A single-sided trans-nasal catheter for smooth and efficient oxygen delivery can improve the safety in patients undergoing pancreato-biliary endoscopy under intravenous sedation: A randomized trial.

Background: Pancreato-biliary endoscopic procedures often need to be performed under deep intravenous sedation. The patients are at an increased risk of respiratory depression influenced by the anatomical dead space of the upper respiratory system. We aimed to evaluate the benefit of oxygen delivery through a single-sided trans-nasal catheter (TC) for patients undergoing pancreato-biliary endoscopy. Methods: Oxygen supplementation during the procedure was provided either by insertion of a single-sided TC or insertion of a conventional nasal catheter (NC). A prospective, single-blind, randomized controlled study was conducted in two groups. Results: The number of patients who indicated a decrease in the peripheral transcutaneous oxygen saturation (SpO2; desaturation) was significantly lower in the TC group than in the counterpart (8/58; 13.8% vs. 26/58; 44.8% p < 0.001). The efficient oxygen delivery in the safe range was better conserved in the TC group than in the NC one. There was no adverse effect on both groups. The maximum SpO2 while the endoscopic procedure was significantly higher in the TC group (99.7% vs. 99.3% p = 0.016) and the minimum SpO2 was also significantly higher in the same group (97.7% vs. 94.1% p < 0.0001), which meant that the efficient oxygen delivery was better maintained in TC group than the NC group. Conclusions: A single-sided TC placed in the pharynx in patients undergoing pancreato-biliary endoscopy prepares a superior condition of the patients for venous sedation, maintained hyper-oxygen saturation and a relatively higher SpO2 level to be maintained in limited conditions to reduce the dead space with acceptable tolerance, as compared to the placement of a conventional NC.

Deficiency of the circadian clock gene Rev-erbα induces mood disorder-like behaviours and dysregulation of the serotonergic system in mice.

Mood disorders such as depression, anxiety, and bipolar disorder are highly associated with disrupted daily rhythms of activity, which are often observed in shift work and sleep disturbance in humans. Recent studies have proposed the REV-ERBα protein as a key circadian nuclear receptor that links behavioural rhythms to mood regulation. However, how the Rev-erbα gene participates in the regulation of mood remains poorly understood. Here, we show that the regulation of the serotonergic (5-HTergic) system, which plays a central role in stress-induced mood behaviours, is markedly disrupted in Rev-erbα-/- mice. Rev-erbα-/- mice exhibit both negative and positive behavioural phenotypes, including anxiety-like and mania-like behaviours, when subjected to a stressful environment. Importantly, Rev-erbα-/- mice show a significant decrease in the expression of a gene that encodes the rate-limiting enzyme of serotonin (5-HT) synthesis in the raphe nuclei (RN). In addition, 5-HT levels in Rev-erbα-/- mice are significantly reduced in the prefrontal cortex, which receives strong inputs from the RN and controls stress-related behaviours. Our findings indicate that Rev-erbα plays an important role in controlling the 5-HTergic system and thus regulates mood and behaviour.

[A case of unresectable advanced gastric cancer with oral mucosal necrosis during combination therapy with nab-paclitaxel plus ramucirumab].

A 61-year-old patient with advanced gastric cancer was treated with ramucirumab plus albumin-suspended paclitaxel as second-line treatment. The treatment resulted in exposure of the right mandible around an implant. The implant was removed, and sequestration was not observed. The patient was diagnosed with oral mucosal necrosis. Thus, implants may cause mucosal necrosis due to angiogenesis inhibitors.

Employment factors associated with daily time management in working people with type 2 diabetes.

AIM: To determine the employment factors associated with daily time management in working people with type 2 diabetics. METHODS: A questionnaire survey was administered to 277 working people with type 2 diabetes. It included a daily time management scale, and questions about age, gender, hemoglobin A1c levels, shift work, managerial position, and average working hours. Multiple regression analysis was used to assess the relationship between daily time management and each factor, adjusted for age, gender, and hemoglobin A1c. RESULTS: Responses were obtained from 220 individuals. Daily time management was associated with managerial position (being a manager) and working hours. Shift work was associated with "adjustment of life rhythms" and managerial position was associated with "adjustment of work" and "goal setting and behaviors consistent with personal values". Hours of work were associated with "adjustment of life rhythms" and "time control". CONCLUSION: When providing support on time management to working people with type 2 diabetes mellitus, any assessment should consider the availability of shift work, whether they are in a managerial position and working hours.

Contribution of chemotherapy to improved prognosis in stage 4 gastric cancer: trend analysis of a regional population-based cancer registry in Japan.

OBJECTIVES: Little is known about time trends in the prognosis of gastric cancer (GC), since the introduction of new chemotherapeutic agents. This study aimed to analyze how the increased number of available chemotherapeutic options affected the prognosis of GC and which patient types benefited within in a large population. METHODS: From a population-based cancer registry in Japan, 35,751 cases of GC were identified. Of these, 8214 cases were stage 4. The time trend for 3-year survival in stage 4 GC according to patient characteristics (age and tumor location) was estimated in relation to the introduction of new anticancer drugs. Multiple imputation was performed for sensitivity analysis to strengthen the missing data. In addition, we estimated the 5-year survival rate for distal-GC (DGC) and proximal-GC (PGC), and the hazard ratio (HR) was estimated by Cox proportional hazard model. RESULTS: Improvement of overall survival was accelerated in stage 4 cases over time. The prognosis was improved from 11.4% to 13.2%, subsequent to the approval of several oncologic drugs since 2009. Younger patients were more likely to have improved survival rates in response to the increase in chemotherapy options (< 60-year-old, 5.4%: 60-70, 2.2%; 70-80, 0.3%) from 2007 to 2015. The HR for DGC vs. PGC was 1.11 (95% CI 1.08-1.15), and PGC showed a higher rate of improved outcomes (2.4% vs. 0.6%). CONCLUSIONS: This analysis showed that improvement in the GC survival rate was accelerated by the introduction of new chemotherapeutic strategies and it was most evident among younger patients and in patients with PGC.

Adverse Effects of Circadian Disorganization on Mood and Molecular Rhythms in the Prefrontal Cortex of Mice.

Disturbance of the daily cycles in sleep and wakefulness induced by conditions such as shift work and jet lag can increase the risk of affective disorders including anxiety and depression. The way such circadian disorganization disrupts the regulation of mood, however, is not well understood. More specifically, the impact of circadian disorganization on the daily rhythms of the neuronal function that controls mood remains unclear. We therefore investigated the effects of circadian disorganization on expression rhythms of clock genes as well as immediate early genes (IEGs) in several mood-controlling regions of the brain. To introduce circadian disorganization of behaviors, we exposed male C57BL/6J mice to chronic reversal of the light-dark cycle and we found a marked negative mood phenotype in these mice. Importantly, the most adverse effect of circadian disorganization on expression rhythms of clock and IEGs was observed in the prefrontal cortex (PFC) when compared to that in other mood-related areas of the brain. Dysregulation of molecular rhythms in the PFC is therefore suggested to be associated with the development of mood disorders in conditions including shift work and jet lag.

Thyroid storm with delayed hyperbilirubinemia and severe heart failure: indication and contraindication of plasma exchange.

SUMMARY: Thyroid storm (TS) is a life-threatening condition that may suffer thyrotoxic patients. Therapeutic plasma exchange (TPE) is a rescue approach for TS with acute hepatic failure, but it should be initiated with careful considerations. We present a 55-year-old male patient with untreated Graves' disease who developed TS. Severe hyperthyroidism and refractory atrial fibrillation with congestive heart failure aggregated to multiple organ failure. The patient was recovered by intensive multimodal therapy, but we had difficulty in introducing TPE treatment considering the risk of exacerbation of congestive heart failure due to plasma volume overload. In addition, serum total bilirubin level was not elevated in the early phase to the level of indication for TPE. The clinical course of this patient instructed delayed elevation of bilirubin until the level of indication for TPE in some patients and also demonstrated the risk of exacerbation of congestive heart failure by TPE. LEARNING POINTS: Our patient with thyroid storm could be diagnosed and treated promptly using Japan Thyroid Association guidelines for thyroid storm. Delayed elevation of serum bilirubin levels could make the decision of introducing therapeutic plasma exchange difficult in cases of thyroid storm with acute hepatic failure. The risk of worsening congestive heart failure should be considered carefully when performing therapeutic plasma exchange.

Development of the Daily Time Management Scale for Use by Working People with Type 2 Diabetes.

AIM: The purpose of this study was to develop a scale to assess daily time management capabilities among working patients with diabetes and to test this scale's reliability and validity. METHODS: A self-administered questionnaire survey was conducted among 277 diabetes outpatients, and data from 220 participants (mean age = 54.3 ± 10.2 years, 76.8% male) were analyzed. Questionnaire items were selected through exploratory factor analysis. During the process of developing the questionnaire, opinions were solicited from experts on education for patients with diabetes, and Cronbach's α was calculated as a coefficient of reliability. Correlations with the Instrument of Diabetes Self-Care Agency (IDSCA) were examined and confirmatory factor analysis was performed to check for validity. RESULTS: Adequacy of a 4-factor, 16-item scale was confirmed. Cronbach's α coefficient was ≥.7 for the entire scale and for the subscale items. There was a significant correlation between total IDSCA scores and various factors (r = .280-.469). However, there was no correlation between the "adjustment of life rhythms" and parts of the IDSCA subscale. CONCLUSION: Although some aspects warrant further investigation, the developed scale provides a reliable and valid means of assessing daily time management capabilities among working patients with diabetes, and can thus be applied to help diabetes patients to manage their daily lives.

Dec1 Deficiency Suppresses Cardiac Perivascular Fibrosis Induced by Transverse Aortic Constriction.

Cardiac fibrosis is a major cause of cardiac dysfunction in hypertrophic hearts. Differentiated embryonic chondrocyte gene 1 (Dec1), a basic helix-loop-helix transcription factor, has circadian expression in the heart; however, its role in cardiac diseases remains unknown. Therefore, using Dec1 knock-out (Dec1KO) and wild-type (WT) mice, we evaluated cardiac function and morphology at one and four weeks after transverse aortic constriction (TAC) or sham surgery. We found that Dec1KO mice retained cardiac function until four weeks after TAC. Dec1KO mice also revealed more severely hypertrophic hearts than WT mice at four weeks after TAC, whereas no significant change was observed at one week. An increase in Dec1 expression was found in myocardial and stromal cells of TAC-treated WT mice. In addition, Dec1 circadian expression was disrupted in the heart of TAC-treated WT mice. Cardiac perivascular fibrosis was suppressed in TAC-treated Dec1KO mice, with positive immunostaining of S100 calcium binding protein A4 (S100A4), alpha smooth muscle actin (αSMA), transforming growth factor beta 1 (TGFß1), phosphorylation of Smad family member 3 (pSmad3), tumor necrosis factor alpha (TNFα), and cyclin-interacting protein 1 (p21). Furthermore, Dec1 expression was increased in myocardial hypertrophy and myocardial infarction of autopsy cases. Taken together, our results indicate that Dec1 deficiency suppresses cardiac fibrosis, preserving cardiac function in hypertrophic hearts. We suggest that Dec1 could be a new therapeutic target in cardiac fibrosis.

Efficacy of Upper Gastrointestinal Endoscopic Examination to Identify Patients with Obstructive Sleep Apnea Syndrome: A Retrospective Cross-Sectional Study.

BACKGROUND/AIMS: Despite the high prevalence of obstructive sleep apnea syndrome (OSAS), most individuals are unaware of its diagnosis. We assessed whether an upper gastrointestinal (GI) endoscopy can accurately predict the incidence of OSAS. METHODS: After endoscopic evaluation of laryngo-pharyngeal collapse, a total of 154 subjects with laryngo-pharyngeal collapse and 52 control subjects underwent polysomnography. Based on the modified Fujita Classification, upper airway obstruction was classified into 3 different types: oropharyngeal, supraglottic and combined type, and associations between upper airway obstruction and OSAS were evaluated. RESULTS: Of 154 subjects with laryngo-pharyngeal collapse, 108 (70.1%) were diagnosed as OSAS, while only 4 (7.7%) control subjects were diagnosed as OSAS (p < 0.001). The sensitivity and specificity of endoscopic diagnosis were 96.4 and 51.1%, respectively. Oropharyngeal involvement was frequently found in 90.2% of the subjects (139/154). The severity of upper airway obstruction was significantly correlated with the apnea-hypopnea index score (r = 0.55, p < 0.001). A multivariate logistic regression analysis revealed that a male sex (OR 5.20; 95% CI 2.65-10.2, p < 0.001), body mass index ≥25 kg/m2 (OR 4.98; 95% CI 2.23-11.2, p = 0.02) and severe obstruction (OR 7.79; 95% CI 3.34-18.2, p < 0.001) were significant independent predictors of severe OSAS. CONCLUSION: A conventional upper GI endoscopic examination might be useful as a diagnostic modality for OSAS.

Clinical Outcomes of Patients with Small Rectal Neuroendocrine Tumors Treated Using Endoscopic Submucosal Resection with a Ligation Device.

BACKGROUND/AIMS: The therapeutic strategies for small rectal neuroendocrine tumors (NETs) have not been standardized. We examined the efficacy and safety of endoscopic submucosal resection with a ligation device (ESMR-L) and the long-term outcomes after endoscopic treatment. METHODS: A total of 181 patients with rectal NETs <10 mm who were treated between May 2002 and May 2017 were retrospectively enrolled. All the lesions had been resected using ESMR-L, and the follow-up strategies were determined according to the pathological examinations. The long-term outcomes after a 53-month follow-up period were also evaluated. RESULTS: R0 resection was achieved in 180 cases (99.4%). Lymphovascular invasion was confirmed in 67 cases (37.0%), while a curative resection was achieved in 114 cases (63.0%). One perforation (0.6%) and 11 cases with delayed bleeding (6.1%) were observed. A multivariate logistic regression analysis revealed that a tumor size > 5 mm (OR 2.06; 95% CI 1.04-4.08, p = 0.04) was a significant independent predictor of the presence of lymphovascular invasion. Of the 67 patients with non-curative resections, 11 patients underwent additional surgery; lymph node metastasis was confirmed in 2 cases (18.2%). No local or distant metastases were observed during the follow-up period in 77 patients with a curative resection, 9 patients who received additional surgery, and 50 patients with non-curative resections. CONCLUSION: ESMR-L is an easy, safe and effective treatment for rectal NETs <10 mm in diameter, and the prognosis of patients seems to be good, despite a relatively high rate of lymphovascular invasion.

Lung-Derived Exosomal miR-483-3p Regulates the Innate Immune Response to Influenza Virus Infection.

Exosomes regulate cell-cell communication by transferring functional proteins and RNAs between cells. Here, to clarify the function of exosomes during influenza virus infection, we characterized lung-derived exosomal microRNAs (miRNAs). Among the detected miRNAs, miR-483-3p was present at high levels in bronchoalveolar lavage fluid (BALF) exosomes during infection of mice with various strains of influenza virus, and miR-483-3p transfection potentiated gene expression of type I interferon and proinflammatory cytokine upon viral infection of MLE-12 cells. RNF5, a regulator of the RIG-I signaling pathway, was identified as a target gene of miR-483-3p. Moreover, we found that CD81, another miR-483-3p target, functions as a negative regulator of RIG-I signaling in MLE-12 cells. Taken together, this study indicates that BALF exosomal miRNAs may mediate the antiviral and inflammatory response to influenza virus infection.

Impact of heart-specific disruption of the circadian clock on systemic glucose metabolism in mice.

The daily rhythm of glucose metabolism is governed by the circadian clock, which consists of cell-autonomous clock machineries residing in nearly every tissue in the body. Disruption of these clock machineries either environmentally or genetically induces the dysregulation of glucose metabolism. Although the roles of clock machineries in the regulation of glucose metabolism have been uncovered in major metabolic tissues, such as the pancreas, liver, and skeletal muscle, it remains unknown whether clock function in non-major metabolic tissues also affects systemic glucose metabolism. Here, we tested the hypothesis that disruption of the clock machinery in the heart might also affect systemic glucose metabolism, because heart function is known to be associated with glucose tolerance. We examined glucose and insulin tolerance as well as heart phenotypes in mice with heart-specific deletion of Bmal1, a core clock gene. Bmal1 deletion in the heart not only decreased heart function but also led to systemic insulin resistance. Moreover, hyperglycemia was induced with age. Furthermore, heart-specific Bmal1-deficient mice exhibited decreased insulin-induced phosphorylation of Akt in the liver, thus indicating that Bmal1 deletion in the heart causes hepatic insulin resistance. Our findings revealed an unexpected effect of the function of clock machinery in a non-major metabolic tissue, the heart, on systemic glucose metabolism in mammals.

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets.

Low pathogenic H7N9 influenza viruses have recently evolved to become highly pathogenic, raising concerns of a pandemic, particularly if these viruses acquire efficient human-to-human transmissibility. We compared a low pathogenic H7N9 virus with a highly pathogenic isolate, and two of its variants that represent neuraminidase inhibitor-sensitive and -resistant subpopulations detected within the isolate. The highly pathogenic H7N9 viruses replicated efficiently in mice, ferrets, and/or nonhuman primates, and were more pathogenic in mice and ferrets than the low pathogenic H7N9 virus, with the exception of the neuraminidase inhibitor-resistant virus, which showed mild-to-moderate attenuation. All viruses transmitted among ferrets via respiratory droplets, and the neuraminidase-sensitive variant killed several of the infected and exposed animals. Neuraminidase inhibitors showed limited effectiveness against these viruses in vivo, but the viruses were susceptible to a polymerase inhibitor. These results suggest that the highly pathogenic H7N9 virus has pandemic potential and should be closely monitored.

Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development.

Epigenetic regulation is required to ensure the precise spatial and temporal pattern of gene expression that is necessary for embryonic development. Although the roles of some epigenetic modifications in embryonic development have been investigated in depth, the role of methylation at lysine 79 (H3K79me) is poorly understood. Dot1L, a unique methyltransferase for H3K79, forms complexes with distinct sets of co-factors. To further understand the role of H3K79me in embryogenesis, we generated a mouse knockout of Mllt10, the gene encoding Af10, one Dot1L complex co-factor. We find homozygous Mllt10 knockout mutants (Mllt10-KO) exhibit midline facial cleft. The midfacial defects of Mllt10-KO embryos correspond to hyperterolism and are associated with reduced proliferation of mesenchyme in developing nasal processes and adjacent tissue. We demonstrate that H3K79me level is significantly decreased in nasal processes of Mllt10-KO embryos. Importantly, we find that expression of AP2α, a gene critical for midfacial development, is directly regulated by Af10-dependent H3K79me, and expression AP2α is reduced specifically in nasal processes of Mllt10-KO embryos. Suppression of H3K79me completely mimicked the Mllt10-KO phenotype. Together these data are the first to demonstrate that Af10-dependent H3K79me is essential for development of nasal processes and adjacent tissues, and consequent midfacial formation.

Glycosylation of the Hemagglutinin Protein of H5N1 Influenza Virus Increases Its Virulence in Mice by Exacerbating the Host Immune Response.

The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to circulate in nature and threaten public health. Although several viral determinants and host factors that influence the virulence of HPAI H5N1 viruses in mammals have been identified, the detailed molecular mechanism remains poorly defined and requires further clarification. In our previous studies, we characterized two naturally isolated HPAI H5N1 viruses that had similar viral genomes but differed substantially in their lethality in mice. In this study, we explored the molecular determinants and potential mechanism for this difference in virulence. By using reverse genetics, we found that a single amino acid at position 158 of the hemagglutinin (HA) protein substantially affected the systemic replication and pathogenicity of these H5N1 influenza viruses in mice. We further found that the G158N mutation introduced an N-linked glycosylation at positions 158 to 160 of the HA protein and that this N-linked glycosylation enhanced viral productivity in infected mammalian cells and induced stronger host immune and inflammatory responses to viral infection. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals.IMPORTANCE Highly pathogenic avian influenza (HPAI) H5N1 viruses continue to evolve in nature and threaten human health. Key mutations in the virus hemagglutinin (HA) protein or reassortment with other pandemic viruses endow HPAI H5N1 viruses with the potential for aerosol transmissibility in mammals. A thorough understanding of the pathogenic mechanisms of these viruses will help us to develop more effective control strategies; however, such mechanisms and virulent determinants for H5N1 influenza viruses have not been fully elucidated. In this study, we identified glycosylation at positions 158 to 160 of the HA protein of two naturally occurring H5N1 viruses as an important virulence determinant. This glycosylation event enhanced viral productivity, exacerbated the host response, and thereby contributed to the high pathogenicity of H5N1 virus in mice.

Catalytic function of the mycobacterial binuclear iron monooxygenase in acetone metabolism.

Mycobacteria such as Mycobacterium smegmatis strain mc(2)155 and Mycobacterium goodii strain 12523 are able to grow on acetone and use it as a source of carbon and energy. We previously demonstrated by gene deletion analysis that the mimABCD gene cluster, which encodes a binuclear iron monooxygenase, plays an essential role in acetone metabolism in these mycobacteria. In the present study, we determined the catalytic function of MimABCD in acetone metabolism. Whole-cell assays were performed using Escherichia coli cells expressing the MimABCD complex. When the recombinant E. coli cells were incubated with acetone, a product was detected by gas chromatography (GC) analysis. Based on the retention time and the gas chromatography-mass spectrometry (GC-MS) spectrum, the reaction product was identified as acetol (hydroxyacetone). The recombinant E. coli cells produced 1.02 mM of acetol from acetone within 24 h. Furthermore, we demonstrated that MimABCD also was able to convert methylethylketone (2-butanone) to 1-hydroxy-2-butanone. Although it has long been known that microorganisms such as mycobacteria metabolize acetone via acetol, this study provides the first biochemical evidence for the existence of a microbial enzyme that catalyses the conversion of acetone to acetol.

The circadian clock maintains cardiac function by regulating mitochondrial metabolism in mice.

Cardiac function is highly dependent on oxidative energy, which is produced by mitochondrial respiration. Defects in mitochondrial function are associated with both structural and functional abnormalities in the heart. Here, we show that heart-specific ablation of the circadian clock gene Bmal1 results in cardiac mitochondrial defects that include morphological changes and functional abnormalities, such as reduced enzymatic activities within the respiratory complex. Mice without cardiac Bmal1 function show a significant decrease in the expression of genes associated with the fatty acid oxidative pathway, the tricarboxylic acid cycle, and the mitochondrial respiratory chain in the heart and develop severe progressive heart failure with age. Importantly, similar changes in gene expression related to mitochondrial oxidative metabolism are also observed in C57BL/6J mice subjected to chronic reversal of the light-dark cycle; thus, they show disrupted circadian rhythmicity. These findings indicate that the circadian clock system plays an important role in regulating mitochondrial metabolism and thereby maintains cardiac function.

Carnosine and anserine ingestion enhances contribution of nonbicarbonate buffering.

PURPOSE: The purpose of the present study was to investigate the effect of supplementation with chicken breast extract (CBEX), which was a rich source of carnosine and anserine, on acid-base balance and performance during intense intermittent exercise. METHODS: Eight male subjects performed intense intermittent exercise that consisted of 10 x 5-s maximal cycle ergometer sprints with a 25-s recovery period between each sprint. The subjects ingested 190 g of the test soup containing either CBEX or a placebo 30 min before the commencement of exercise. Arterial blood samples were collected at rest and during exercise to estimate the carnosine and anserine concentrations, pH, and bicarbonate concentration ([HCO3-]). RESULTS: Concentrations of anserine and its related amino acid significantly increased 30 min after CBEX supplementation, as compared with their values at rest. However, carnosine did not increase significantly. Following CBEX supplementation, the pH was significantly higher (P < 0.05) at the end of exercise, and [HCO3-] was also significantly higher (P < 0.05) during the latter half of exercise and after exercise. There were no significant differences in the total power and mean power of each set between the CBEX and placebo supplemented groups. CONCLUSION: Although oral supplementation with CBEX (which is a rich source of carnosine and anserine) increased the contribution of the nonbicarbonate buffering action and decreased bicarbonate buffering action in blood, intense intermittent exercise performance did not improve significantly.

Analysis of the structure of the AVR1-CO39 avirulence locus in virulent rice-infecting isolates of Magnaporthe grisea.

The AVR1-CO39 gene that came from a Magnaporthe grisea isolate from weeping lovegrass controls avirulence on the rice cultivar CO39. AVR1-CO39 was not present in the genome of the rice-infecting M. grisea isolate Guyll from French Guyana, suggesting that the gene had been deleted. Molecular analysis of the deletion breakpoints in the AVR1-CO39 locus revealed the presence of a truncated copy of a previously unknown retrotransposon at the left-hand border. At the right-hand border was a truncated copy of another repetitive element that is present at multiple locations in the genome of Guyll. The structures of avr1-CO39 loci were further examined in 45 rice-infecting isolates collected in Brazil, China, Japan, India, Indonesia, Mali, and the Philippines. Most isolates showed no hybridization signal with the AVR1-CO39 probe and had the same locus structure as Guyll. Some isolates from Japan showed a signal with the AVR1-CO39 probe, but the region specifying avirulence activity was rearranged. These findings suggest that widespread virulence to 'CO39' among rice-infecting M. grisea isolates is due to ancestral rearrangements at the AVR1-CO39 locus that may have occurred early in the evolution of pathogenicity to rice.