X -linked inheritance of primary ciliary dyskinesia and retinitis pigmentosa due to RPGR variant: A case report and literature review.

Bronchiectasis is a chronic respiratory condition characterized by irreversible bronchial dilation, often caused by infection or inflammation. It can be associated with primary ciliary dyskinesia (PCD), a hereditary disorder affecting cilia function in various organs and flagella. PCD's genetic heterogeneity leads to varying disease severity. PCD may be more prevalent in Asia, but its diagnosis is often delayed in Japan. This study reviewed a case of PCD and retinitis pigmentosa (RP) with the relevant literature. The patient had a persistent cough, sputum, and diffuse bronchiectasis. He was diagnosed with a combination of PCD and RP, with the presence of an X-linked retinitis pigmentosa GTPase regulator (RPGR) variant confirmed through electron microscopy, retinal scan, and genetic testing. Although co-occurrence of bronchiectasis and RP is rare, PCD should be considered in cases of persistent wet cough in childhood or unidentified bronchiectasis aetiology. Ophthalmologists should consider concomitant PCD in RP patients.

Delayed visit and treatment of lung cancer during the coronavirus disease 2019 pandemic in Japan: a retrospective study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on cancer care remains a concern. We aimed to evaluate access to diagnosis and treatment for lung cancer during the pandemic. METHODS: Times (days) from lung cancer symptom onset or referral to visit (pre-visit time), from visit to diagnosis (pre-diagnosis time), and from diagnosis to treatment (pre-treatment time) during the pandemic were compared with the times during the pre-pandemic period. RESULTS: The number of patients diagnosed with lung cancer was 82 and 75 during the pandemic and pre-pandemic periods, respectively. The percentage of patients with advanced-stage cancer was higher (65.9% vs. 46.7%), the percentage of patients treated with surgery was lower and the percentage treated with medication was higher (24.4% vs. 41.3% and 57.3% vs. 40.0%, respectively), the pre-visit time was longer (28.2 vs. 11.4 days), and the pre-treatment time for surgery was longer (67.3 vs. 45.6 days) during the pandemic compared with the times during the pre-pandemic period, respectively. CONCLUSIONS: The COVID-19 pandemic resulted in delayed diagnoses, which could have led to patients being diagnosed with advanced disease. The pandemic also resulted in delayed therapy owing to the requirement for available intensive care unit beds for emergencies, including surgery.

Short-term intermittent cigarette smoke exposure enhances alveolar type 2 cell stemness via fatty acid oxidation.

BACKGROUND: Cigarette smoke (CS) is associated with chronic obstructive pulmonary disease (COPD) and cancer. However, the underlying pathological mechanisms are not well understood. We recently reported that mice exposed to long-term intermittent CS for 3 months developed more severe emphysema and higher incidence of adenocarcinoma than mice exposed to long-term continuous CS for 3 months and long-term continuous CS exposure activated alveolar stem cell proliferation. However, the influence of variations in the CS exposure pattern in alveolar stem cell in unknown. Here, we exposed mice to 3 weeks of continuous or intermittent CS to identify whether different CS exposure patterns would result in differential effects on stem cells and the mechanisms underlying these potential differences. METHODS: Female mice expressing GFP in alveolar type 2 (AT2) cells, which are stem cells of the alveolar compartment, were exposed to mainstream CS via nasal inhalation. AT2 cells were collected based on their GFP expression by flow cytometry and co-cultured with fibroblasts in stem cell 3D organoid/colony-forming assays. We compared gene expression profiles of continuous and intermittent CS-exposed AT2 cells using microarray analysis and performed a functional assessment of a differentially expressed gene to confirm its involvement in the process using activator and inhibitor studies. RESULTS: AT2 cells sorted from intermittent CS-exposed mice formed significantly more colonies compared to those from continuous CS-exposed mice, and both CS-exposed groups formed significantly more colonies when compared to air-exposed cells. Comparative microarray analysis revealed the upregulation of genes related to fatty acid oxidation (FAO) pathways in AT2 cells from intermittent CS-exposed mice. Treatment of intermittent CS-exposed mice with etomoxir, an inhibitor of the FAO regulator Cpt1a, for 5 weeks resulted in a significant suppression of the efficiency of AT2 cell colony formation. In vitro treatment of naïve AT2 cells with a FAO activator and inhibitor further confirmed the relationship between FAO and AT2 stem cell function. CONCLUSIONS: Alveolar stem cell function was more strongly activated by intermittent CS exposure than by continuous CS exposure. We provide evidence that AT2 stem cells respond to intermittent CS exposure by activating stem cell proliferation via the activation of FAO.

Characteristics of chronic obstructive pulmonary disease patients with robust progression of emphysematous change.

Emphysema is a major pathological change in chronic obstructive pulmonary disease (COPD). However, the annual changes in the progression of emphysematous have not been investigated. We aimed to determine possible baseline predicting factors of the change in emphysematous progression in a subgroup of COPD patients who demonstrated rapid progression. In this observational study, we analyzed patients with COPD who were followed up by computed tomography (CT) at least two times over a 3-year period (n = 217). We divided the annual change in the low attenuation area percentage (LAA%) into quartiles and defined a rapid progression group (n = 54) and a non-progression group (n = 163). Predictors of future changes in emphysematous progression differed from predictors of high LAA% at baseline. On multivariate logistic regression analysis, low blood eosinophilic count (odds ratio [OR], 3.22; P = 0.04) and having osteoporosis (OR, 2.13; P = 0.03) were related to rapid changes in emphysematous progression. There was no difference in baseline nutritional parameters, but nutritional parameters deteriorated in parallel with changes in emphysematous progression. Herein, we clarified the predictors of changes in emphysematous progression and concomitant deterioration of nutritional status in COPD patients.

Exposure to Cigarette Smoke Enhances the Stemness of Alveolar Type 2 Cells.

Chronic exposure to cigarette smoke (CS) causes chronic inflammation, oxidative stress, and apoptosis of epithelial cells, which results in destruction of the lung matrix. However, the mechanism by which the lung fails to repair the CS-induced damage, thereby succumbing to emphysema, remains unclear. Alveolar type 2 (AT2) cells comprise the stem cells of the alveolar compartments and are responsible for repairing and maintaining lung tissues. In this study, we examined the effect of chronic CS on AT2 stem cells. Adult mice expressing GFP in their AT2 cells were exposed to CS for > 3 months. Histological assessment showed that CS not only induced emphysematous changes but also increased the number of AT2 cells compared with that of air-exposed lungs. Assessment of sorted GFP+/AT2 cells via the stem cell three-dimensional organoid/colony-forming assay revealed that the number and size of the colonies formed by the CS-exposed AT2 stem cells were significantly higher than those of air-exposed control AT2 cells. Although CS-exposed lungs had more apoptotic cells, examination of the surviving AT2 stem cells in two-dimensional in vitro culture revealed that they developed a higher ability to resist apoptosis. Microarray analysis of CS-exposed AT2 stem cells revealed the upregulation of genes related to circadian rhythm and inflammatory pathways. In conclusion, we provide evidence that AT2 stem cells respond to chronic CS exposure by activating their stem cell function, thereby proliferating and differentiating faster and becoming more resistant to apoptosis. Disturbances in expression levels of several circadian rhythm-related genes might be involved in these changes.

Characteristics of Chronic Obstructive Pulmonary Disease Patients with Pulmonary Hypertension Assessed by Echocardiography in a Three-Year Observational Cohort Study.

Background: Pulmonary hypertension (PH) is a major comorbidity of chronic obstructive pulmonary disease (COPD). However, the association of PH detected by echocardiography and COPD-related outcome in longitudinal follow-up has not been elucidated. In this study, we aimed to investigate the relationship between clinical characteristics of COPD patients with PH detected by echocardiography and various outcome parameters such as COPD exacerbation and health status over a three-year observation period. Methods: In this observational study, we analyzed patients with COPD who underwent chest computed tomography and echocardiography at baseline (n = 183). Results: The prevalence of PH was 21.9% (40 patients). The median estimated systolic pulmonary artery pressure in patients with PH was 38.8 mmHg. COPD patients with PH were older, had a lower body mass index, scored worse in the COPD Assessment Test and St. George's Respiratory Questionnaire, and exhibited a lower diffusing capacity of the lung for carbon monoxide in comparison to patients without PH. In computed tomography images, the percentages of low-attenuation areas (LAA%) and interstitial abnormalities were higher in COPD patients with PH than in those without PH. Higher values for LAA% (LAA ≥ 30%) and interstitial abnormalities independently increased the risk of PH. The ratio of main pulmonary diameter to aortic artery diameter was significantly correlated with estimated systolic pulmonary artery pressure. In the follow-up analysis, the frequency of exacerbations in three years was significantly higher in patients with PH compared to patients without PH. Conclusion: In this study, we identified the clinical characteristics of COPD patients with PH detected by echocardiography. The presence of PH assessed by echocardiography was related to future COPD exacerbations and closely related to radiographical emphysema.

Predictive and modifying factors of bone mineral density decline in patients with COPD.

RATIONALE: Various determinants of osteoporosis have been previously identified. However, only a few longitudinal studies have examined related factors. We aimed to investigate factors predicting and modifying rapid decline of bone mineral density in patients with chronic obstructive pulmonary disease. METHODS: We analyzed patients with chronic obstructive pulmonary disease whose bone mineral density were measured at least three times over three years (n = 111). We divided annual per cent changes of bone mineral density in different body parts into tertiles. Rapid decliners (n = 33) were defined as those with the largest decline in at least two parts; all other participants were defined as non-rapid decliners (n = 78). RESULTS: At enrollment, bone mineral density did not differ between the two groups. However, rapid decliners had a significantly greater rate of new vertebral fractures over 3 years compared with non-rapid decliners. On multivariate logistic regression analysis, age, moderate to severe emphysema, no daily exercise habits, and anemia increased the likelihood of rapid decliners. Furthermore, patients who newly started and continued bisphosphonate exhibited higher annual per cent changes of bone mineral density than did those without bisphosphonate use. CONCLUSIONS: A rapid decline in bone mineral density correlates to a higher likelihood of vertebral fracture. We clarified the predictors of bone mineral density decline and demonstrated that bisphosphonate use might modify bone mineral density in patients with chronic obstructive pulmonary disease.

Clinical utility of blood neutrophil-lymphocyte ratio in Japanese COPD patients.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is a biomarker of inflammation in chronic obstructive pulmonary disease (COPD) patients. But, a meaningful threshold and the longitudinal changes are unknown. We aimed to investigate the association between NLR and the clinical characteristics of COPD patients and to determine a meaningful threshold and the longitudinal changes for NLR. METHODS: Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. We performed a blood examination and a pulmonary function test. Blood examination was completed at baseline and annually thereafter, at a time when the disease was stable. Two hundred seventy-four patients who had at least 3 blood examinations over 3 years were included. RESULTS: Baseline NLR was correlated with baseline C-reactive protein (CRP) (r = 0.18, p = 0.003) and SAA (r = 0.34, p <  0.001). We defined an NLR score of 2.7 as the arbitrary cut-off value based on upper quartile points. COPD patients with NLR ≥ 2.7 were older (p = 0.037), had a lower BMI (p = 0.005) and a lower %FEV1 (p = 0.0003) compared to patients with NLR < 2.7. Receiver-operating-characteristic (ROC) curves showed the optimal cutoff for the baseline NLR in the predicting moderate/severe exacerbation to be 2.7, which was same as the upper quartile points. Follow-up analysis over 3 years revealed that the differences in the trends of NLR among the three groups based on the categories of exacerbations (moderate or severe, mild, no exacerbation) were significant (p = 0.006). CONCLUSIONS: NLR is associated with COPD severity and exacerbations. For predicting exacerbations, we estimated the threshold of NLR to be 2.7 at baseline. TRIAL REGISTRATION: Clinical trial registered with the University Hospital Medication Information Network ( UMIN000003470 , April 10, 2010).

Intermittent Exposure to Cigarette Smoke Increases Lung Tumors and the Severity of Emphysema More than Continuous Exposure.

Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)-induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence of adenocarcinomas. Furthermore, intermittent CS exposure elicited a marked increase in M2-polarized macrophages within and near the developed tumors. By employing a CS exposure protocol with repeated cycles of cessation and relapse, we provide evidence that intermittent CS exposure enhances tumorigenesis and emphysema progression more than that of continuous CS exposure.

Characteristics of patients with increasing COPD assessment test scores within 3 years.

BACKGROUND: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a subjective measure of quality of life. The aim of this study was to examine the characteristics of COPD patients with increasing CAT scores within 3 years. METHODS: Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. St. George's Respiratory Questionnaire (SGRQ) and CAT were completed at baseline and annually thereafter. Patients who had at least 3 CAT scores were included (n = 315). The ΔCAT score/year and ΔSGRQ score/year were calculated by the slope between each of the measures and the date of measurement. RESULTS: The median ΔCAT score/year was 0.4, and ΔCAT score/year was significantly correlated with ΔSGRQ total score/year. Using an annual cut-off CAT score of +2 points, patients who deteriorated (n = 79) were older, had lower %FEV1, and more severe emphysema on computed tomography scan at baseline than patients who did not deteriorate. The baseline value was not a determinant of subsequent changes in the CAT score. Longitudinal changes in the CAT score were positively correlated with those in the SGRQ score. CONCLUSIONS: Old age and severe COPD, not the CAT score at one time point, predicted worsening quality of life.

Relationship between diminution of small pulmonary vessels and emphysema in chronic obstructive pulmonary disease.

OBJECTIVES: To investigate the relationship between small pulmonary vessels and extent of emphysema on CT in individual lungs with chronic obstructive pulmonary disease (COPD). METHODS: Forty-nine patients were included. The percentage of cross-sectional area of vessels <5mm2 (%CSA <5) and extent of emphysema were assessed. RESULTS: Less than half of the COPD patients demonstrated an inverse correlation between %CSA <5 and percentage of low attenuation area (LAA%). In the remaining patients, %CSA <5 was homogeneously distributed. CONCLUSION: Not all patients with COPD demonstrated an inverse correlation of the distributions between %CSA <5 and LAA% in individual lungs.

Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease.

BACKGROUND: Only a few studies have evaluated the radiologic features of pre-existing structural abnormalities where lung cancer may develop. This study aimed to analyze the computed tomography (CT) images of lung areas where new cancer developed in chronic obstructive pulmonary disease (COPD) patients. PATIENTS AND METHODS: We conducted a multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research, to assess the incidence of lung cancer. Emphysema and interstitial abnormalities were evaluated in 240 COPD patients who had baseline CT scans applicable for further digital analyses. For patients who developed lung cancer during the 3-year follow-up period, the local spherical lung density of the precancerous area was individually quantified. RESULTS: Lung cancer was newly diagnosed in 21 participants (2.3% per year). The percent-age of low attenuation area in patients who developed lung cancer was higher than that of the other patients (20.0% vs 10.4%, P=0.014). The presence of emphysema (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.0-29.0, P=0.049) or interstitial lung abnormalities (OR 15.6, 95% CI 4.4-65.4, P<0.0001) independently increased the risk for lung cancer. Compared with the density of the entire lung, the local density of the precancerous area was almost the same in patients with heterogeneous emphysema, but it was higher in most patients with interstitial abnormalities. CONCLUSION: The presence of emphysema or interstitial abnormalities or a combination of both were independent predictors of lung cancer development in COPD patients. Furthermore, lung cancer most often developed in non-emphysematous areas or in interstitial abnormalities.

Edoxaban treatment for pulmonary arterial thromboembolism associated with azygous vein aneurysm.

A 76-year-old woman, diagnosed 5 years previously with an asymptomatic mediastinal bronchogenic cyst, was referred to our department as the mass had grown slightly larger. Contrast-enhanced computed tomography and magnetic resonance imaging scans revealed an azygous vein aneurysm with a pulmonary arterial thromboembolism. The patient was treated with heparin for 5 days, and anticoagulation therapy with edoxaban was continued for 12 months. The thrombus resolved, and the aneurysm remained unchanged. An azygous vein aneurysm is a very rare condition that causes pulmonary arterial thromboembolism. Although surgical resection is indicated for patients with azygous vein aneurysms with a risk of rupture and pulmonary embolism, we chose anticoagulation therapy because of the patient's advanced age. This case suggests that the azygous vein aneurysm is one of the differential diagnoses for a mediastinal mass and that anticoagulation therapy can be the treatment of choice for pulmonary arterial thromboembolism with an azygous vein aneurysm.

Identification of five clusters of comorbidities in a longitudinal Japanese chronic obstructive pulmonary disease cohort.

BACKGROUND AND OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from various comorbidities. Recently, cluster analysis has been proposed to examine the phenotypic heterogeneity in COPD. In order to comprehensively understand the comorbidities of COPD in Japan, we conducted multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research (K-CCR). In this cohort, comorbid diagnoses were established by both objective examination and review of clinical records, in addition to self-report. We aimed to investigate the clustering of nineteen clinically relevant comorbidities and the meaningful outcomes of the clusters over a two-year follow-up period. MATERIAL AND METHODS: The present study analyzed data from COPD patients whose data of comorbidities were completed (n = 311). Cluster analysis was performed using Ward's minimum-variance method. RESULTS: Five comorbidity clusters were identified: less comorbidity; malignancy; metabolic and cardiovascular; gastroesophageal reflux disease (GERD) and psychological; and underweight and anemic. FEV1 did not differ among the clusters. GERD and psychological cluster had worse COPD assessment test (CAT) and Saint George's respiratory questionnaire (SGRQ) at baseline compared to the other clusters (CAT: p = 0.0003 and SGRQ: p = 0.00046). The rate of change in these scores did not differ within 2 years. The underweight and anemic cluster included subjects with lower baseline ratio of predicted diffusing capacity (DLco/VA) compared to the malignancy cluster (p = 0.036). CONCLUSIONS: Five clusters of comorbidities were identified in Japanese COPD patients. The clinical characteristics and health-related quality of life were different among these clusters during a follow-up of two years.

Impact of mild exacerbation on COPD symptoms in a Japanese cohort.

BACKGROUND: Patients with COPD might not report mild exacerbation. The frequency, risk factors, and impact of mild exacerbation on COPD status are unknown. OBJECTIVES: The present study was performed to compare features between mild exacerbation and moderate or severe exacerbation in Japanese patients with COPD. PATIENTS AND METHODS: An observational COPD cohort was designed at Keio University and affiliated hospitals to prospectively investigate the management of COPD comorbidities. This study analyzes data only from patients with COPD who had completed annual examinations and questionnaires over a period of 2 years (n=311). RESULTS: Among 59 patients with mild exacerbations during the first year, 32.2% also experienced only mild exacerbations in the second year. Among 60 patients with moderate or severe exacerbations during the first year, 40% also had the same severity of exacerbation during the second year. Findings of the COPD assessment test and the symptom component of the St George's Respiratory Questionnaire at steady state were worse in patients with mild exacerbations than in those who were exacerbation free during the 2-year study period, although the severity of the ratio of predicted forced expiratory volume in 1 second did not differ between them. Severe airflow limitation (the ratio of predicted forced expiratory volume in 1 second <50%) and experience of mild exacerbations independently advanced the likelihood of an elevated COPD assessment test score to ≥2 per year. CONCLUSION: The severity of COPD exacerbation seemed to be temporally stable over 2 years, and even mild exacerbations adversely impacted the health-related quality of life of patients with COPD.

Estrogen induces stromal cell-derived factor 1 (SDF-1/CXCL12) production in human endometrial stromal cells: a possible role of endometrial epithelial cell growth.

Estradiol enhanced stromal cell-derived factor 1 (SDF-1/CXCL12) production levels in human endometrial stromal cells (ESCs) in a time- and dose-dependent manner that could be completely abolished by ICI 182,780 (estrogen receptor antagonist) and medroxyprogesterone acetate. Although SDF-1 was undetectable in the Ishikawa human endometrial epithelial cell line, its receptor (CXCR4) messenger RNA levels in Ishikawa cells were much higher than those in ESCs, and furthermore SDF-1 induced the proliferation of Ishikawa cells; SDF-1 secreted from ESCs may play a role in endometrial epithelial cell growth in the paracrine system.

Estrogen and selective estrogen receptor modulators regulate vascular endothelial growth factor and soluble vascular endothelial growth factor receptor 1 in human endometrial stromal cells.

OBJECTIVE: To determine whether 17beta-estradiol (E(2)) and selective estrogen receptor modulators can regulate vascular endothelial growth factor (VEGF) and soluble VEGF receptor 1 (sVEGFR-1) as a VEGF antagonist in human endometrial stromal cells (ESCs). DESIGN: In vitro experiment. SETTING: Research laboratory at Kansai Medical University. PATIENT(S): Sixteen patients undergoing hysterectomy for benign reasons. INTERVENTION(S): The ESCs were cultured with E(2), 4-hydroxytamoxifen (OHT), and raloxifene. MAIN OUTCOME MEASURE(S): The VEGF and sVEGFR-1 messenger RNA (mRNA) levels in ESCs were determined using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Free (unbound) VEGF and sVEGFR-1 protein levels from ESCs were measured using ELISA kits. RESULT(S): The E(2) significantly induced VEGF mRNA levels, whereas E2 caused a significant decrease in sVEGFR-1 messenger RNA (mRNA) levels. The E(2) or OHT significantly increased the VEGF production levels and attenuated the sVEGFR-1 production compared with control, but raloxifene had no significant effect. The decrease in levels of free VEGF was proportional to the increase in sVEGFR-1 levels in the culture media of ESCs. CONCLUSION(S): The E(2) or OHT stimulates VEGF production and concurrently attenuates sVEGFR-1 production in ESCs. This consequential increase in VEGF:sVEGFR-1 ratio might enhance the biological effects of VEGF on the angiogenic environment in human endometrium.

Management of transvaginal ultrasound-guided absolute ethanol sclerotherapy for ovarian endometriotic cysts.

PURPOSE: Endometriosis and endometriotic ovarian cysts are common gynecologic diseases. Excision of the cyst wall by laparotomy or laparoscopy is the standard treatment for endometriotic ovarian cysts. However, some young patients with cysts would prefer not to have an abdominal incision. We reviewed and assessed the effectiveness of transvaginal ultrasound-guided ethanol sclerotherapy in these patients. METHODS: Eighteen patients with endometriotic ovarian cysts underwent transvaginal ultrasound-guided aspiration and ethanol sclerotherapy using spinal anesthesia. The contents of the cysts were drained and sent for cytological examination. The cyst cavities were washed with absolute ethanol, and the cysts were then filled with absolute ethanol for 5 min. The patients were followed up with transvaginal ultrasonography. RESULTS: The transvaginal ethanol sclerotherapy was completed in all cases. The mean long diameter of the cysts was 50 mm (31-100 mm), and the mean operative duration was 22 min (8-45 min). Malignant cells were not isolated from the aspirated fluid in any case. There were no significant intra- or postoperative complications. Two patients (11.1%) had a recurrence at 3 and 32 months after ethanol sclerotherapy, respectively. CONCLUSIONS: Transvaginal ultrasound-guided absolute ethanol sclerotherapy is useful for ovarian endometriotic cysts, particularly in young patients or in patients who would like to become pregnant. However, careful selection based on ultrasonography or magnetic resonance imaging findings and the age of the patients is critical.

Benign endometrial adenofibroma and polyp in patients receiving tamoxifen: findings on transvaginal ultrasonography and magnetic resonance imaging.

Tamoxifen, a selective estrogen receptor modulator, is widely used to treat breast cancer, but an association has been reported between tamoxifen and the development of endometrial lesions, including endometrial carcinoma, endometrial polyps, and endometrial hyperplasia. There have also recently been a few reports on the relation between tamoxifen and adenofibroma. We present two case reports, one of a patient with a uterine adenofibroma and one of a patient with an endometrial polyp, both of whom received tamoxifen. Cases 1 and 2 are 75- and 65-year-old postmenopausal women, respectively, undergoing tamoxifen therapy. In both cases, endometrial thickening and many small cysts in the uterine cavity were revealed by transvaginal ultrasonography or magnetic resonance imaging. Postoperative microscopic examination confirmed the mass as an adenofibroma in case 1 and as an endometrial polyp in case 2.

Characterization of the splice sites in GT-AG and GC-AG introns in higher eukaryotes using full-length cDNAs.

For the purpose of analyzing the relation between the splice sites and the order of introns, we conducted the following analysis for the GT-AG and GC-AG splice site groups. First, the pre-mRNAs of H. sapiens, M. musculus, D. melanogaster, A. thaliana and O. sativa were sampled by mapping the full-length cDNA to the genomes. Next, the consensus sequences at different regions of pre-mRNAs were analyzed in the five species. We also investigated the mononucleotide and dinucleotide frequencies in the extensive regions around the 5' splice sites (5'ss) and 3' splice sites (3'ss). As a result, differential frequencies of nucleotides at the first 5'ss in both the GT-AG and GC-AG splice site groups were observed in A. thaliana and O. sativa pre-mRNAs. The trend, which indicates that GC 5'ss possess strong consensus sequences, was observed not only in mammalian pre-mRNAs but also in the pre-mRNAs of D. melanogaster, A. thaliana and O. sativa. Furthermore, we examined the consensus sequences of the constitutive and alternative splice sites. It was suggested that in the case of the alternative GC-AG introns, the tendency to have a weak consensus sequence at 5'ss is different between H. sapiens and M. musculus pre-mRNAs.