least one cardiometabolic abnormality. Elevated systolic blood pressure was the most common abnormality. None of the participants developed metabolic syndrome or type 2 diabetes mellitus. Body mass index-standard deviation score and hip/height ratio were strongly correlated with percent body fat assessed by dual energy X-ray absorptiometry although no significant association was found between anthropometric measurements or body fat mass and any cardiometabolic risk factors. No significant difference in body fat mass, as well as body mass index-standard deviation score and hip/height, was found between cardiometabolically normal group and cardiometabolically abnormal groups. These results suggest that not only weight gain and hip/height changes should be monitored but also individual cardiometabolic risk factors should be evaluated to avoid cardiometabolic events in the healthcare management of pediatric patients with achondroplasia/hypochondroplasia.

Parental somatogonadal COL2A1 mosaicism contributes to intrafamilial recurrence in a family with type 2 collagenopathy.

The COL2A1 gene encodes the alpha-1 chain of procollagen type 2. Pathogenic variants in the COL2A1 gene are associated with several different types of skeletal dysplasia collectively known as type 2 collagenopathies. Type 2 collagenopathies have an autosomal dominant inheritance. Some germline or somatogonadal mosaicism cases have been reported. We investigated whether somatogonadal mosaicism occurred in a family with two children suspected of type 2 collagenopathies or related diseases. First, we detected a pathogenic variant in the COL2A1 gene in the two affected children by whole exome sequencing (WES). Next, we performed targeted deep sequencing to their parents without the variant by WES. A low level of COL2A1 mosaicism was revealed in the mother's tissues. We concluded that the mother had somatogonadal mosaicism with the COL2A1 mutation arose in the epiblast, and that the intrafamilial recurrence rate of the disease by the somatogonadal mosaicism was higher than by the germline mosaicism. This report suggests that parental low-level mosaicism should be evaluated in those parents with children carrying de novo germline mutations and the targeted deep sequencing is useful to detect them.

Functional analysis of monocarboxylate transporter 8 mutations in Japanese Allan-Herndon-Dudley syndrome patients.

Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.

Final adult height in long-term growth hormone-treated achondroplasia patients.

The objective of this study was to evaluate the gain in final height of achondroplasia (ACH) patients with long-term growth hormone (GH) treatment. We analyzed medical data of 22 adult patients (8 males and 14 females) treated with GH at a dose of 0.05 mg/kg/day. Optionally, tibial lengthening (TL) was performed with the Ilizalov method in 15 patients and TL as well as femoral lengthening (FL) in 6 patients. Concomitant gonadal suppression therapy with buserelin acetate was applied in 13 patients. The mean treatment periods with GH were 10.7 ± 4.0 and 9.3 ± 2.5 years for males and females, respectively. GH treatment augmented the final height +0.60 ± 0.52 SD (+3.5 cm) and +0.51 ± 1.29 SD (+2.8 cm) in males and females compared to non-treated ACH patients, respectively. Final height of ACH patients that underwent GH and TL increased +1.72 ± 0.72 SD (+10.0 cm) and +1.95 ± 1.34 SD (+9.8 cm) in males and females, respectively. GH, TL, and FL increased their final height +2.97 SD (+17.2 cm) and +3.41 ± 1.63 SD (+17.3 cm) in males and females, respectively. Gonadal suppression therapy had no impact on final height. CONCLUSIONS: Long-term GH treatment contributes to 2.6 and 2.1% of final adult height in male and female ACH patients, respectively.

A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation.

Osteopetrosis is a rare genetic disorder characterized by increased bone mineral density (BMD) due to osteoclast failure. T-cell immune regulator 1 (TCIRG1) plays crucial roles on osteoclast function, and its mutation causes autosomal recessive osteopetorosis. However, mutations in TCIRG1 have never been identified in autosomal dominant osteopetrosis (ADO). A 3-year-old boy was first presented to the clinic because of spontaneous radius and femur fractures. He has optic atrophy. The areal BMD at the lumbar spine was 1274 g/cm2 (233% of normal). Laboratory tests revealed no remarkable abnormal findings, including anemia, except for extremely elevated serum tartrate-resistant acid phosphatase-5b (14,600 mU/dL). Radiographically, the skull base, pelvis, and vertebrae showed a focal sclerosis. Genetic analysis revealed a novel de novo heterozygous missense mutation (His242Arg). Taken together with the mutation, his mild clinical features were diagnosed as ADO. This case implies that TCIRG1 could become a genetic candidate for ADO in addition to malignant forms such as ARO.

A patient with pachydermoperiostosis harboring SLCO2A1 variants with a history of differentiating from acromegaly.

Pachydermoperiostosis (PDP) is a rare hereditary disease characterized by digital clubbing, pachydermia, and periostosis. We describe a Japanese male patient with PDP who was differentially diagnosed with acromegaly by identification of compound heterozygous variants in SLCO2A1. Recent studies have reported various clinical manifestations, as well as skeletal and dermal features, in patients with PDP. Genetic testing provided not only PDP diagnosis and differentiation from acromegaly, but also information about possible complications and comorbidities throughout life.

Association of trabecular bone score and bone mineral apparent density with the severity of bone fragility in children and adolescents with osteogenesis imperfecta: A cross-sectional study.

Osteogenesis imperfecta (OI) is a hereditary skeletal disease characterized by bone fragility. Areal bone mineral density (BMD), evaluated by dual-energy X-ray absorptiometry (DXA), is used to assess bone brittleness. The height-adjusted BMD Z-score (BMDHAZ) is calculated in children and adolescents with OI to reduce the confounding factor of short stature. However, even with the BMDHAZ, severity evaluation in children and adolescents with OI is challenging because certain abnormalities in bone quality cannot be accurately assessed by BMD analysis. The trabecular bone scores (TBS) and bone mineral apparent density (BMAD), which represent the structural integrity of bone and bone-size-associated BMD, respectively, are associated with fracture risk. Recently, age- and sex-specific reference ranges have been reported, enabling the calculation of Z-scores for children. To evaluate which density measurements show the highest correlation with fracture risk, we analyzed the associations between the Z-scores of TBS, BMAD, and BMDHAZ, fracture rate, and genetic variants. We retrospectively reviewed 42 participants with OI aged 5 to 20 years who underwent DXA. COL1A1/2 pathogenic variants were detected in 41 of the 42 participants. In participants with nonsense and frameshift variants (n = 17) resulting in haploinsufficiency and mild phenotype, the TBS Z-score was negatively correlated with fracture rate (FR) (r = -0.50, p = 0.042). In participants with glycine substitution (n = 9) causing the severe phenotype, the BMAD Z-scores were negatively correlated with FR (r = -0.74, p = 0.022). No correlation between the BMDHAZ and FR was observed in both groups. These findings suggest that the TBS and BMAD are useful in assessing children and adolescents with OI with specific genetic variants.

Risk factors for readmission in schizophrenia treated with combined psychoeducation and standard therapy.

BACKGROUND: We conducted a historical cohort study of patients with schizophrenia to identify more robust risk factors at discharge that contribute to readmission within a year. METHODS AND FINDINGS: The subjects underwent brief psychoeducation during hospitalization. Multivariate analysis was conducted using factors selected in the univariate analysis. Using logistic regression analysis, the number of hospital admissions (P = .01) and Schedule for Assessment of Insight Japanese version score (P = .04) were identified as risk factors for readmission, with odds ratios of 0.70 and 1.18, respectively. CONCLUSIONS: These results suggest that improvement in insight and early intervention may lead to a more stable community life.

Identification of factors associated with the efficacy of atomoxetine in adult attention-deficit/hyperactivity disorder.

AIM: Atomoxetine (ATX) is a non-central stimulant and a standard treatment for adult attention-deficit/hyperactivity disorder (ADHD). The long-term efficacy of Atomoxetine is about 40% at 6 months. The variability in efficacy between individuals is thought to be related to patient-specific factors, but no detailed research has been conducted. In this retrospective cohort study, we aimed to identify the factors associated with Atomoxetine efficacy. METHODS: A total of 147 patients with attention-deficit/hyperactivity disorder aged ≥18 years who were using Atomoxetine for the first time were included in this study. The outcome was treatment success (treatment maintained for at least 6 months and improvement in symptoms). Symptom assessment was based on the overall improvement in symptoms judged by an expert physician. RESULTS: Of the patient sample, 103 (70.1%) achieved the outcome. Logistic regression analysis identified "the maximum dose of ATX" and "gambling habit" as factors associated with efficacy ( P  < 0.05). In the process of Atomoxetine titration, the larger the maximum dose, the higher the efficacy was shown to be. Gambling habits may be indicative of impulsivity, which is among the core symptoms of attention-deficit/hyperactivity disorder. Thus, a gambling habit may be considered a surrogate marker for impulsivity. CONCLUSIONS: Knowledge of these factors will help healthcare professionals to predict the likely efficacy of Atomoxetine in a given patient before subscribing it, facilitating individualized pharmacotherapy for adult attention-deficit/hyperactivity disorder.

Pathogenic variants of the GNAS gene introduce an abnormal amino acid sequence in the ß6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families.

Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of GNAS, which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of GNAS (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the ß6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP.

Characteristics of driving self-assessments and factors related to inaccurate self-assessment in Japanese older adults.

Older adults are considered to decide their driving behaviors based their own assessment of their driving performance, and thus it is important that these self-assessments be accurate. Therefore, this study aimed to clarify how older drivers assess their driving performance and examine factors related to the level of inaccuracy in their self-assessments. Japanese drivers aged 70 years or older (N = 181) were asked to assess their own driving performance by questionnaire and then to drive on a public road while wearing an electronic device that measured their actual driving behaviors. They were accompanied by a driving instructor who sat in the passenger seat and assessed their driving performance. The results showed that older drivers' self-assessments were significantly higher than the experts' assessments of their driving performance. This tendency applied to all driving competencies, including overall rating, speed, and scanning. In addition, there were greater discrepancies between self-assessments and expert assessments for drivers who were rated poorly by experts compared with those who were highly rated. Drivers with a greater rating discrepancy were likely to drive faster around an intersection with a stop sign. This discrepancy was also related to a low entropy rate (low randomness in head rotation) around a signalized T-junction. These findings based on on-road driving assessments provide credible evidence of performance overestimation by older drivers. Furthermore, the results suggest that making older drivers recognize the evaluative criteria might be effective for reducing the discrepancy between self-assessments and expert assessments. It was also suggested that improving the accuracy of one's self-assessment had the potential to improve driving behaviors such as choice of speed and scanning behavior.

Effect of educational intervention addressing inaccurate self-assessment of driving performance in older Japanese adults.

To maintain road safety for older drivers as well as other road users, it is important to provide interventions that improve self-awareness and behaviors in older drivers. We developed an intervention that provides feedback on accuracy of self-awareness of driving performance using a workbook, and examined its effectiveness using a prospective design with a follow-up after two months. Japanese drivers aged between 69 and 87 (Mean = 73.96) years were assigned to either the intervention group (n = 26) or the wait-list control group (n = 27). All participants were asked to assess their own driving performance by completing a questionnaire. They also completed an on-road driving assessment that involved driving on a public road while wearing an electronic device that measured their actual driving behaviors, accompanied by a driving instructor who sat in the passenger seat and assessed the participant's driving performance (expert assessment). Thereafter, only the intervention group received the immediate intervention (first wave). One month later, the intervention group completed the booster intervention by post. Two months after the first wave, both groups completed the questionnaire and on-road driving assessment again (second wave). Result revealed that discrepancy between self-assessment and expert assessment reduced in only the intervention group between the two waves. This finding suggests that the intervention was able to improve the accuracy of self-assessment. Furthermore, the expert assessment improved in the intervention group between the two waves, but this change was not observed in the control group. Similar trend was evident for vehicle speed at intersections with a stop sign but the result was not statistically significant. Changes in head rotation at intersections requiring turn in the intervention group did not differ from those in the control group. Improved accuracy of self-assessment as a result of the intervention could have led to improved general driving performance, but did not influence head rotation.

Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling.

X-linked hypophosphatemic rickets (XLH) is an inheritable type of rickets caused by inactivating variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, which results in the overproduction of fibroblast growth factor 23 (FGF23). The mechanism by which PHEX impairment leads to FGF23 overproduction is unknown. Because little is known regarding the genotype-phenotype correlation in Japanese XLH, we summarized the available clinical and genetic data and analyzed the genotype-phenotype relationships using 3-dimensional (3D) structure modeling to clarify the XLH pathophysiology. We retrospectively reviewed the clinical features and performed genetic analysis of 39 Japanese patients with XLH from 28 unrelated pedigrees carrying any known or novel PHEX variant. To predict changes in the 3D structure of mutant PHEX, we constructed a putative 3D model of each mutant and evaluated the effect of structural alteration by genotype-phenotype correlation analysis. Genetic analysis revealed 23 PHEX variants, including eight novel variants. They were associated with high i-FGF23 levels, hypophosphatemia, phosphaturia, high alkaline phosphatase levels, and short stature. No gene dosage effect or genotype-phenotype correlation was observed when truncating and non-truncating variants were compared. However, the conservation of the zinc-binding site and cavity in PHEX had an impact on the elevation of i-FGF23 levels. Via genotype-phenotype relationship analysis using 3D modeling, we showed that the zinc-binding site and cavity in PHEX can play a critical role in its function. These findings provide new genetic clues for investigating the function of PHEX and the pathogenesis of XLH.

Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats.

Introduction: Cannabidiol (CBD) is known to affect the pharmacokinetics of other drugs through metabolic inhibition of CYP2C19 and CYP3A4. However, there is a lack of in vivo evidence for such drug interactions. Therefore, we investigated the saturability of CBD metabolism and CBD-drug interactions through inhibition of CYP3A in vivo. Materials and Methods: A nanoemulsion formulation of CBD (CBD-NE) was orally administered to rats at doses of 5, 10, 25, and 50 mg/kg, and plasma concentrations of CBD were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to examine the dose-dependency of CBD exposure (area under the curve [AUC]). To examine the effect of a CYP3A inhibitor on CBD pharmacokinetics, rats were orally pretreated with 50 mg/kg ketoconazole (KCZ), a strong CYP3A inhibitor, before oral administration of CBD-NE at doses of 10 and 50 mg/kg, and plasma concentrations of CBD were measured using LC-MS/MS. Moreover, 13C-erythromycin was orally administered following administration of either NE (without CBD), as a control, or CBD-NE at 1, 10, and 50 mg/kg, and 13C-breath response was measured by using an infrared analyzer. Results: After administration of various doses of the nanoemulsified CBD formulation to rats, the exposure of CBD (i.e., the AUC calculated from the plasma concentration-time profile) increased in a greater than dose-proportional manner, especially at doses above 10 mg/kg. The AUC and maximum plasma concentration (Cmax) of CBD after oral administration of CBD-NE (10 mg/kg) increased approximately three times by the coadministration of KCZ. Moreover, according to the CBD-induced changes of 13C-breath response, the metabolism of 13C-erythromycin was shown to be inhibited by CBD at doses of 10 and 50 mg/kg, but not at 1 mg/kg. Conclusions: Nonlinear disposition and CYP-mediated drug interactions of CBD at doses exceeding 10 mg/kg were demonstrated for the first time in vivo in rats. Given the present results, it is proposed that caution for dose-dependent drug interactions should be considered for CBD.

Effect of visible presence of policing activities on drivers' vigilance and intention to refrain from non-driving activities: A scenario-based survey of general Japanese drivers.

Driver distraction is an important issue for road safety. The visible presence of policing activities alongside roadways seems to be significant in preventing driver distraction and other unsafe driving behaviors. The purpose of this study was to provide evidence of the effectiveness of visible policing presence on drivers' self-reported intention to refrain from non-driving activities and that this effectiveness can be enhanced by manipulating deployment even with limited resources. We conducted a scenario-based survey to compare drivers' self-reported intention to refrain from non-driving activities and their vigilance state across several hypothetical driving situations. The three aims of the study were to examine whether drivers' self-reported vigilance and intention to refrain from non-driving activities were associated with (a) the presence or absence of common forms of roadside policing, (b) the agent (police vs. civilian) and medium (human vs. advertisement) of road safety interventions, and (c) different forms of policing (police officer vs. police car) and their respective levels of conspicuousness. Japanese drivers (N = 367) were randomly assigned to receive one of three booklets that included a scenario-based survey. The three booklets contained different combinations of various hypothetical driving scenarios based on the three experiment designs (a, b, c) described above. Participants were asked to rate their vigilance and their intention to refrain from non-driving activities in hypothetical driving situations that varied by the presence or absence of policing and how conspicuous that presence was. We conducted repeated measures within-subject analysis of variance using the three experimental designs. The results showed that the presence of a single police unit engaged in policing activities was associated with more vigilance and greater intention to refrain from non-driving activities. The results suggested that effectiveness of visible policing could be enhanced by increasing conspicuousness of police officers in order to help drivers more easily recognize the presence of police without having to purchase extra equipment. These findings provide useful insights for traffic police to conduct routine policing practices more efficiently to address non-driving activities. Future research is needed to examine these results in a real-world setting.

Development of a Novel Nano-emulsion Formulation to Improve Intestinal Absorption of Cannabidiol.

BACKGROUND: Cannabidiol (CBD) is highly lipophilic, and its oral bioavailability is known to be very low in humans. In this study, we developed a novel nanoemulsion preparation of CBD (CBD-NE) to improve the poor solubility and absorption of CBD. The pharmacokinetic profiles of CBD in rats were evaluated after oral administrations of CBD oil and CBD-NE, and the effect of bile secretion on CBD absorption was also evaluated. METHODS: The CBD-NE formulation developed in this study consisted of vitamin E acetate, ethanol, Tween-20, and distilled water (1.7/3.8/70/24.5, w/w%). A CBD oil formulation (CBD oil, control) 100 mg/kg or CBD-NE 50 mg/kg was orally administered to rats, and the blood samples were collected over time. Moreover, the CBD oil or CBD-NE was orally administered to bile-fistulated rats, and the pharmacokinetic profiles of CBD were also evaluated. CBD concentrations in plasma were measured using LC-MS/MS. RESULTS: The particle size of CBD-NE was 35.3 ± 11.8 nm. Mean Tmax of CBD-NE was shortened significantly by the factor of 3 (from 8.00 to 2.40 h, p < 0.001) and AUC0-∞/dose increased by 65% (from 0.272 ± 0.045 to 0.448 ± 0.087 h L/kg) compared with CBD oil. AUC0-∞/dose and Cmax/dose after oral administration of CBD oil were significantly reduced by the factor of 27 and 23 (p < 0.05 and p < 0.01), respectively, in bile-fistulated rats compared with the untreated rats. In contrast, all pharmacokinetic parameters after oral administration of CBD-NE were not significantly different between the untreated and bile-fistulated rats. Therefore, these results demonstrated that conventional CBD oil formulation but not CBD-NE requires bile-mediated micelle formation. CONCLUSIONS: The novel NE formulation developed in this study successfully improved the absorption of CBD regardless of bile secretion. The newly developed oral CBD-NE preparation could be useful to achieve a more stable and quicker onset of action by CBD.

Predictors of driving outcomes including both crash involvement and driving cessation in a prospective study of Japanese older drivers.

The first aim of this study was to investigate predictors of future traffic crash involvement, taking into account bias in the handling of data for former drivers. The second aim was to compare characteristics of former drivers and crash-involved drivers in order to gain an understanding of appropriate driving cessation among older drivers. In all, 154 drivers aged 70 years or older participated in the baseline interview and the follow-up survey conducted two years later. In the baseline interview, participants were asked to respond to a questionnaire, take the Useful Field of View test® (UFOV), and complete the Mini-Mental State Examination. In the follow-up survey, participants were asked by mail or telephone whether they had stopped driving. Participants reporting that they still drove were invited to participate in a subsequent interview. Based on the information obtained in the follow-up survey, participants were classified as follows: driving cessation group (n=26); crash-involved group (n=18); and crash-free group (n=110). A multinomial logistic regression was then used to analyse the data. Contrary to the results of previous studies, we found older age to be associated with crash involvement but not with driving cessation. The cessation group had more decreased cognitive processing speed than the crash-involved and crash-free groups. Crash history was also predictive of crash involvement. Participants who were subject to license renewal between baseline and follow-up had a greater tendency to continue driving. Results suggested that age and crash history could potentially identify high-risk older drivers. The predictive power of cognitive processing speed is reduced under certain conditions. License-renewal procedures may induce Japanese older adults to continue driving. Future studies should use a large national sample to confirm the results of the present study.

The effect of PKC activity on the TTX-R sodium currents from rat nodose ganglion neurons.

To determine how protein kinase C (PKC) activity influences properties of the tetrodotoxin-resistant sodium current (TTX-R I(Na)) in neonatal rat nodose ganglion (NG) neurons, we assessed the effects of phorbol,-12-myristate,13-acetate (PMA), one of the PKC activators, and staurosporine, one of the PKC inhibitors, on the current. PMA (30 and 100 nM) induced an increase in the peak current amplitude of normalized current-voltage curves, a leftward shift in the potential for half activation (V(1/2)) of normalized conductance-voltage curves and a leftward shift of V(1/2) potential for steady-state inactivation curves. The effects of staurosporine (0.1 and 1 muM) on the peak current amplitude and the V(1/2) potential for activation were opposite compared with those seen after PMA application. Staurosporine (1 muM) antagonized PMA (100 nM)-induced modification of TTX-R I(Na). These results suggest that the basal TTX-R I(Na) obtained from neonatal NG neurons is controlled by the level of PKC activity.