Non-stapling thoracoscopic surgery for spontaneous pneumothorax in young patients.

OBJECTIVES: Spontaneous pneumothorax in young patients has a high recurrence rate, even after surgical treatment, and bulla neogenesis around stapled lesions has been reported as a cause of postoperative recurrence. We investigate the clinical safety and long-term outcome of non-stapling thoracoscopic surgery for spontaneous pneumothorax in young patients. METHODS: Twenty-seven non-stapling thoracoscopic surgeries for pneumothorax in 24 patients younger than 25 years were retrospectively reviewed. The non-stapling surgical techniques used to treat bullae included thoracoscopic suture plication, soft-coagulation, covering, and ligation. Long-term follow-up was conducted by telephone or by a mailed questionnaire. RESULTS: In 22 (81.5%) operations, suture plication, soft-coagulation, and covering procedures were used in combination. The median number of bullae treated in one operation was 2 (range, 0-6). The median operative time was 97 min, and the median postoperative drainage and postoperative hospital stay periods were 1 and 3 days, respectively. No complications of grade 2 or higher were observed. Patients were followed for at least 30 (median, 37) months. The postoperative recurrence rate was 3.7%, with one case of recurrence due to bulla neogenesis at a distant site. CONCLUSION: Non-stapling thoracoscopic surgery with covering procedure for pneumothorax in young patients might reduce postoperative recurrence.

Computational study of the impact of nucleotide variations on highly conserved proteins: In the case of actin.

Sequencing of individual human genomes enables studying relationship among nucleotide variations, amino acid substitutions, effect on protein structures and diseases. Many studies have found general tendencies, for instance, that pathogenic variations tend to be found in the buried regions of the protein structures, that benign variations tend to be found on the surface of the proteins, and that variations on evolutionary conserved residues tend to be pathogenic. These tendencies were deduced from globular proteins with standard evolutionary changes in amino acid sequences. In this study, we investigated the variation distribution on actin, one of the highly conserved proteins. Many nucleotide variations and three-dimensional structures of actin have been registered in databases. By combining those data, we found that variations buried inside the protein were rather benign and variations on the surface of the protein were pathogenic. This idiosyncratic distribution of the variation impact is likely ascribed to the extensive use of the surface of the protein for protein-protein interactions in actin.

Protein Data Bank Japan: Celebrating our 20th anniversary during a global pandemic as the Asian hub of three dimensional macromolecular structural data.

Protein Data Bank Japan (PDBj), a founding member of the worldwide Protein Data Bank (wwPDB) has accepted, processed and distributed experimentally determined biological macromolecular structures for 20 years. During that time, we have continuously made major improvements to our query search interface of PDBj Mine 2, the BMRBj web interface, and EM Navigator for PDB/BMRB/EMDB entries. PDBj also serves PDB-related secondary database data, original web-based modeling services such as Homology modeling of complex structure (HOMCOS), visualization services and utility tools, which we have continuously enhanced and expanded throughout the years. In addition, we have recently developed several unique archives, BSM-Arc for computational structure models, and XRDa for raw X-ray diffraction images, both of which promote open science in the structural biology community. During the COVID-19 pandemic, PDBj has also started to provide feature pages for COVID-19 related entries across all available archives at PDBj from raw experimental data and PDB structural data to computationally predicted models, while also providing COVID-19 outreach content for high school students and teachers.

Co-Development of Oncology Drugs and Companion Diagnostics: Analyses of Approval Lags and Drug Development Periods in Recently Approved Cases in Japan.

BACKGROUND: The utilization of biomarkers has become increasingly active to enhance efficiency of clinical development. This study evaluated the current situation and quantitative impact of co-development of companion diagnostics (CDx) on the oncology drug development in Japan. METHODS: Based on publicly available information about the oncology drugs and CDx approved in Japan in 2010-2020, we evaluated the approval lag time between drugs and CDx, and the duration between the pivotal study start date and the new drug application submission date (the time to application). Influences of multiple factors including the use of CDx on the time to application were also analyzed. RESULTS: A diagnostic test was mostly used from an early development phase such as phase1/2 study, and the median approval lag has tended to decrease when approved CDx were used (- 507 vs. - 25 days for newly developed CDx). The shorter median times to application were observed in Drugs with CDx (1204 days) compared to Targeted therapies without CDx (1423 days) or Other drugs without CDx (1853 days), although both the cancer types and the implementation of multi-regional clinical trials have a larger impact on the time to application compared to the use of CDx. CONCLUSIONS: The use of CDx from the early development phase and the global development strategy could have a positive contribution on the development period of oncology drugs, which will facilitate patients' earlier access to the optimal treatment.

Systemic Anaplastic Large T-Cell Lymphoma with Initial Presentation of Dysuria in a Dog.

A 6-year-old spayed female Akita Dog had dysuria, severe urinary retention and miliary masses in the vagina. Computed tomography revealed a mass at the urethrovaginal junction. The dog died 2 months after initial presentation. At necropsy, the urethrovaginal mass was greyish‒white, solid and 9 × 6 × 6 cm in size with circumferential thickening of the urethral wall. Multiple whitish nodules were seen in the visceral organs and skin. Histopathologically, the urethrovaginal mass comprised a diffuse population of medium-sized to large round neoplastic cells with ovoid to bean-shaped nuclei and eosinophilic cytoplasm. Aberrantly large neoplastic cells with eccentric, horseshoe-shaped or irregularly-shaped nuclei and abundant eosinophilic cytoplasm resembled 'hallmark cells' of human anaplastic large cell lymphoma. Similar neoplastic lesions were present in all the grossly visible masses. Neoplastic cells were diffusely immunopositive for CD3 and occasionally for CD30 and granzyme B. On the basis of the clinical, pathological and immunohistochemical findings, the case was diagnosed as systemic anaplastic large cell lymphoma arising from the lower urinary tract.

[Surgical Strategy for Multiple Synchronous Primary Lung Cancer Showing Ground Glass Opacities:Percutaneous Preoperative Computed Tomography-guided Lipiodol Marking Followed by Video-assisted Thoracic Surgery].

From May 2006 to March 2018, a total of 30 patients with multiple ground glass opacities( GGO) lessor equal to 2.0 cm underwent percutaneous preoperative computed tomography (CT)-guided Lipiodolmarking and subsequent video-assisted thoracic surgery( VATS). There were 22 patients with 2 GGOs,6 patients with 3 GGOs, 1 patient with 4 GGOs, and 1 patient with 5 GGOs. Of the 71 CT-guided Lipiodolmarking procedures were successfully completed. All 71 Lipiodol spots were detected with C-armshapedfluoroscopy and completely resected. Pneumothorax was the most common complication andoccurred in 22 (73.3%) of 30 cases. There were severe complications in two (6.7%) cases of pneumothoraxrequiring chest tube placement and three( 10.0%) cases of bloody sputum. Of 30 cases multipleGGOs revealed 24 synchronous lung cancer (19 patients with double lung cancer, 3 patients with triplelung cancer, 1 patient with quadruple lung cancer, and 1 patient with quintuple lung cancer). PreoperativeCT-guided lipiodol marking and VATS resection is a safe and reliable method for synchronous multiplelung cancer showing GGO.

[A Case of Spindle Cell Tumor in the Gastric Mucosa Treated with Laparoscopic Local Gastrectomy].

The patient was a 43-year-old man. An upper gastrointestinal endoscopic examination revealed a gastric submucosal tumor(SMT)-like, elevated 8-mm lesion in the greater curvature of the upper body of the stomach. It was diagnosed as spindle cell tumor on the basis of biopsy findings, and a gastrointestinal stromal tumor(GIST)was suspected. Various immunohistochemical staining techniques were used; however, a definitive diagnosis could not be achieved. There was no evidence of distant metastasis even on thoracoabdominal computed tomography imaging; thus, the patient was referred to our department for definitive diagnosis and surgical treatment. Laparoscopic local gastrectomy with concomitant intraoperative gastroscopy was performed. Pathological examination of the resected specimen showed a type Ⅱc-like lesion with a maximum diameter of 6 mm in the mucosal layer along with spindle cell proliferation. Immunostaining was negative for c- kit, DOG1, CD34, S-100, SMA, WT-1, desmin(N), EMA, and keratin(pan)and positive for ß-catenin, Bcl-2, and vimentin; furthermore, low Ki-67(MIB-1)expression was detected. Therefore, GIST, solitary fibrous tumor, leiomyoma, leiomyosarcoma, desmoid tumor, spindle cell carcinoma, and synovial sarcoma were excluded, and an unclassifiable spindle cell tumor arising from the gastric mucosa was diagnosed. The patient has remained recurrence-free for 1 year and 8 months post-operatively and is currently under careful outpatient follow-up.

A case of gastric ischemia caused by massive gastric dilatation due to superior mesenteric artery syndrome.

Gastric ischemia is extremely rare and its endoscopic findings appear similar to those of malignant tumors, which makes accurate diagnosis difficult. We present the case of a 41-year-old woman who was admitted to our hospital for severe abdominal pain and vomiting. Laboratory data at the time of admission indicated high serum levels of C-reactive protein, fibrin/fibrinogen degradation products and D-dimer. An abdominal computed tomography (CT) scan revealed a massive dilatation of the stomach and descending portion of the duodenum, which abruptly narrowed at the portion between the superior mesenteric artery and the aorta, indicating massive gastric and duodenal dilatation due to superior mesenteric artery syndrome. Decompression of the upper gastrointestinal tract using a nasogastric tube was started immediately. An esophagogastroduodenoscopy revealed a massive, irregular ulcerative lesion with ill-defined boundaries located in the posterior wall along the greater curvature of the stomach. Although this lesion mimicked a malignant lesion, the biopsy findings revealed a benign gastric ulcer, indicating that the lesion was gastric ischemia caused by the increased intragastric pressure resulting from the massive dilatation. The gastric ischemia healing process was successfully observed through repeated endoscopic examinations of the upper gastrointestinal tract. The patient's abdominal symptoms disappeared within 10 days and she was discharged from the hospital 23 days after the abdominal episode. This case highlights gastric ischemia associated with an acute massive gastric dilatation resulting in increased intragastric pressure caused by superior mesenteric artery syndrome.

A novel strain of endophytic Streptomyces for the biocontrol of strawberry anthracnose caused by Glomerella cingulata.

Anthracnose caused by Glomerella cingulata is one of the most devastating diseases of strawberry in Japan, particularly during its nursery period in the summer. In this study, we aimed to isolate and screen endophytic actinobacteria, to identify potential biocontrol agents capable of suppressing strawberry anthracnose. A total of 226 actinobacteria were successfully isolated from surface-sterilized strawberry tissues. In the first screening, 217 out of 226 actinobacteria isolates were studied for their suppression effect on strawberry anthracnose using a detached leaflet assay. It was discovered that isolates MBFA-172 and MBFA-227 markedly suppressed the development of anthracnose lesions. The efficacy of both isolates was then tested on two-month-old strawberry plug seedlings in a controlled environmental chamber. It was found that isolate MBFA-172 provided consistent disease suppression and was thus selected as a final candidate for further evaluation in a glasshouse experiment. Results showed that the severity as well as incidence rate of strawberry anthracnose was significantly reduced by treatment with isolate MBFA-172 compared with that of untreated control. Accordingly, the disease control efficacy provided by MBFA-172 was statistically comparable to the chemical fungicide propineb. A re-isolation experiment using a spontaneous thiostrepton-resistant mutated strain of isolate MBFA-172 revealed that it efficiently colonized the above-ground tissues of strawberry plants for at least three weeks after spray treatment. Using cultural, morphological, and physiological tests combined with 16S rRNA-based molecular analysis, MBFA-172 was identified as a moderately thermophilic Streptomyces thermocarboxydus-related species. Upon review, our results strongly indicated that MBFA-172 is a promising biocontrol agent for strawberry anthracnose.

Safety and reliability of computed tomography-guided lipiodol marking for undetectable pulmonary lesions.

OBJECTIVES: This study aimed to evaluate the safety and reliability of percutaneous computed tomography (CT)-guided lipiodol marking for undetectable pulmonary lesions before video-assisted thoracic surgery (VATS). METHODS: We retrospectively analysed the cases of CT-guided lipiodol marking followed by VATS in 9 institutes from May 2006 to March 2018. Lipiodol (0.2-0.5 ml) was percutaneously injected closely adjacent to undetectable pulmonary lesions with computed-tomography guidance. Lipiodol spots were identified using C-arm-shaped fluoroscopy during VATS. We grasped the lipiodol spots, including the target lesions, with ring-shaped forceps and resected them. RESULTS: Of 1182 lesions, 1181 (99.9%) were successfully marked. In 1 case, the injected lipiodol diffused, and no spot was created. Of the 1181 lesions, 1179 (99.8%) were successfully resected with intraoperative fluoroscopy. Two lipiodol spots were not detected because of the lipiodol distribution during the division of pleural adhesions. The mean lesion size was 9.1 mm (range 1-48 mm). The mean distance from the pleural surface was 10.2 mm (range 0-43 mm). Lipiodol marking-induced pneumothorax occurred in 495 (57.1%) of 867 cases. Of these, chest drainage was required in 59 patients (6.8%). The other complications were 19 (2.2%) cases of bloody sputum, 3 (0.35%) cases of intravascular air, 1 (0.12%) case of pneumonia and 1 (0.12%) case of cerebral infarction. There were no lipiodol marking-induced deaths or sequelae. CONCLUSIONS: Preoperative CT-guided lipiodol marking followed by VATS resection was shown to be a safe and reliable procedure with a high success rate and acceptably low severe complication rate.

Relationship between conformation shift and disease related variation sites in ATP-binding cassette transporter proteins.

Transport of small molecules across the cell membrane is a crucial biological mechanism for the maintenance of the cell activity. ABC transporter family is a huge group in the transporter membrane proteins and actively transports the substrates using the energy derived from ATP hydrolysis. In humans, there are 48 distinct genes for ABC transporters. A variation of a single amino acid in the amino acid sequence of ABC transporter has been known to be linked with certain disease. The mechanism of the onset of the disease by the variation is, however, still unclear. Recent progress in the method to measure the structures of huge membrane proteins has enabled determination of the 3D structures of ABC transporters and the accumulation of coordinate data of ABC transporter has enabled us to obtain clues for the onset of the disease caused by a single variation of amino acid residue. We compared the structures of ABC transporter in apo and ATP-binding forms and found a possible conformation shift around pivot-like residues in the transmembrane domains. When this conformation change in ABC transporter and the location of pathogenic variation were compared, we found a reasonable match between the two, explaining the onset of the disease by the variation. They likely cause impairment of the pivot-like movement, weakening of ATP binding and weakening of membrane surface interactions. These findings will give a new interpretation of the variations on ABC transporter genes and pave a way to analyse the effect of variation on protein structure and function.

Direct generation of frequency-bin entangled photons via two-period quasi-phase-matched parametric downconversion.

We report a simple scheme for direct generation of frequency-bin entangled photon pairs via spontaneous parametric downconversion. Our fabricated nonlinear optical crystal with two different poling periods can simultaneously satisfy two different, spectrally symmetric nondegenerate quasi-phase-matching conditions, enabling the direct generation of entanglement in two discrete frequency-bin modes. Our produced photon pairs exhibited Hong-Ou-Mandel interference with high-visibility beating oscillations- a signature of two-mode frequency-bin entanglement. Moreover, we demonstrate deterministic entanglement-mode conversion from frequency-bin to polarization modes, with which our source can be more versatile for various quantum applications. Our scheme can be extended to direct generation of high-dimensional frequency-bin entanglement, and thus will be a key technology for frequency-multiplexed optical quantum information processing.

Effects of Process Parameters on Material Removal in Vibration-Assisted Polishing of Micro-Optic Mold.

Process parameter conditions such as vibrating motion, abrasives, pressure and tool wear play an important role in vibration-assisted polishing of micro-optic molds as they strongly affect material removal efficiency and stability. This paper presents an analytical and experimental investigation on the effects of process parameters, aimed at clarifying interrelations between material removal and process parameters which affect polishing quantitatively. The material removal rate (MRR) and surface roughness which represent the polishing characteristics were examined under different vibrating motions, grain sizes of abrasives and polishing pressure. The effects of pressure and tool wear conditions on tool influence function were analyzed. The results showed that 2D vibrating motion generated better surface roughness with higher material removal efficiency while a smaller grain size of abrasives created better surface roughness but lower material removal efficiency. MRR gradually decreases with the increase of polishing pressure when it exceeds 345 kPa, and it was greatly affected by the wear of polisher when wear diameter on the polisher's head exceeds 300 µm.

Relationship Between the Review Time and Various PMDA Consultations in Recent New Drug Approval Cases in Japan.

BACKGROUND: It is considered important that the applicants and reviewers communicate well from the development stage and that both mutually understand the development strategy and application contents in conducting the review efficiently after the application is submitted. Therefore, we focus on Pharmaceuticals and Medical Devices Agency (PMDA) consultations from the viewpoint of communication before the application and clarify the issues to consider in the challenge to reduce the review time in terms of the relationship between the review time and various PMDA consultations. METHODS: We investigated the relationship between the review time and various PMDA consultations for the drugs with new active ingredients approved in Japan using public information from the PMDA. RESULTS: Review times tended to be shorter as more PMDA consultations were conducted. In standard review products, statistically significant differences were noted in the review times (median). When looking at the results of the cases of each category of PMDA consultations, variations in the review times were greater as the consultations were conducted in the later stages of clinical development. Review times tended to be shorter when prior assessment consultations were conducted. In standard review products, significant reductions were noted with the review time (median). CONCLUSIONS: It was suggested that conducting more PMDA consultations might lead to shorter review times. Regarding the review times, variations from the standard review time could possibly be smaller by conducting PMDA consultations from the early stage of clinical development in Japan. It was suggested that review times could possibly be further reduced by conducting prior assessment consultations.

Glycemic variability in continuous glucose monitoring is inversely associated with baroreflex sensitivity in type 2 diabetes: a preliminary report.

BACKGROUND: It is presently unclear whether glycemic variability (GV) is associated with baroreflex sensitivity (BRS), which is an early indicator of cardiovascular autonomic neuropathy. The present study is the first to examine the relationships between BRS and GV measured using continuous glucose monitoring (CGM). METHODS: This was a multicenter, prospective, open-label clinical trial. A total of 102 patients with type 2 diabetes were consecutively recruited for this study. GV was assessed by measuring the standard deviation (SD), glucose coefficient of variation (CV), and the mean amplitude of glycemic excursions (MAGE) during CGM. The BRS was analyzed from electrocardiogram and blood pressure recordings using the sequence method on the first day of hospitalization. RESULTS: A total of 94 patients (mean diabetes duration 9.7 ± 9.6 years, mean HbA1c 61.0 ± 16.8 mmol/mol [7.7 ± 1.5%]) were analyzed. In the univariate analysis, CGM-SD (r = - 0.375, p = 0.000), CGM-CV (r = - 0.386, p = 0.000), and MAGE (r = - 0.395, p = 0.000) were inversely related to BRS. In addition to GV, the level of BRS correlated with the coefficient of variation in the R-R intervals (CVR-R) (r = 0.520, p = 0.000), heart rate (HR) (r = - 0.310, p = 0.002), cardio-ankle vascular index (CAVI) (r = - 0.326, p = 0.001), age (r = - 0.519, p = 0.000), and estimated glomerular filtration rate (eGFR) (r = 0.276, p = 0.007). Multiple regression analysis showed that CGM-CV and MAGE were significantly related to a decrease in BRS. These findings remained after adjusting the BRS for age, sex, hypertension, dyslipidemia, HR, eGFR, CAVI, and CGM-mean glucose. Additionally, BRS was divided according to quartiles of the duration of diabetes (Q1-4). BRS decreased after a 2-year duration of diabetes independently of age and sex. CONCLUSIONS: GV was inversely related to BRS independently of blood glucose levels in type 2 diabetic patients. Measurement of BRS may have the potential to predict CV events in consideration of GV. Trial registration UMIN Clinical Trials Registry UMIN000025964, 28/02/2017.

Primary Aldosteronism With Type 2 Diabetes Mellitus Requires More Antihypertensive Drugs for Blood Pressure Control: A Retrospective Observational Study.

BACKGROUND: Diabetes mellitus (DM) and primary aldosteronism (PA) have been reported to induce drug-resistant hypertension and atherosclerosis. It is likely that blood pressure (BP) control becomes far more difficult in PA patients with DM. However, precise clinical characteristics of PA with type 2 DM especially in the aspect of BP control are not clear. METHODS: The study included 18 patients who were diagnosed as PA with DM and 52 PA patients without DM who matched age and sex and chosen as a control group. We have compared differences in BP control, use of antihypertensive agents and clinical characteristics between PA patients with and without DM. RESULTS: There was no difference with regard to the duration of hypertension and BP control between either group. Interestingly, the PA with DM group was found to require more antihypertensive agents than the PA without DM group (number of antihypertensive agents used, 2.0 ± 1.5 vs. 1.3 ± 1.1; P < 0.05, respectively). In the 28 patients who underwent measurement of central BP (CBP) values, plasma aldosterone concentration (PAC) was high in the PA with DM group. Furthermore, a positive correlation was shown between PAC and CBP (r = 0.58; P < 0.01); the higher the PAC, the higher the CBP of patient. CONCLUSIONS: These results might suggest that hypertension becomes more difficult to control in PA patients with DM in the future.

New tools and functions in data-out activities at Protein Data Bank Japan (PDBj).

The Protein Data Bank Japan (PDBj), a member of the worldwide Protein Data Bank (wwPDB), accepts and processes the deposited data of experimentally determined biological macromolecular structures. In addition to archiving the PDB data in collaboration with the other wwPDB partners, PDBj also provides a wide range of original and unique services and tools, which are continuously improved and updated. Here, we report the new RDB PDBj Mine 2, the WebGL molecular viewer Molmil, the ProMode-Elastic server for normal mode analysis, a virtual reality system for the eF-site protein electrostatic molecular surfaces, the extensions of the Omokage search for molecular shape similarity, and the integration of PDBj and BMRB searches.

Time-dependent effects of ipragliflozin on behaviour and energy homeostasis in normal and type 2 diabetic rats: continuous glucose telemetry analysis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote urinary glucose excretion. Conversely, they cause behavioural changes, such as hyperphagia, that result in a positive energy balance. The relationship between energy homeostasis and SGLT2 inhibitors-induced behavioural changes remains unclear. Here we show that ipragliflozin, a SGLT2 inhibitor, time-dependently affects behaviour and enhances energy expenditure in normal and type 2 diabetic Goto-Kakizaki (GK) rats, using continuous glucose telemetry. Alongside increased urinary glucose excretion, ipragliflozin increased total food and water intakes in normal and GK rats. In normal rats, ipragliflozin treatment acutely disturbed the circadian rhythms of food and water intakes, activity, and body temperature. Subsequently, these rhythms gradually returned towards a normal state. However, activity and body temperature remained suppressed. In GK rats, ipragliflozin did not affect circadian rhythms. Blood glucose values assessed by glucose telemetry were significantly reduced in both ipragliflozin-treated groups. Despite these behavioural and glycaemic changes, ipragliflozin significantly increased oxygen consumption during dark and light periods in both groups. Ipragliflozin reduced body weight in normal rats only. Thus, ipragliflozin decreases blood glucose beyond compensatory hyperphagia in normal and GK rats, resulting in enhanced basal energy expenditure, despite acutely altering circadian rhythms in normoglycaemic individuals.