[Optimal search conditions for identification of patients with chronic myeloid leukemia from Japanese National Health Insurance data].

This study investigated which conditions could be used to identify patients with chronic myeloid leukemia (CML) from a National Health Insurance claims dataset. During April 2012 and September 2018, 1,789,462 employees were enrolled in the dataset for Shizuoka Prefecture residents. The number of patients with the ICD-10 code for CML was 761. Among them, 246 who had been prescribed a tyrosine kinase inhibitor were considered as having true CML. The positive predictive value was calculated as 32.3% when CML was identified by ICD-10 code alone. Combination of ICD-10 code with prescribed drugs was required to accurately identify patients with CML from the insurance database.

Longitudinal analysis of long-term outcomes of colorectal cancer after laparotomy and laparoscopic surgery: The Shizuoka study.

BACKGROUND: Long-term cancer prognosis after initial surgical procedures is an unlikely endpoint for clinical trials. Medical claim databases may aid in addressing this issue regardless of limited information on disease and patient background. However, the long-term prognosis (especially regarding long-term care needs) following surgical procedures remains unclear. This study aimed to assess whether long-term outcomes, such as the exacerbation of long-term care needs and mortality, differ with surgical methods. METHODS: Using a longitudinal study with linkage between medical claim and long-term care database, patients with primary colorectal cancer who underwent initial colonoscopies were identified through anonymized data in Japan (Shizuoka Kokuho Database, 2012-2018). Odds ratios (ORs) for long-term outcomes (long-term care needs and all-cause mortality during a 6.5-year follow-up period) were analyzed using logistic regression to compare laparoscopy and endoscopic surgery to laparotomy. RESULTS: Overall, 3,744 primary colorectal cancer cases (822 laparotomies, 705 laparoscopies, and 2,217 endoscopic surgeries) were included. Compared to the laparotomy group, the crude OR for exacerbation of long-term care needs in the laparoscopic surgery group was 0.376 (95% confidence interval, 0.227, 0.624), while the OR for all-cause mortality was 0.22 (0.329, 0.532). CONCLUSION: This is the first study to analyze long-term prognosis after surgery for patients with colorectal cancer to combine medical and long-term needs data. As the national health insurance claim database rarely includes information on cancer stage and comorbidities, better prognosis on endoscopic surgery may need careful interpretation. Therefore, laparoscopy has superior outcomes in terms of long-term care needs and mortality compared to those of laparotomy.

Mosaic TP53 Mutation on Tumour Development in Pigs: A Case Study.

Pigs rarely develop cancer; however, tumour protein p53 (TP53)-modified pigs may have an increased incidence of cancer. In this study, two pigs with mosaic mutations induced by gene editing were compared to determine the role of the wild-type TP53 sequence in tumorigenesis and to speculate how amino acid changes in TP53 sequences are related to tumorigenesis. The pig without tumours had a wild-type TP53 sequence and a 1-bp deletion in the TP53 sequence that resulted in a premature stop codon. In contrast, the pig with nephroblastoma had 6- and 7-bp deletions in the TP53 sequence, resulting in the absence of two amino acids and a premature stop codon, respectively. Our results indicated that TP53 mutations with truncated amino acids may be related to tumour formation.

Intratumoral Air Bubbles and Hematemesis As Predictors of Pseudoaneurysm Rupture in Unresected Pancreatic Cancer.

Objective Pseudoaneurysm rupture associated with unresected pancreatic cancer can cause rare but fatal hemobilia and gastrointestinal bleeding. This study aimed to identify factors predicting pseudoaneurysm rupture. Methods We conducted a single-center case-control study of unresected pancreatic cancer patients treated at Shizuoka General Hospital between January 2011 and July 2020 using a retrospective cancer registry database. Included in the study were 611 consecutive patients with unresected pancreatic cancer, of whom 55 developed overt upper gastrointestinal bleeding or hemobilia. Twenty patients were excluded, as they had not undergone contrast-enhanced computed tomography (CT) or angiography. Patients were classified into pseudoaneurysm and non-pseudoaneurysm groups. One patient with arterial bleeding but without obvious pseudoaneurysm was included in the pseudoaneurysm group. Factors predicting pseudoaneurysm rupture at the onset of overt gastrointestinal bleeding were investigated using a logistic regression analysis. CT findings revealing air bubbles inside the tumor were described as intratumoral air bubbles. Results Thirty-five patients were included (15 in the pseudoaneurysm group, 20 in the non-pseudoaneurysm group). In the multivariate analysis, intratumoral air bubbles [odds ratio (OR), 12.9; 95% confidence interval (CI), 2.14-77.9; p=0.005] and hematemesis (OR, 6.30; 95% CI, 1.03-38.6; p=0.047) were independent predictors of pseudoaneurysm rupture. In addition, patients who experienced successful hemostasis and were re-administered chemotherapy survived more than six months. Conclusion This study reveals that intratumoral air bubbles and hematemesis may predict pseudoaneurysm rupture at the onset of overt gastrointestinal bleeding. For patients presenting these findings, an examination with conventional or CT angiography may lead to an early diagnosis and improve the patient prognosis.

Nationwide survey of refractory asthma with bronchiectasis by inflammatory subtypes.

RATIONALE: Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. OBJECTIVE: We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. METHODS: We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. RESULTS: In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. CONCLUSIONS: Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.

Anatomy-based prediction method for determining ipsilateral lung doses in postoperative breast radiation therapy assisted by diagnostic computed tomography images.

Background: This study aimed to investigate whether ipsilateral lung doses (ILDs) could be predicted by anatomical indexes measured using diagnostic computed tomography (CT) prior to the planning stage of breast radiation therapy (RT). Materials and methods: The thoracic diameters and the length of lines drawn manually were measured on diagnostic CT images. The parameters of interest were the skin maximum lung distance (sMLD), central lung distance (CLD), Haller index (HI), and body mass index (BMI). Lung dose-volume histograms were created with conformal planning, and the lung volumes receiving 5-40 Gy (V5-V40) were calculated. Linear regression models were used to investigate the correlations between the anatomical indexes and dose differences and to estimate the slope and 95% confidence intervals (CIs). Results: A total of 160 patients who had undergone three-dimensional conformal RT after breast-conserving surgery were included. Univariable analysis revealed that the sMLD (p < 0.001), CLD (p < 0.001), HI (p = 0.002), and BMI (p < 0.001) were significantly correlated with the V20. However, multivariable analysis revealed that only the sMLD (slope: 0.147, p = 0.001, 95% CI: 0.162-0.306) and CLD (0.157, p = 0.005, 0.048-0.266) were strongly correlated with the V20. The p-value for the sMLD was the lowest among the p-values for all indexes, thereby indicating that the sMLD had the best predictive power for ILD. Conclusions: sMLD and CLD are anatomical markers that can be used to predict ILD in whole breast RT. An sMLD > 20.5 mm or a CLD > 24.3 mm positively correlated with a high ILD.

Unique membranous gastrin receptor expression of parietal cells and its distribution pattern in the gastric oxyntic mucosa and fundic gland polyps.

The aim of this study was to clarify the correlation between gastrin receptor (GR) expression in the gastric oxyntic mucosa and fundic gland polyps (FGPs) and the histological and immunohistochemical findings of the mucosa as well as the history of proton pump inhibitor (PPI) administration. The unique membranous linear positivity of GR in parietal cells was reproducibly observed by immunohistochemistry, which was also validated by immunofluorescence. Further histological and immunohistochemical examination of 34 oxyntic mucosae and 43 FGPs revealed the following: 1) parietal cells (PCs) with membranous linear GR expression (mGR) were observed to be limited to the isthmus-neck region in the normal state; 2) appearance of PCs with mGR in the deep oxyntic gland regions was significantly related to the PPI medication history; 3) PCs with mGR were more frequently observed in the deep oxyntic gland regions when the oxyntic mucosa showed derangement of mucosal component cell compartmentalization revealed by MUC5AC and MUC6 immunohistochemistry, which was also significantly related to the PPI use; and 4) PCs with intense membranous linear positivity of GR were observed to be diffusely distributed in all of the cases of FGPs. In conclusion, the distribution of unique GR membranous linear expression in PCs of the oxyntic mucosa under PPI medication and FGPs could reflect the pathologic mucosal state characterized by derangement of the compartmentalization of mucosal component cells, which could be another basis for evaluating physiologic and/or pathophysiologic conditions of the gastric mucosa.

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

A new susceptibility index to predict the risk of severe herpes zoster-associated pain: A Japanese regional population-based cohort study, the Shizuoka study.

BACKGROUND: Approximately 7-20% of patients with herpes zoster (HZ) develop zoster-associated pain (ZAP). ZAP not only impairs quality of life and psychological well-being, but also can reduce work effectiveness, which has negative economic effects. Reports of ZAP risk factors are inconsistent. OBJECTIVE: To confirm risk factors for the development of severe ZAP in HZ patients in Japan using a large-scale database, the Shizuoka Kokuho Database. METHODS: A population-based cohort study using the Shizuoka Kokuho Database was conducted. Of 792,647 patients, 7491 (0.95%) experienced "severe ZAP" (as defined in this study). We developed a ZAP risk prediction scoring system by identifying risk factors using logistic regression analysis of several candidate risk factors for severe ZAP: age, sex, seasonality, and presence of comorbidities (using the Charlson comorbidity index), excluding HIV/AIDS. RESULTS: We identified peripheral vascular disease and the onset from October to December as novel risk factors for severe ZAP, in addition to the previously reported risk factors of age and comorbidities (cerebral vascular disease, chronic pulmonary disease, rheumatic disease, peptic ulcer, liver disease, diabetes, and malignant neoplasms with/without metastasis). In contrast, dementia was found to reduce ZAP risk. We developed a susceptibility index to predict the risk of ZAP. CONCLUSION: We newly demonstrated that peripheral vascular disease and the onset from October to December are ZAP risk factors. Our comorbidity findings support previous observations. The susceptibility index proposed here provides a new approach to the prevention of ZAP using early intervention for high-risk patients.

Brachial artery transposition versus catheters as tertiary vascular access for maintenance hemodialysis: a single-center retrospective study.

Some hemodialysis patients are not suitable for creation of an arteriovenous fistula (AVF) or arteriovenous graft (AVG). However, they can receive a tunneled cuffed central venous catheter (tcCVC), but this carries risks of infection and mortality. We aimed to evaluate the safety and effectiveness of brachial artery transposition (BAT) versus those of tcCVC. This retrospective study evaluated hemodialysis patients who underwent BAT or tcCVC placement because of severe heart failure, hand ischemia, central venous stenosis or occlusion, inadequate vessels for creating standard arteriovenous access, or limited life expectancy. The primary outcome was whole access circuit patency. Thirty-eight patients who underwent BAT and 25 who underwent tcCVC placement were included. One-year patency rates for the whole access circuit were 84.6% and 44.9% in the BAT and tcCVC groups, respectively. The BAT group was more likely to maintain patency (unadjusted hazard ratio: 0.17, 95% confidence interval: 0.05-0.60, p = 0.006). The two groups did not have significantly different overall survival (log-rank p = 0.146), although severe complications were less common in the BAT group (3% vs. 28%, p = 0.005). Relative to tcCVC placement, BAT is safe and effective with acceptable patency in hemodialysis patients not suitable for AVF or AVG creation.

Data Resource Profile of Shizuoka Kokuho Database (SKDB) Using Integrated Health- and Care-insurance Claims and Health Checkups: The Shizuoka Study.

BACKGROUND: Analyzing real-world data, including health insurance claims, may help provide insights into preventing and treating various diseases. We developed a database covering Shizuoka Prefecture (Shizuoka Kokuho Database [SKDB]) in Japan, which included individual-level linked data on health- and care-insurance claims and health checkup results. METHODS: Anonymized claims data on health insurance (National Health Insurance [age <75 years] and Latter-Stage Elderly Medical Care System [age ≥75 years]), care insurance, subscriber lists, annual health checkups, and all dates of death were collected from 35 municipalities in Shizuoka Prefecture. To efficiently link claims and health checkups, unique individual IDs were assigned using a novel procedure. RESULTS: From April 2012 to September 2018, the SKDB included 2,230,848 individuals (men, 1,019,687; 45.7%). The median age (min-max) of men and women was 60 (0-106) and 62 (0-111) years, respectively. During the study period, the median subscription time was 4.4 years; 40.8% of individuals continuously subscribed for the 6.5 years; 213,566 individuals died. Health checkup data were available for 654,035 individuals, amounting to 2,469,648 records. Care-service recipient data were available for 283,537 individuals; they used care insurance to pay for care costs. CONCLUSION: SKDB, a population-based longitudinal cohort, provides a comprehensive dataset covering health checkups, disorders, medication, and care service. This database may provide a robust platform to identify epidemiological problems and generate hypotheses for preventing and treating disorders in the elderly.

Characteristics of and reasons for patients with chronic obstructive pulmonary disease to continue smoking, quit smoking, and switch to heated tobacco products.

INTRODUCTION: Smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and smoking cessation is the most effective treatment for patients with COPD. However, few studies have investigated the continuation/cessation of smoking and heated tobacco products (HTP) in patients with COPD. The objective of this study was to examine the characteristics of patients with COPD, those who are current smokers and those who switched from cigarettes to HTP, and to examine the reason for the continuation or cessation of smoking. METHODS: This multicenter, cross-sectional study included 411 outpatients with COPD. Data for this study were part of a study conducted for a comprehensive evaluation of the smoking status and clinical factors in patients with COPD and their families. RESULTS: Logistic regression analysis revealed that a younger age, longer duration of smoking, fewer daily cigarettes, and lower modified Medical Research Council (mMRC) dyspnea score, and a lower Simplified Nutritional Appetite Questionnaire (SNAQ) score for appetite, were characteristics of current smokers (age OR=0.94; duration of smoking OR=1.07; number of cigarettes per day OR=0.94; mMRC OR=0.68; SNAQ OR=0.83; p<0.05). The logistic regression analysis model showed that a younger age and higher education level were associated with the use of HTP (age OR=0.83; higher education level OR=4.63; p<0.05). Many of the current smokers displayed smoking behaviors that are not guaranteed to be safe, such as reducing smoking or switching to lighter cigarettes or HTP. CONCLUSIONS: Patients with COPD who continue smoking tended to have low appetite as well as smoking behaviors that are not guaranteed to be safe. Physicians should provide appropriate guidance to these patients on smoking cessation.

Oxytetracycline-hydrocortisone ointment reduces the occurrence of both dry socket and post-extraction pain after third molar extraction: An observational study.

OBJECTIVES: Dry socket and post-extraction pain are typical discomforts experienced by patients after tooth extraction. In this study, we inserted gauze coated with oxytetracycline-hydrocortisone ointment into the extraction socket immediately after lower third molar extraction and then evaluated the occurrence of dry socket and post-extraction pain compared with gauze non-insertion. METHODS: This retrospective study was carried out on patients undergoing lower third molar extraction in the Department of Oral Surgery at Shizuoka Prefectural General Hospital in Shizuoka, Japan from November 2018 to October 2019. A comparison was carried out between a gauze-insertion group and a non-insertion group. The occurrence versus non-occurrence of dry socket was determined, and degree of pain was assessed based on a visual analogue scale (VAS) and on patients reporting the number of loxoprofen sodium oral analgesic tablets (60mg/tablet) that they had taken. Dry socket was defined as patient-reported spontaneous pain that did not subside 1 to 3 days postoperatively. Spontaneous post-extraction pain was recorded four times: on the operative day, on the first postoperative day (POD1), on POD3, and during suture removal (POD7). RESULTS: The occurrence of dry socket was lower in the gauze-insertion group than in the non-insertion group (0.9%, 2/215 vs. 19.6%, 9/46, p<0.001). The results also showed that both VAS-defined pain level and the number of analgesic tablets taken were lower in the gauze-insertion group than in the non-insertion group on POD3 and POD7. CONCLUSIONS AND CLINICAL RELEVANCE: Inserting gauze coated with oxytetracycline-hydrocortisone ointment into the extraction socket immediately after third molar extraction reduces the occurrence of both dry socket and post-extraction pain.

Statin Exposure and Pancreatic Cancer Incidence: A Japanese Regional Population-Based Cohort Study, the Shizuoka Study.

Preclinical studies suggest that statins contribute to the prevention of pancreatic cancer; however, the results of epidemiologic studies are inconsistent. Furthermore, sufficient data are unavailable for the general population of Asia. Here, we conducted an observational study using a comprehensive patient-linked, longitudinal health insurance database comprising the records of 2,230,848 individuals residing in Shizuoka Prefecture, Japan, from April 2012 to September 2018. We included individuals older than 40 years with data for medical examinations and statin exposure (≥365 statin prescription days). To balance baseline characteristics between the statin exposure and statin nonexposure groups, we used inverse probability of treatment propensity score weighting method. We estimated hazard ratios for associations with pancreatic cancer using the Cox proportional hazards regression model. Among 2,230,848 individuals, we included 100,537 in the statin exposure group (24%) and 326,033 in the statin nonexposure group (76%). Among the statin exposure group (352,485 person-years) and the statin nonexposure group (1,098,463 person-years), 394 (1.12 per 1,000 person-years) and 1176 (1.07 per 1,000 person-years) developed pancreatic cancer, respectively (P = 0.464). After adjustments using inverse probability of treatment weighting, the statin exposure group was associated with a decreased incidence of pancreatic cancer (hazard ratio, 0.84; 95% confidence intervals, 0.72-0.99; P = 0.036). In conclusion, the current Japanese regional population-based cohort study shows that statin exposure was associated with a lower incidence of pancreatic cancer. PREVENTION RELEVANCE: This study may support the possible role of statins in preventing pancreatic cancer in the general population in Japan.

Modified Glasgow Prognostic Score is predictive of prognosis for non-small cell lung cancer patients treated with stereotactic body radiation therapy: a retrospective study.

We aimed to assess the predictive value of the modified Glasgow prognostic score (mGPS) in patients with non-small cell lung cancer (NSCLC) who underwent stereotactic body radiation therapy (SBRT). We retrospectively reviewed the records of 207 patients, with a median age of 79 years. The pretreatment mGPS was calculated and categorized as high (mGPS = 1-2) or low (mGPS = 0). The median follow-up duration was 40.7 months. The five-year overall survival (OS), progression-free survival (PFS) and time to progression (TTP) rates were 44.3%, 36% and 54.4%, respectively. Multivariate analysis revealed that mGPS was independently predictive of OS (hazard ratio [HR] 1.67; 95% confidence interval 1.14-2.44: P = 0.009), PFS (HR 1.58; 1.10-2.28: P = 0.014) and TTP (HR 1.66; 1.03-2.68: P = 0.039). Patients who had high mGPS showed significantly worse OS (33.3 vs 64.5 months, P = 0.003) and worse PFS (23.8 vs 39 months, P = 0.008) than those who had low mGPS. The data showed a trend that patients with high mGPS suffered earlier progression compared to those with low mGPS (54.3 vs 88.1 months, P = 0.149). We confirmed that mGPS is independently predictive of prognosis in NSCLC patients treated with SBRT.

Efficacy of Bioshell Calcium Oxide Water as Disinfectants to Enable Face Mask Reuse.

Bioshell calcium oxide (BiSCaO) is derived from scallop shells and after heat treatment exhibits broad microbicidal activity. BiSCaO Water is a disinfectant prepared by collecting the aqueous layer after adding BiSCaO powder to water, is colorless and transparent, and has a pH of 12.8. We compared the utility of commercially available BiSCaO Water, ethanol, sodium hypochlorite, hypochlorous acid and hydrogen peroxide solutions as sterilization agents to enable the reuse of surgical and N95 face masks. The microbicidal efficacy of each disinfectant was evaluated using pieces of surgical and N95 face masks contaminated with normal bacterial flora. The results suggest that BiSCaO Water has excellent disinfection activity toward contaminated polypropylene masks and has minimal adverse effect on the structure of non-woven masks.

Introduction of a point mutation in the KRAS gene of in vitro fertilized porcine zygotes via electroporation of the CRISPR/Cas9 system with single-stranded oligodeoxynucleotides.

This study aimed to investigate the efficiency of KRAS gene editing via CRISPR/Cas9 delivery by electroporation and analyzed the effects of the non-homologous end-joining pathway inhibitor Scr7 and single-stranded oligodeoxynucleotide (ssODN) homology arm length on introducing a point mutation in KRAS. Various concentrations (0-2 µM) of Scr7 were evaluated; all concentrations of Scr7 including 0 µM resulted in the generation of blastocysts with a point mutation and the wild-type sequence or indels. No significant differences in the blastocyst formation rates of electroporated zygotes were observed among ssODN homology arm lengths, irrespective of the gRNA (gRNA1 and gRNA2). The proportion of blastocysts carrying a point mutation with or without the wild-type sequence and indels was significantly higher in the ssODN20 group (i.e., the group with a ssODN homology arm of 20 bp) than in the ssODN60 group (gRNA1: 25.7% vs. 5.4% and gRNA2: 45.5% vs. 5.9%, p < .05). In conclusion, the CRISPR/Cas9 delivery with ssODN via electroporation is feasible for the generation of point mutations in porcine embryos. Further studies are required to improve the efficiency and accuracy of the homology-directed repair.

Histopathologic Change of a Case of Gastric Oxyntic Neoplasm (Gastric Adenocarcinoma of Fundic Gland Mucosa Type) Through 5 Years With Concurrent Other Oxyntic Gland Lesions.

Some gastric epithelial neoplasms show predominant chief cell differentiation (oxyntic gland neoplasms), in which the entity of "gastric adenocarcinoma of fundic gland type" was firstly designated, whereas a possible more aggressive subgroup "gastric adenocarcinoma of fundic gland mucosa type" (GA-FGM) was subsequently proposed. However, the histopathologic progression mode of these neoplasms has not been sufficiently reported. In this article, we describe a case of GA-FGM in which we could observe its progression during 5 years. The tumor was removed by endoscopic submucosal dissection 5 years after the first biopsy, which had already shown a feature of oxyntic gland neoplasm. During the follow-up period, the endoscopy revealed little change in the tumor appearance. However, the histology of endoscopic submucosal dissection showed submucosal extension with its histological progression. Besides, other oxyntic gland neoplasms of the stomach were observed metachronously or synchronously, giving an implication about a common pathogenetic basis of these lesions.

Prenatal exposure to nicotine disrupts synaptic network formation by inhibiting spontaneous correlated wave activity.

Correlated spontaneous activity propagating over a wide region of the central nervous system is expressed during a specific period of embryonic development. We previously demonstrated using an optical imaging technique with a voltage-sensitive dye that this wave-like activity, which we referred to as the depolarization wave, is fundamentally involved in the early process of synaptic network formation. We found that the in ovo application of bicuculline/strychnine or d-tubocurarine, which blocked the neurotransmitters mediating the wave, significantly reduced functional synaptic expression in the brainstem sensory nucleus. This result, particularly for d-tubocurarine, an antagonist of nicotinic acetylcholine receptors, suggested that prenatal nicotine exposure associated with maternal smoking affects the development of neural circuit formation by interfering with the correlated wave. In the present study, we tested this hypothesis by examining the effects of nicotine on the correlated activity and assessing the chronic action of nicotine in ovo on functional synaptic expression along the vagal sensory pathway. In ovo observations of chick embryo behavior and electrical recording using in vitro preparations showed that the application of nicotine transiently increased embryonic movements and electrical bursts associated with the wave, but subsequently inhibited these activities, suggesting that the dominant action of the drug was to inhibit the wave. Optical imaging with the voltage-sensitive dye showed that the chronic exposure to nicotine in ovo markedly reduced functional synaptic expression in the higher-order sensory nucleus of the vagus nerve, the parabrachial nucleus. The results suggest that prenatal nicotine exposure disrupts the initial formation of the neural circuitry by inhibiting correlated spontaneous wave activity.