Impact of the coronavirus disease 2019 pandemic on hospital admissions for idiopathic pulmonary fibrosis: a nationwide population-based study.

BACKGROUND: Previous studies have consistently reported a decrease in hospital admissions for respiratory diseases during the coronavirus disease 2019 (COVID-19) pandemic. However, the impact of the pandemic on idiopathic pulmonary fibrosis (IPF) admissions remains unknown. METHODS: This study used data from the Korean National Health Insurance Service database. IPF was defined based on the International Classification of Diseases 10th Revision (ICD-10) and rare intractable disease (RID) codes. The rate of IPF admissions was calculated by dividing the number of IPF admissions by the prevalence of IPF. The rate of IPF admissions during the COVID-19 pandemic (2020-2021) was compared with the mean rate of admissions during the prepandemic period (2017-2019) and presented as the rate ratio (RR). A sensitivity analysis was conducted on patients treated with systemic corticosteroids during IPF admission. RESULTS: In patients with IPF defined based on the ICD-10 (analysis 1), the RRs significantly decreased from March in 2020 to December 2021, except for June and September in 2020. Similarly, in patients with IPF defined based on the ICD-10 and RID (analysis 2), the RRs significantly decreased from March 2020 to December 2021, except for June and September 2020. In the sensitivity analysis of analysis 1, the RR significantly decreased in 2020 (0.93; 95%CI: 0.88-0.99; P = 0.029), whereas the RR in 2021 was not significantly different. The RRs in the sensitivity analysis of analysis 2 significantly decreased to 0.85 (0.79-0.92; P < 0.001) in 2020 and 0.82 (0.76-0.88; P < 0.001) in 2021. In the subgroup analysis, the rates of IPF admissions significantly decreased in 2020 and 2021 across both sexes, patients aged ≥ 60 years, and all household income groups. CONCLUSIONS: The rate of IPF admissions significantly decreased during the COVID-19 pandemic. This result indicates that preventive measures against COVID-19 may effectively mitigate IPF exacerbation. Therefore, it is assumed that there is a close relationship between respiratory viral infections and IPF exacerbations.

Association between Condylar Bone Density and Disk Displacement in the Temporomandibular Joint.

Measuring bone density (BD) is a common method of determining bone quality; however, the relationship between condylar BD and the occurrence of temporomandibular joint (TMJ) disorders has not been investigated. To address this knowledge gap, we aimed to investigate condylar BD in terms of TMJ disk displacement (TMJ DD) using computed tomography (CT) and magnetic resonance imaging (MRI). We classified TMJ MRI results according to the position of the disk: normal disk position (Normal), anterior disk displacement with reduction (ADDR), and anterior disk displacement without reduction (ADDNR). After retrospectively evaluating 86 female condyles, we determined the total, cortical, and trabecular BD in the upper-joint portion of the condyle and the whole condyle using CT data. To standardize condylar BD, we calculated the BD ratios by dividing the condylar BD by the cervical axis BD. The Kruskal-Wallis test analyzed the differences in BD measurements in the TMJ DD patient groups and showed significant between-group differences in condylar BD. The total and trabecular BD was significantly higher in ADDNR condyles than in Normal or ADDR condyles (Normal = ADDR < ADDNR). However, there was no significant difference in the cortical BD among the three TMJ DD groups. The BD ratios showed a similar tendency with condylar BD. These results suggest that increased condylar BD - specifically total and trabecular BD - may be significantly associated with ADDNR condyles. Our findings will help clinicians determine the course of treatment for patients with disk-related TMJ disorders.

Impact of High Risk of Obstructive Sleep Apnea on Health-Related Quality of Life: The Korean National Health and Nutrition Survey 2019-2021.

Background/Objectives: Obstructive sleep apnea (OSA) impairs quality of life (QoL). However, its disease burden in the general population remains unknown. We aimed to investigate the association between OSA and health-related QoL in the general Korean population. Methods: This study analyzed cross-sectional datasets of adults (≥40 years) in the Korean National Health and Nutrition Examination Survey 2019-2021. QoL was assessed using the 3-level EuroQoL 5-dimension component (EQ-5D-3L). The high risk of OSA was determined using the STOP-Bang questionnaire (score ≥ 3). Demographic and clinical factors were included in linear regression analyses to identify the factors associated with EQ-5D-3L. Results: Of the 8966 total participants, 6792 (75.8%) and 2174 (24.2%) were classified as having a low risk and high risk of OSA, respectively. The high risk OSA group showed significantly lower QoL scores when compared with the low risk OSA group (0.939 ± 0.003 vs. 0.951 ± 0.002, p < 0.001). However, the mean difference was within the minimal clinically important difference (MCID) of EQ-5D-3L. Only females exceeded the MCID for the EQ-5D-3L. Elderly females with a high risk of OSA showed the lowest QoL. The regression coefficient of high risk OSA in the multivariate model was -0.018 (95% CI: -0.025--0.01, p < 0.001). Patient demographics and comorbidities also showed significant associations with the EQ-5D-3L. Their regression coefficient was higher than that of high risk OSA. Conclusions: The impact of high risk OSA on QoL manifested differently according to age and sex. The impact of comorbidities on QoL was greater than that of high risk OSA, highlighting the important role of comorbidities and the need for their adjustment in the assessment of QoL.

Inhaled Corticosteroids May Not Affect the Clinical Outcomes of Pneumonia in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Although inhaled corticosteroids (ICS) is reportedly associated with a higher risk of pneumonia in chronic obstructive pulmonary disease (COPD), the clinical implications of ICS have not been sufficiently verified to determine their effect on the prognosis of pneumonia. METHODS: The electronic health records of patients hospitalized for pneumonia with underlying COPD were retrospectively reviewed. Pneumonia was confirmed using chest radiography or computed tomography. The clinical outcomes of pneumonia in patients with COPD who received ICS and those who received long-acting bronchodilators other than ICS were compared. RESULTS: Among the 255 hospitalized patients, 89 met the inclusion criteria. The numbers of ICS and non-ICS users were 46 and 43, respectively. The CURB-65 (confusion, uremia, respiratory rate, blood pressure, age ≥65 years) scores at the initial presentation of pneumonia were comparable between the two groups. The proportions of patients with multilobar infiltration, pleural effusion, and complicated pneumonia in the radiological studies did not vary between the two groups. Additionally, the defervescence time, proportion of mechanical ventilation, intensive care unit admission, length of hospital stays, and mortality rate at 30 and 90 days were not significantly different between the two groups. ICS use and blood eosinophils count were not associated with all pneumonia outcomes and mortality in multivariate analyses. CONCLUSION: The clinical outcomes of pneumonia following ICS use in patients with COPD did not differ from those in patients treated without ICS. Thus, ICS may not contribute to the severity and outcomes of pneumonia in patients with COPD.

Incidence, Prevalence, and Mortality of Eosinophilic Granulomatosis With Polyangiitis in Korea: A Nationwide Population-Based Study.

PURPOSE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of vasculitis with multiorgan involvement. The incidence and prevalence of EGPA vary geographically and ethnically. This study investigated the incidence, prevalence, and mortality of EGPA in a nationwide population-based cohort in Korea. METHODS: This retrospective cohort study used data from the National Health Insurance database that covers almost all Korean residents. EGPA was identified using relevant diagnostic codes from 2007 to 2018. Newly diagnosed EGPA cases since 2007 and patients who visited outpatient clinics for EGPA at least three times were included. Age- and sex-adjusted standardized incidence and prevalence rates were analyzed. RESULTS: A total of 843 patients with EGPA were identified. The mean annual standardized incidence between 2007 and 2018 was 1.2 (per 1,000,000 individuals). The incidence of EGPA has increased from 1.1 (per 1,000,000 individuals) in 2007 to 1.6 (per 1,000,000 individuals) in 2017. The standardized prevalence of EGPA has increased from 1.1(per 1,000,000 individuals) in 2007 to 11.2 (per 1,000,000 individuals) in 2018. The incidence and prevalence of EGPA were higher in women than in men. The standardized mortality rate was 1.61 (95% confidence interval [CI], 1.34-1.93) in total population, 1.59 (95% CI, 1.23-2.02) in males, and 1.63 (95% CI, 1.22-2.13) in females. CONCLUSIONS: The incidence of EGPA has increased over the past decade. Incidence and prevalence rates were higher in females than in males. The overall mortality rate associated with EGPA was higher than that in the general population.

Risk of Cardiovascular Events Associated with Chronic Obstructive Pulmonary Disease and/or Metabolic Syndrome: A Large-Scale Nationwide Population-Based Cohort Study.

Purpose: Chronic obstructive pulmonary disease (COPD) and metabolic syndrome (MetS) are among the most prevalent conditions that might predispose individuals to life-threatening events. We aimed to examine their associations with cardiovascular (CV) events and mortality using a large-scale population dataset from the National Health Information Database in Korea. Patients and Methods: This population-based cohort study enrolled adults aged ≥40 years who had undergone more than two health examinations between 2009 and 2011. They were divided into four groups based on the presence of COPD and MetS. Analysis of the outcomes and CV events or deaths was performed from 2014 to 2019. We compared CV event incidence and mortality rates using a multivariate Cox proportional hazards model and Kaplan-Meier curves. Results: Totally, 5,101,810 individuals were included, among whom 3,738,458 (73.3%) had neither COPD nor MetS, 1,193,014 (23.4%) had only MetS, 125,976 (2.5%) had only COPD, and 44,362 (0.9%) had both. The risk of CV events was significantly higher in individuals with both COPD and MetS than in those with either COPD or MetS alone (HRs: 2.4 vs 1.6 and 1.8, respectively; all P <0.001). Similarly, among those with both COPD and MetS, all-cause and CV mortality risks were also elevated (HRs, 2.9 and 3.0, respectively) compared to the risks in those with either COPD (HRs, 2.6 and 2.1, respectively) or MetS (HRs, 1.7 and 2.1, respectively; all P <0.001). Conclusion: The comorbidity of MetS in patients with COPD increases the incidence of CV events and all-cause and cardiovascular mortality rates.

Inhaled Corticosteroids and the Risk of Nontuberculous Mycobacterial Pulmonary Disease in Chronic Obstructive Pulmonary Disease: Findings from a Nationwide Population-Based Study.

Studies have shown increased nontuberculous mycobacterial pulmonary disease (NTM) incidence with inhaled corticosteroid (ICS) use in patients with chronic respiratory diseases; however, this association in chronic obstructive pulmonary disease (COPD) remains insufficiently studied. Using a nationwide population-based database of the Korean National Health Insurance Service, newly diagnosed COPD patients (2005-2018) treated with inhaled bronchodilators were selected. An NTM case was defined by the presence of the first diagnostic code following inhaled bronchodilator use. Results indicated that ICS users did not have an increased risk of NTM disease compared to non-ICS users (hazard ratio (HR), 1.121; 95% confidence interval (CI), 0.950-1.323; p = 0.176). However, in a subgroup analysis, the highest quartile of the cumulative ICS dose was associated with the development of NTM (1.200, 0.950-1.323, p = 0.050). Medium (1.229, 1.008-1.499, p = 0.041) and high daily doses of ICS (1.637, 1.241-2.160, p < 0.001) were associated with an increased risk of NTM disease. There was no difference in the risk of NTM according to ICS type. ICS use may increase the risk of developing NTM disease in patients with COPD. Physicians should weigh the potential benefits and risks of ICS, especially when using high doses and prolonged durations.

Wnt5a-dopamine D2 receptor interactions regulate dopamine neuron development via extracellular signal-regulated kinase (ERK) activation.

The dopamine D2 receptor (D2R) plays an important role in mesencephalic dopaminergic neuronal development, particularly coupled with extracellular signal-regulated kinase (ERK) activation. Wnt5a protein is known to regulate the development of dopaminergic neurons. We analyzed the effect of Wnt5a on dopaminergic neuron development in mesencephalic primary cultures from wild-type (WT) and D2R knock-out (D2R(-/-)) mice. Treatment with Wnt5a increased the number and neuritic length of dopamine neurons in primary mesencephalic neuronal cultures from WT mice, but not from D2R(-/-) mice. The effect of Wnt5a was completely blocked by treatment with D2R antagonist or inhibitors of MAPK or EGFR. Wnt5a-mediated ERK activation in mesencephalic neuronal cultures was inhibited by treatment of D2R antagonist and EGFR inhibitors in WT mice. However, these regulations were not observed for D2R(-/-) mice. Co-immunoprecipitation and displacement of [(3)H]spiperone from D2R by Wnt5a demonstrated that Wnt5a could bind with D2R. This interaction was confirmed by GST pulldown assays demonstrating that the domain including transmembrane domain 4, second extracellular loop, and transmembrane domain 5 of D2R binds to Wnt5a. These results suggest that the interaction between D2R and Wnt5a has an important role in dopamine neuron development in association with EGFR and the ERK pathway.

Selection of Representative Questionnaire Items from the Asthma Control Test.

Asthma is a disease characterized by the appearance of transient or persistent symptoms in response to allergens, viral upper respiratory infections, and cold air. Asthma treatment aims to control, rather than cure, and digital systems can be useful in this regard. However, conventional assessment methods for asthma control are not suitable for digital healthcare. Therefore, we aimed to select representative questionnaire items suitable for digitally assessing the asthma control status. We analyzed the Asthma Control Test (ACT) and selected representative items. Throughout the year 2020, ACT results (2019 in total) collected from patients (>18 years old) with a principal diagnosis of asthma were analyzed. Individual questionnaire items were tested using Pearson's correlation and receiver operating characteristic curves. Of the five questionnaire items, Q1, Q2, Q3, and Q5 yielded significant findings. Among these questionnaires, Q2 was the most descriptive and correlated questionnaire. Q5 was also significant but it was excluded since it was unable to apply to the digital health care system for asthma assessment method. The remaining three questionnaire items were selected and their sensitivity and specificity were assessed. Eight methods were analyzed, and the sum of scores of Q1−Q3 had the highest sensitivity and specificity (97% and 91%, respectively). The results suggested that, instead of the full items of ACT, the sum of Q1−Q3 can be used to assess the asthma control status. These findings will serve as the foundation for developing digital asthma control assessment tools.

Adherence to Long-Acting Inhaler Use for Initial Treatment and Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Retrospective Cohort Study.

We aimed to determine the effect of long-acting inhaler use adherence on acute exacerbations in treatment-naïve patients with chronic obstructive pulmonary disease (COPD) using claims data from the Korean Health Insurance Review and Assessment Service from July 2015−December 2016. Patients with COPD aged ≥ 40 years who used long-acting inhalers were enrolled and observed for 6 months. Medication adherence was determined by the medication possession ratio (MPR); patients were categorized to adherence (MPR ≥ 80%) and non-adherence (MPR < 80%) groups. Ultimately, 3959 patients were enrolled: 60.4% and 39.6% in the adherence and non-adherence groups, respectively. The relative risk of acute exacerbation in the non-adherence group was 1.58 (95% confidence interval [CI] 1.25−1.99) compared with the adherence group. The adjusted logistic regression analysis revealed a relative risk of acute exacerbation in the non-adherence vs. adherence group of 1.68 (95% CI 1.32−2.14) regarding the number of inhalers used. Poor adherence to long-acting inhalers influenced increased acute exacerbation rates among patients with COPD. The acute exacerbation of COPD risk requiring hospitalization or ED visits was high in the non-adherence group, suggesting that efforts to improve medication adherence may help reduce COPD exacerbations even in the initial management of treatment-naïve patients.

Risk of Tuberculosis Caused by Fluticasone Propionate versus Budesonide in Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Study.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), inhaled corticosteroids (ICSs) are recommended for use by patients with frequent exacerbations and blood eosinophilia. However, ICSs are often inappropriately prescribed and overused. COPD studies have reported an increased risk of tuberculosis among ICS users. This study aimed to compare the risk of tuberculosis according to the different ICS components. METHODS: This study was conducted using a nationwide, population-based cohort. Patients newly diagnosed with COPD between 2005 and 2018, and treated with either fluticasone propionate or budesonide, were selected. The patients were followed up until the development of tuberculosis. RESULTS: After propensity score matching, 16,514 fluticasone propionate and 16,514 budesonide users were identified. The incidence rate of tuberculosis per 100,000 person-years was 274.73 for fluticasone propionate and 214.18 for budesonide. The hazard ratio of tuberculosis in fluticasone propionate compared with budesonide was 1.28 (95% confidence interval 1.05-1.60). The risk of tuberculosis for fluticasone propionate increased with higher ICS cumulative doses: 1.01 (0.69-1.48), 1.16 (0.74-1.81), 1.25 (0.79-1.97), and 1.82 (1.27-2.62) from the lowest to highest quartiles, respectively. CONCLUSION: Fluticasone propionate is associated with a higher risk of tuberculosis than budesonide. ICS components can differently affect the risk of tuberculosis in patients with COPD.

Relationship of computed tomography-verified degenerative condylar morphology with temporomandibular joint disk displacement and sex.

OBJECTIVE: This study investigated the association of computed tomography (CT)-verified degenerative condylar changes with disk displacement (DD) and sex. STUDY DESIGN: Multidetector CT and cone beam CT scans of 165 condyles were evaluated for erosion, osteophyte formation, flattening, subcortical sclerosis, generalized sclerosis, subcortical defects, and loose joint bodies. Disk position was determined using magnetic resonance imaging. The association of degenerative alterations with disk position and sex was analyzed. RESULTS: The risks of erosion, osteophyte formation, and flattening were significantly increased by 3.72, 9.00, and 6.35 times, respectively, in the joints with DD without reduction (DDNR); however, the risks of these changes did not increase significantly in joints with DD with reduction. The risks of extensive erosion and slight and moderate osteophyte formation significantly increased only in the joints with DDNR. The degenerative changes were more likely to exist together in the joints with DDNR than in those with a normal disk position. The association of DD and most degenerative morphologies was not significantly influenced by sex. CONCLUSIONS: Erosion, osteophyte formation, and flattening were significantly associated with DDNR, regardless of sex.

Influence of the Depth of the Convolutional Neural Networks on an Artificial Intelligence Model for Diagnosis of Orthognathic Surgery.

The aim of this study was to investigate the relationship between image patterns in cephalometric radiographs and the diagnosis of orthognathic surgery and propose a method to improve the accuracy of predictive models according to the depth of the neural networks. The study included 640 and 320 patients requiring non-surgical and surgical orthodontic treatments, respectively. The data of 150 patients were exclusively classified as a test set. The data of the remaining 810 patients were split into five groups and a five-fold cross-validation was performed. The convolutional neural network models used were ResNet-18, 34, 50, and 101. The number in the model name represents the difference in the depth of the blocks that constitute the model. The accuracy, sensitivity, and specificity of each model were estimated and compared. The average success rate in the test set for the ResNet-18, 34, 50, and 101 was 93.80%, 93.60%, 91.13%, and 91.33%, respectively. In screening, ResNet-18 had the best performance with an area under the curve of 0.979, followed by ResNets-34, 50, and 101 at 0.974, 0.945, and 0.944, respectively. This study suggests the required characteristics of the structure of an artificial intelligence model for decision-making based on medical images.

Changes in condylar dimensions in temporomandibular joints with disk displacement.

OBJECTIVES: The aim of this study was to investigate the condylar dimensions of the temporomandibular joint (TMJ) with respect to disk displacements and sex by using computed tomography (CT) and magnetic resonance imaging (MRI). STUDY DESIGN: Disk displacements were divided into 3 groups based on MRI findings: normal disk position (NR), disk displacement with reduction (DDR), and disk displacement without reduction (DDNR). After the angular and linear condylar dimensions were calculated from CT images, differences in condylar dimensions with respect to disk displacements and sex were analyzed with 2-way analysis of variance. RESULTS: Condylar depth and condylar height were significantly smaller in condyles with DDNR compared with those with NR or DDR (NR = DDR > DDNR). Condylar width gradually decreased significantly from NR to DDNR (NR > DDR > DDNR). The anterior condylar angle was significantly larger in condyles with NR compared with those with DDR or DDNR (NR > DDR = DDNR). Condyles with DDNR exhibited significantly larger horizontal condylar angles than those with NR or DDR (NR = DDR < DDNR). Altered condylar dimensions associated with disk displacement were not significantly different between men and women. CONCLUSIONS: Condylar dimensions may be significantly associated with disk displacements of the TMJ, irrespective of sex.

Medial knee osteoarthritis precedes medial meniscal posterior root tear with an event of painful popping.

BACKGROUND: An event of painful popping is a highly predictive clinical sign of medial meniscal posterior root tears (MMPRTs) in middle-aged to older patients. There are lacks of studies about the prevalence of a painful popping event and the condition of the medial compartment at the time of popping event in MMPRTs. HYPOTHESIS: We hypothesized that most of MMPRTs with a single painful popping event would show pre-existed pathologic medial meniscal extrusion (MME) and articular cartilage degeneration, and larger contact area of medial femoral condyle to medial tibial plateau could affect the MME. In addition, MME would be correlated with knee osteoarthritis. PATIENTS AND METHODS: Thirty-eight patients (mean age 58.5±10.5) who had painful popping within 3 weeks were included. On MRIs, absolute MME, relative percentage of extrusion (RPE), MME-medial femoral condyle (MFC)/medial tibial condyle (MTC) at 0° ratio, and medial compartments' Modified Outerbridge Scale (MOS) were evaluated. Kellgren-Lawrence (K-L) grade was also assessed. RESULTS: The MME parameters including absolute MME, RPE, and the ratio between MME and MFC/MTC at 0° were 2.9±1.2mm, 22.0±10.3%, and 3.2±1.3. Patients who with MOS and K-L grade≥2 were 33 (86.8%) and 32 (84.2%). Patients were divided into MME≥3mm (group G, n=20) and MME<3mm (groupL, n=18). The MME parameters were significantly greater in group G than group L (all, p<0.001). The group G had worse osteoarthritis progression in terms of MOS and K-L grade than the group L (p=0.035 and 0.077, respectively) MME≥3mm showed significantly association with MOS≥3 (p=0.045). DISCUSSION: More than 80% of MMPRT patients with an event of painful popping within 3 weeks showed that medial compartment degeneration preceded the event of popping. Therefore, identification of MME and articular cartilage degeneration at the time of painful popping in MMPRTs could be helpful when the surgeon determines the most appropriate treatment. LEVEL OF EVIDENCE: IV, Case-series.

Relationships between temporomandibular joint disk displacements and condylar volume.

OBJECTIVES: The aim of this study was to assess the relationship between mandibular condylar volume and disk displacement status in adult males and females. STUDY DESIGN: We evaluated 122 temporomandibular joints in 61 patients using magnetic resonance imaging (MRI) and computed tomography (CT). MRI data were used to assign disk status as normal disk position (NR), disk displacement with reduction (DDR), or disk displacement without reduction (DDNR). CT data were used to calculate total condylar volume and its components, cortical volume, and trabecular volume. The relationships among condylar volume, disk status, and gender were tested with 2-way analysis of variance. RESULTS: Condylar volumes significantly correlated with disk displacement, tending to decrease as displacement increased. There were significant differences in both total condylar volume and trabecular volume among the DD status (NR > DDR > DDNR), whereas cortical volume was significantly different only between NR/DDR and DDNR (NR/DDR > DDNR). The volume decreases associated with temporomandibular joint DD were found in both males and females, with greater decreases in men than in women as DD progressed. CONCLUSIONS: Condylar volumes are significantly associated with disk displacement status. Joints with nonreducing disks showed the smallest condylar volumes in both males and females.

The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation.

Because the dopaminergic pathways in the midbrain have been closely associated with serious neuropsychiatric disorders, the elucidation of the mechanisms underlying dopaminergic neuronal development should provide some important clues for related disorders. In mice lacking the dopamine D2 receptor (D2R-/-), stereological cell counting analysis showed that the number of mesencephalic tyrosine hydroxylase (TH) cells was significantly low during ontogeny, compared with that observed in wild-type (WT) mice, thereby indicating an alteration in dopaminergic neuronal development in the absence of D2R. The results of immunohistochemical and reverse transcription-PCR analyses revealed that the expression of Nurr1, an orphan nuclear receptor, as well as Ptx3 expression, was selectively reduced in D2R-/- mice during the embryonic stage. A reporter gene assay using the Nur response element linked to the luciferase reporter gene indicated that the stimulation of D2R results in the activation of the Nurr1-mediated reporter gene. This D2R-mediated Nur response element-dependent transcriptional activity was regulated via the activation of extracellular signal-regulated kinase (ERK). Furthermore, quinpirole treatment was shown to elicit an increase in the number of TH-positive neurons, as well as the neuritic extension of TH neurons, coupled with ERK activation and Nurr1 activation in the TH-positive neurons in primary mesencephalic cultures from WT mice. However, this regulation was not detected in the D2R-/- mice. These results suggest that signaling through D2R in association with Nurr1 using ERK, plays a critical role in mesencephalic dopaminergic neuronal development.