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Previous studies have demonstrated the higher accuracy of frequency-domain optical coherence tomography (FD-OCT) for quantitative measurements in comparison with intravascular ultrasound (IVUS). However, those analyses were based on the cross-sectional images. The aim of this study was to assess the accuracy of FD-OCT for longitudinal geometric measurements of coronary arteries in comparison with IVUS. Between October 2011 and March 2012, we performed prospective FD-OCT and IVUS examinations in consecutive 77 patients who underwent percutaneous coronary intervention with single stent. Regression analysis and Bland-Altman analysis revealed an excellent correlation between the FD-OCT-measured stent lengths and IVUS-measured stent lengths (r = 0.986, p < 0.001; mean difference = −0.51 mm). There was an excellent agreement between the actual stent lengths and the FD-OCT-measured stent lengths (r = 0.993, p < 0.001) as well as between the actual stent lengths and the IVUS-measured stent lengths (r = 0.981, p < 0.001). The difference between the actual stent lengths and the FD-OCT-measured stent lengths was significantly smaller than that between the actual stent lengths and the IVUS-measured stent lengths (0.15 ± 0.68 vs. 0.70 ± 1.15 mm, p < 0.001). Both FD-OCT (mean difference = −0.04 and −0.04 mm, respectively) and IVUS (mean difference = −0.06 and −0.06 mm, respectively) showed an excellent intra-observer and inter-observer reproducibility for the stent length measurements. In conclusion, FD-OCT provides accurate longitudinal measurement with excellent intra-observer and inter-observer reproducibility. FD-OCT might be a reliable technique for longitudinal geometric measurement in human coronary arteries. [ABSTRACT FROM AUTHOR]

CD4+ T follicular helper ( TFH) cells are central for generation of long-term B-cell immunity. A defining phenotypic attribute of TFH cells is the expression of the chemokine R CXCR5, and TFH cells are typically identified by co-expression of CXCR5 together with other markers such as PD-1, ICOS, and Bcl-6. Herein, we report high-level expression of the nutrient transporter folate R 4 ( FR4) on TFH cells in acute viral infection. Distinct from the expression profile of conventional TFH markers, FR4 was highly expressed by naive CD4+ T cells, was downregulated after activation and subsequently re-expressed on TFH cells. Furthermore, FR4 expression was maintained, albeit at lower levels, on memory TFH cells. Comparative gene expression profiling of FR4hi versus FR4lo Ag-specific CD4+ effector T cells revealed a molecular signature consistent with TFH and TH1 subsets, respectively. Interestingly, genes involved in the purine metabolic pathway, including the ecto-enzyme CD73, were enriched in TFH cells compared with TH1 cells, and phenotypic analysis confirmed expression of CD73 on TFH cells. As there is now considerable interest in developing vaccines that would induce optimal TFH cell responses, the identification of two novel cell surface markers should be useful in characterization and identification of TFH cells following vaccination and infection. [ABSTRACT FROM AUTHOR]

Abstract: Foxp3-expressing regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance and homeostasis. One of the key issues for understanding Treg immunobiology is to determine how they suppress excessive or aberrant immune responses. Although a number of molecules have been reported to contribute to Treg suppressive function, the importance and precise role of each molecule is not clear. In this review, we propose and discuss that two modes of suppression can be distinguished. In the physiological and steady state, activation of naïve T cells can be suppressed by natural Tregs via deprivation of activation signals including CD28 signal and IL-2 from antigen-reactive T cells, keeping the latter in a naïve state in lymphoid tissues. These deprivation mechanisms are transiently abrogated in inflammatory conditions, allowing T cells to respond to antigen. In contrast, in highly inflammatory environments, for example, in microbial infection, activated Tregs acquire the capacity to kill or inactivate effector T cells and antigen-presenting cells, for example, via granzyme/perforin formation and IL-10 secretion, thereby actively damping excessive immune responses. Understanding these processes will help effectively controlling physiological and pathological immune responses via Tregs. [Copyright &y& Elsevier]

The detection of cracks on concrete surfaces is the most important step during the inspection of concrete structures. Conventional crack detection methods are performed by experienced human inspectors who sketch crack patterns manually; however, such detection methods are expensive and subjective. Therefore, automated crack detection techniques that utilize image processing have been proposed. Although most the image-based approaches focus on the accuracy of crack detection, the computation time is also important for practical applications because the size of digital images has increased up to 10 megapixels. We introduce an efficient and high-speed crack detection method that employs percolation-based image processing. We propose termination- and skip-added procedures to reduce the computation time. The percolation process is terminated by calculating the circularity during the processing. Moreover, percolation processing can be skipped in subsequent pixels according to the circularity of neighboring pixels. The experimental result shows that the proposed approach efficiently reduces the computation cost. [ABSTRACT FROM AUTHOR]

Naturally occurring CD4+CD25~ regulatory T cells (Treg) suppress in vitro the proliferation of other T cells in a cell-contact-dependent manner. Dendritic cells (DCs) appear to be a target of Treg-mediated immune suppression. We show here that, in coculture of dye-labeled Treg cells and CD4+ CD25- naïve T cells in the presence of I cell receptor stimulation, Treg cells, which are more mobile than naïve T cells in vitro, out-compete the latter in aggregating around DCs. Deficiency or blockade of teukocyte function-associated antigen-i (LFA-i) (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic I lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming aggregates, Treg cells specifically down-regulate the expression of CD80/86, but not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of strong DC-maturating stimuli, such as GM-CSF, TNF-α, IFN-γ, type I IFN, and lipopolysaccharide. Taken together, as a possible mechanism of in vitro Treg-mediated cell contact-dependent suppression, we propose that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. Both steps prevent antigen-reactive naïve T cells from being activated by antigen-presenting DCs, resulting in specific immune suppression and tolerance. [ABSTRACT FROM AUTHOR]

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of Cd4+ and CD8+ T cells, including interferon (IFN)-γ-secreting cells, infiltrated regressing tumors. Tumor-specific IFN-γ-secreting CD4+ and CDS+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-γ-intact mice but not IFN-γ-deficient mice. Furthermore, coadministration of anti-GITR and anti-CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg-specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg-mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-γ, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers. [ABSTRACT FROM AUTHOR]

Streptomycin (STR) is recommended for the management of multidrug-resistant tuberculosis (MDR-TB). Streptomycin resistance-conferring mutation types and frequency are shown to be influenced by genotypes of circulating strains in a population. This study aimed to characterize the mutations in MDR-TB isolates and examine their relationship with the genotypes in Zambia. A total of 138 MDR-TB isolates stored at the University Teaching Hospital Tuberculosis Reference Laboratory in Zambia were analyzed using spoligotyping and sequencing of STR resistance-associated genes. Streptomycin resistance was observed in 65.9% (91/138) of MDR-TB isolates. Mutations in rpsL, rrs, and gidB accounted for 33%, 12.1%, and 49.5%, respectively. Amino acid substitution K43R in rpsL was strongly associated with the CAS1_Kili genotype (p < 0.0001). The combination of three genes could predict 91.2% of STR resistance. Clustering of isolates based on resistance-conferring mutations and spoligotyping was observed. The clustering of isolates suggests that the increase in STR-resistant MDR-TB in Zambia is largely due to the spread of resistant strains from inadequate treatment. Therefore, rapid detection of STR resistance genetically is recommended before its use in MDR-TB treatment in Zambia. [ABSTRACT FROM AUTHOR]

Background: Enteric infections are a major public health issue in developing countries. Antimicrobial resistance is also a problem for enteric infection. OPS-2071 is a novel quinolone antibiotic with low oral absorption and potent antibacterial activity against Clostridioides difficile.Objectives: This study was conducted to confirm the antimicrobial activity of OPS-2071 against major enteropathogenic bacteria and to evaluate the risk of emergence of drug resistance.Methods: The antibacterial activity was evaluated by the agar dilution method. The inhibitory activity against DNA gyrase and topoisomerase IV was determined by supercoiling assay and decatenation assay, respectively. The mutant prevention concentration and frequency of spontaneous resistance were determined by inoculation on drug-containing agar.Results: Compared with the reference drugs, the antibacterial activity of OPS-2071 was more potent against Gram-positive bacteria and Campylobacter jejuni, including quinolone-resistant strains. Against other Gram-negative bacteria, OPS-2071 was comparable to existing quinolones. The inhibitory activities against DNA gyrase with quinolone-resistant mutations closely correlated with the antibacterial activity. Spontaneous resistance to OPS-2071 was not observed in Staphylococcus aureus and Escherichia coli and was lower than that of existing quinolones and higher than that of azithromycin in C. jejuni. The mutant prevention concentration of OPS-2071 was lower than that of tested compounds in S. aureus and C. jejuni and slightly higher than that of existing quinolones in E. coli.Conclusions: The broad and potent in vitro antibacterial activity and lower risk of drug resistance suggested that OPS-2071 may be useful for enteric infections caused by major pathogens including quinolone-resistant Campylobacter. [ABSTRACT FROM AUTHOR]

Introduction: The spread of coronavirus disease 2019 (COVID-19) is having a profound effect on global health. In this study, we investigated early predictors of severe prognosis from the perspective of liver injury and risk factors for severe liver injury in patients with COVID-19. Methods: We examined prognostic markers and risk factors for severe liver injury by analyzing clinical data measured throughout the course of the illness and the disease severity of 273 patients hospitalized for COVID-19. We assessed liver injury on the basis of aminotransferase concentrations and fibrosis-4 (FIB-4) index on admission, peak aminotransferase concentration during hospitalization, aminotransferase peak-to-average ratio, and albumin and total bilirubin concentrations. Furthermore, we analyzed age, aspartate aminotransferase (AST) concentrations, FIB-4 index on admission, hypertension, diabetes mellitus (DM), dyslipidemia, cerebral infarction, myocardial infarction, and body mass index as mortality risk factors. Results: We identified advanced age as a risk factor. Among biochemical variables, AST concentration and FIB-4 index on admission were associated with high mortality. AST on admission and peak AST during hospitalization were significantly higher in the non-surviving (n = 45) than the discharged group (n = 228). Multivariable Cox hazards analyses for mortality showed significant hazard ratios for age, peak AST, and FIB-4 index on admission (p = 0.0001 and 0.0108, respectively), but not in a model including AST and FIB-4 index on admission. Furthermore, the AST peak was significantly higher among non-surviving patients with DM than in those without DM. Conclusions: We found that advanced age, high AST, and FIB-4 index on admission and a higher peak AST during hospitalization are risk factors for poor COVID-19 prognosis. Furthermore, DM was a risk factor for exacerbation of liver injury among non-surviving patients. The AST concentration and FIB-4 index should be assessed periodically throughout hospitalization, especially in patients with high AST values on admission and those with DM. [ABSTRACT FROM AUTHOR]

A 56-year-old female was admitted to our hospital because of respiratory symptoms. Her admission ECG showed normal sinus rhythm and standard echocardiographic evaluation showed no structural or functional abnormalities. She was diagnosed as having sarcoidosis by imaging modalities and mediastinum lymph node biopsy. In this case, 2-dimensional speckle-tracking echocardiography (STE) demonstrated abnormal regional myocardial function and delayed enhancement cardiac magnetic resonance imaging revealed a high intensity area in the same segments. This case suggests that STE is potentially useful for the detection of cardiac sarcoidosis in the early phase. [ABSTRACT FROM AUTHOR]

Fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis (Mtb), caused by amino acid substitutions in DNA gyrase, has been increasingly reported worldwide. WQ-3810 is a newly developed FQ that is highly active against FQ-resistant pathogens; however, its activity against Mtb has not been evaluated. Herein we examined the efficacy of WQ-3810 against Mtb through the use of recombinant Mtb DNA gyrases. In addition, in vitro antimycobacterial activity of WQ-3810 was evaluated against recombinant Mtb var. bovis Bacille Calmette–Guérin strains in which gyrase-coding genes were replaced with Mtb variants containing resistance-conferring mutations. WQ-3810 showed a higher inhibitory activity than levofloxacin against most recombinant DNA gyrases with FQ-resistance mutations. Furthermore, WQ-3810 showed inhibition even against a DNA gyrase variant harboring a G88C mutation which is thought to confer the highest resistance against FQs in clinical Mtb isolates. In contrast, the FQ susceptibility test showed that WQ-3810 had relatively weak mycobactericidal activity compared with moxifloxacin. However, the combination of WQ-3810 and ethambutol showed the greatest degree of synergistic activity against recombinant strains. Since FQs and ethambutol have been used in multi-drug therapy for tuberculosis, WQ-3810 might represent a new, potent anti-tuberculosis drug that can be effective even against FQ-resistant Mtb strains. [ABSTRACT FROM AUTHOR]

A 70-year-old man with lung adenocarcinoma had undergone right lower lobectomy and lymph node dissection. Only 6 months later under adjuvant uracil and futraful therapy, the patient developed a solitary bone metastasis in the right 8th rib. Due to positive mutation of epidermal growth factor receptor (EGFR) exon 21 L858R in the primary cancer, the patient received osimertinib monotherapy, leading to massive calcification of the osteolytic bone metastasis with significant decrease of standard uptake value on positron emission tomography. After 12 months of osimertinib monotherapy, slight enlargement of the ground glass nodule, i.e., presumed noninvasive lung cancer, in the right upper lobe, and no further occurrence of metastatic foci made us to resect both the lung nodule and the bone metastasis. Pathological examination showed the lung nodule to be noninvasive adenocarcinoma and the bone metastasis to have no viable cancer cells. The patient was discharged on the 8th postoperative day without any complication. On developing a therapeutic strategy for advanced/recurrent EGFR mutation-positive lung adenocarcinoma, oncologists should note the possibility of pathological complete response to newly developed EGFR tyrosine kinase inhibitors including osimertinib for a presumed cure of oligometastatic lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

A 65-year-old woman with prolonged cough and presumed pulmonary hypertrophic osteoarthropathy was referred to our hospital. Computed tomography showed 2 tumors larger than 3 cm in size and massive hilar lymph node enlargement in the right lung. Pathological examination of the transbronchial lung biopsy specimen showed atypical malignant cells, presumed adenocarcinoma, with 1% positivity of programmed cell death 1 ligand (PD-L1). Three courses of chemoimmunotherapy with pembrolizumab (400 mg q3w), carboplatin (AUC 5 mg/mL · min q3w), and pemetrexed (500 mg/m2 q3w) were well tolerated and brought about a quasi-complete response both of the lung tumors and lymph nodes and complete symptom relief of the pulmonary hypertrophic osteoarthropathy, finally leading to the surgical intervention, that is, lobectomy and lymph node dissection. Postoperative pathological examination showed no viable cancer foci both in the lung tumors and lymph nodes. The patient recovered uneventfully. Physicians should note the combination chemoimmunotherapy including pembrolizumab, with curative intent, to optimally treat patients with locally advanced non-small cell lung cancer (NSCLC) even if the NSCLC bears a small amount of PD-L1. [ABSTRACT FROM AUTHOR]

Purpose Of Review: To clarify the hurdles to generation of human islets via blastocyst complementation and to identify techniques to overcome them.Recent Findings: Blastocyst complementation is a promising method for generating functional islets from pluripotent stem cells which are identical to in vivo islets. Studies have reported successful generation of mouse pancreas in rats and rat pancreas in mice via interspecies blastocyst complementation and have shown the possibility for generation of human organs in xenogeneic animals. However, there remain hurdles to generating human islets in animals. The major hurdles to generating human islets include difficulty in engineering human-animal chimeras due to the cellular status of human pluripotent stem cells, immunological rejection of donor tissue in xenogeneic animals, and ethical concerns. [ABSTRACT FROM AUTHOR]

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor. Here, conversely, we show that mouse PSCs can efficiently differentiate into the metanephric mesenchyme in rat, allowing the generation of mouse PSC-derived kidney in anephric Sall1 mutant rat. Glomerular epithelium and renal tubules in the kidneys are entirely composed of mouse PSC-derived cells expressing key functional markers. Importantly, the ureter-bladder junction is normally formed. These data provide proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation. The use of pluripotent-stem cell derived organs for transplantation would be promising, if organs can be grown in a suitable host. Here, the authors use interspecific blastocyst complementation to generate a mouse pluripotent stem cell-derived kidney in anephric Sall1 mutant rats. [ABSTRACT FROM AUTHOR]

To study development of the conceptus in xenogeneic environments, we assessed interspecies chimera formation as well as tetraploid complementation between mouse and rat. Overall contribution of donor PSC-derived cells was lower in interspecies chimeras than in intraspecies chimeras, and high donor chimerism was associated with anomalies or embryonic death. Organ to organ variation in donor chimerism was greater in interspecies chimeras than in intraspecies chimeras, suggesting species-specific affinity differences among interacting molecules necessary for organogenesis. In interspecies tetraploid complementation, embryo development was near normal until the stage of placental formation, after which no embryos survived. [ABSTRACT FROM AUTHOR]

An 83-year-old man with core needle biopsy-proven Gleason score 5 prostate cancer had received radiotherapy including 18 Gy brachytherapy to the prostate cancer, leading to no locoregional and distant recurrence for more than 5 years with the normalization of elevated prostate-specific antigen (PSA) level before the radiotherapy. Due to the enlargement of coexisting ground glass nodule (GGN) in the left lung from 1 to 2.1 cm, the patient underwent wide resection of the GGN 7 years later. Under the diagnosis of adenocarcinoma in situ of the lung, follow-up computed tomography 6 months after the wide resection showed a rapid enlargement of a solid nodule having been judged as a presumed inflammatory nodule in the middle lobe, highly suggesting a malignant neoplasm of the lung. Due to both the tall columnar atypical cells with trabecular pattern on frozen section and no elevation of serum PSA level, we judged the nodule as a primary adenocarcinoma of the lung and further resected the middle lobe with lymph node dissection. Immunostaining of the tumor showed all the CK7, CK20, TTF-1, napsin A, synaptophysin, chromogranin, CD56, CDX2, p53, beta-catenin, and MUC2 negative, and PSA highly positive, clearly showing the solid nodule as a solitary lung metastasis of the prostate cancer. Physicians should note the possible solitary lung metastasis of prostate cancer, especially bearing indolent biology, with no elevation of the PSA level even after the completion of standard 5-year follow-up. [ABSTRACT FROM AUTHOR]

Bats are of significant interest as reservoirs for various zoonotic viruses with high diversity. During the past two decades, many herpesviruses have been identified in various bats worldwide by genetic approaches, whereas there have been few reports on the isolation of infectious herpesviruses. Herein, we report the prevalence of herpesvirus infection of bats captured in Zambia and genetic characterization of novel gammaherpesviruses isolated from striped leaf-nosed bats (Macronycteris vittatus). By our PCR screening, herpesvirus DNA polymerase (DPOL) genes were detected in 29.2% (7/24) of Egyptian fruit bats (Rousettus aegyptiacus), 78.1% (82/105) of Macronycteris vittatus, and one Sundevall's roundleaf bat (Hipposideros caffer) in Zambia. Phylogenetic analyses of the detected partial DPOL genes revealed that the Zambian bat herpesviruses were divided into seven betaherpesvirus groups and five gammaherpesvirus groups. Two infectious strains of a novel gammaherpesvirus, tentatively named Macronycteris gammaherpesvirus 1 (MaGHV1), were successfully isolated from Macronycteris vittatus bats, and their complete genomes were sequenced. The genome of MaGHV1 encoded 79 open reading frames, and phylogenic analyses of the DNA polymerase and glycoprotein B demonstrated that MaGHV1 formed an independent lineage sharing a common origin with other bat-derived gammaherpesviruses. Our findings provide new information regarding the genetic diversity of herpesviruses maintained in African bats. [ABSTRACT FROM AUTHOR]

When a metal electrode is inserted into a part of a plant, and another metal electrode is placed in the soil, an electrical potential difference is generated between the two electrodes. The plant has a lower potential than the soil. The generated voltage from the electrical potential difference between one plant and the adjacent soil is small (several hundred millivolts), and the current is extremely low (several hundred nanoamperes). However, in order to boot up some electrical circuits, the voltage and current need to be in the volt and microampere order, respectively. If the electrical potential difference between one plant and the soil is used as a power supply, it is necessary to develop a nanoscale electrical device that can work with extremely low wattage. Here we report a novel green battery composed of 10 pot plants by serial-parallel connections. The developed battery could generate almost 3 V and 3 µA to drive electric devices. We designed an LED blinking circuit composed of discrete semiconductor parts, which was driven by the generated plant power, and confirmed its performance through the experiments. © 2012 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc. [ABSTRACT FROM AUTHOR]

The number of multi-drug-resistant tuberculosis (MDR-TB) cases is rising worldwide. As a countermeasure against this situation, the implementation of rapid molecular tests to identify MDR-TB would be effective. To develop such tests, information on the frequency and distribution of mutations associating with phenotypic drug resistance in Mycobacterium tuberculosis is required in each country. During 2010, the common mutations in the rpoB , katG and inhA of 178 phenotypically MDR M. tuberculosis isolates collected by the National Tuberculosis Control Program (NTP) in Myanmar were investigated by DNA sequencing. Mutations affecting the 81-bp rifampicin (RIF) resistance-determining region (RRDR) of the rpoB were identified in 127 of 178 isolates (71.3%). Two of the most frequently affected codons were 531 and 526, with percentages of 48.3% and 14.0% respectively. For isoniazid (INH) resistance, 114 of 178 MDR-TB isolates (64.0%) had mutations in the katG in which a mutation-conferring amino acid substitution at codon 315 from Ser to Thr was the most common. Mutations in the inhA regulatory region were also detected in 20 (11.2%) isolates, with the majority at position −15. Distinct mutation rate and pattern from surrounding countries might suggest that MDR-TB has developed and spread domestically in Myanmar. [ABSTRACT FROM AUTHOR]

In vitro generation of hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) has the potential to provide novel therapeutic approaches for replacing bone marrow (BM) transplantation without rejection or graft versus host disease. Hitherto, however, it has proved difficult to generate truly functional HSCs transplantable to adult host mice. Here, we demonstrate a unique in vivo differentiation system yielding engraftable HSCs from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis. In mice, we found that iPSC-derived HSCs migrate from teratomas into the BM and their intravenous injection into irradiated recipients resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Using this in vivo generation system, we could demonstrate that X-linked severe combined immunodeficiency (X-SCID) mice can be treated by HSCs derived from gene-corrected clonal iPSCs. It should also be noted that neither leukemia nor tumors were observed in recipients after transplantation of iPSC-derived HSCs. Taken our findings together, our system presented in this report should provide a useful tool not only for the study of HSCs, but also for practical application of iPSCs in the treatment of hematologic and immunologic diseases. [ABSTRACT FROM AUTHOR]

Blastocyst complementation is an intriguing way of generating humanized animals for organ preparation in regenerative medicine and establishing novel models for drug development. Confirming that complemented organs and cells work normally in chimeric animals is critical to demonstrating the feasibility of blastocyst complementation. Here, we generated thymus-complemented chimeric mice, assessed the efficacy of anti-PD-L1 antibody in tumor-bearing chimeric mice, and then investigated T-cell function. Thymus-complemented chimeric mice were generated by injecting C57BL/6 (B6) embryonic stem cells into Foxn1nu/nu morulae or blastocysts. Flow cytometry data showed that the chimeric mouse thymic epithelial cells (TECs) were derived from the B6 cells. T cells appeared outside the thymi. Single-cell RNA-sequencing analysis revealed that the TEC gene-expression profile was comparable to that in B6 mice. Splenic T cells of chimeric mice responded very well to anti-CD3 stimulation in vitro; CD4+ and CD8+ T cells proliferated and produced IFNγ, IL-2, and granzyme B, as in B6 mice. Anti-PD-L1 antibody treatment inhibited MC38 tumor growth in chimeric mice. Moreover, in the chimeras, anti-PD-L1 antibody restored T-cell activation by significantly decreasing PD-1 expression on T cells and increasing IFNγ-producing T cells in the draining lymph nodes and tumors. T cells produced by complemented thymi thus functioned normally in vitro and in vivo. To successfully generate humanized animals by blastocyst complementation, both verification of the function and gene expression profiling of complemented organs/cells in interspecific chimeras will be important in the near future. [ABSTRACT FROM AUTHOR]

Background: Recent advances in cancer immunotherapy have been remarkable, with many reports on the clinical effects of immune checkpoint inhibitors. Nivolumab has been covered by the national health insurance in Japan as a third-line agent for advanced and recurrent gastric cancer since September 2017. The objective response rate for nivolumab for gastric cancer is 11.2%. However, patients' quality of life during this treatment has not been examined. Here, we report a case in which multidisciplinary treatment, including with nivolumab, resulted in long-term survival and improved quality of life.Case Presentation: A 70-year-old Asian woman was referred for surgery for gastric cancer. Postoperative pathological examination revealed peritoneal dissemination, and the patient was diagnosed with stage IV gastric cancer. Therefore, she was treated with S-1 and cisplatin based on negative immunohistochemical staining of resected specimens for human epidermal growth factor receptor 2. However, owing to instability and adverse events, treatment was subsequently changed to S-1 monotherapy. Two years after changing to S-1 monotherapy, she developed recurrence of peritoneal dissemination and was treated with docetaxel. Radiation therapy was also used because the recurrent lesions were local. However, 6 months later, new peritoneal dissemination and lymph node metastasis were observed and nivolumab was started. Subsequent abdominal computed tomography revealed a marked reduction in the disseminated nodules and lymphadenopathy. After 54 cycles of nivolumab, the lesions had disappeared completely. The patient has not developed side effects, including immune-responsive adverse events, has improved quality of life, and is returning to work. She is currently taking nivolumab, and there is no evidence of recurrence approximately 3 years after starting nivolumab.Conclusions: Nivolumab may have beneficial effects in some patients with advanced or recurrent gastric cancer. Although the prognosis for gastric cancer and peritoneal dissemination is poor, multidisciplinary treatment that includes nivolumab may lead to long-term survival. [ABSTRACT FROM AUTHOR]

Background: Early routine intubation in motor-complete cervical spinal cord injury (CSCI) above the C5 level is a conventional protocol to prevent unexpected respiratory exacerbation (RE). However, in the context of recent advances in multidisciplinary respiratory management, the absolute indication for intubation in patients with CSCI based on initial neurologic assessment is controversial because of the drawbacks of intubation. This study aimed to redetermine the most important predictor of RE following CSCI after admission without routine intubation among patients admitted with motor-complete injury and/or injury above the C5 level to ensure timely intubation.Methods: We performed a retrospective review of patients with acute traumatic CSCI admitted to our hospital without an initial routine intubation protocol from January 2013 to December 2017. CSCI patients who developed RE (defined as unexpected emergent intubation for respiratory resuscitation) were compared with those who did not. Baseline characteristics and severity of trauma data were collected. Univariate analyses were performed to compare treatment data and clinical outcomes between the two groups. Further, multivariate logistic regression was performed with clinically important independent variables: motor-complete injury, neurologic level above C5, atelectasis, and copious airway secretion (CAS).Results: Among 58 patients with CSCI, 35 (60.3%) required post-injury intubation and 1 (1.7%) died during hospitalization. Thirteen (22.4%) had RE 3.5 days (mean) post-injury; 3 (37.5%) of eight patients with motor-complete CSCI above C5 developed RE. Eleven of the 27 (40.7%) patients with motor-complete injury and five of the 22 (22.7%) patients with neurologic injury above C5 required emergency intubation at RE. Three of the eight CSCI patients with both risk factors (motor-complete injury above C5) resulted in emergent RE intubation (37.5%). CAS was an independent predictor for RE (odds ratio 7.19, 95% confidence interval 1.48-42.72, P = 0.0144) in multivariate analyses.Conclusion: Timely intubation post-CSCI based on close attention to CAS during the acute 3-day phase may prevent RE and reduce unnecessary invasive airway control even without immediate routine intubation in motor-complete injury above C5. [ABSTRACT FROM AUTHOR]

Background: Pteropine orthoreovirus (PRV) is an emerging bat-borne zoonotic virus that causes severe respiratory illness in humans. Although PRVs have been identified in fruit bats and humans in Australia and Asia, little is known about the prevalence of PRV infection in Africa. Therefore, this study performed an PRV surveillance in fruit bats in Zambia. Methods: Egyptian fruit bats (Rousettus aegyptiacus, n = 47) and straw-colored fruit bats (Eidolon helvum, n = 33) captured in Zambia in 2017–2018 were screened for PRV infection using RT-PCR and serum neutralization tests. The complete genome sequence of an isolated PRV strain was determined by next generation sequencing and subjected to BLAST and phylogenetic analyses. Replication capacity and pathogenicity of the strain were investigated using Vero E6 cell cultures and BALB/c mice, respectively. Results: An PRV strain, tentatively named Nachunsulwe-57, was isolated from one Egyptian fruit bat. Serological assays demonstrated that 98% of sera (69/70) collected from Egyptian fruit bats (n = 37) and straw-colored fruit bats (n = 33) had neutralizing antibodies against PRV. Genetic analyses revealed that all 10 genome segments of Nachunsulwe-57 were closely related to a bat-derived Kasama strain found in Uganda. Nachunsulwe-57 showed less efficiency in viral growth and lower pathogenicity in mice than another PRV strain, Miyazaki-Bali/2007, isolated from a patient. Conclusions: A high proportion of Egyptian fruit bats and straw-colored fruit bats were found to be seropositive to PRV in Zambia. Importantly, a new PRV strain (Nachunsulwe-57) was isolated from an Egyptian fruit bat in Zambia, which had relatively weak pathogenicity in mice. Taken together, our findings provide new epidemiological insights about PRV infection in bats and indicate the first isolation of an PRV strain that may have low pathogenicity to humans. Author summary: Pteropine orthoreovirus (PRV) is a causative agent of acute respiratory illness in humans in tropical and sub-tropical regions in Southeast Asia. PRVs have been originally isolated from fruit bats, and it is assumed that PRVs spread to humans by both bat-to-human and human-to-human transmission. Recently, an PRV was also detected from a fruit bat in the Afrotropical region and might potentially cause an emerging infection of the bat-borne zoonotic virus in Africa. However, little is known about the prevalence of PRV infection in Africa. In this study, we demonstrated the high prevalence of PRV infection in bat populations in Zambia and isolated a new strain of PRV from Egyptian fruit bats. In addition, we found that the bat-derived PRV strain had lower pathogenicity in mice than a human-derived PRV strain isolated from a patient in Southeast Asia. Our findings provide new epidemiological information about PRV in fruit bats in the Afrotropical region and indicate the first isolation of an PRV strain that may cause attenuated infection in humans. [ABSTRACT FROM AUTHOR]

The prediction of a perioperative adverse cardiovascular event (PACE) is an important clinical issue in the medical management of patients undergoing noncardiac surgery. Although several predictors have been reported, simpler and more practical predictors of PACE have been needed. The aim of this study was to investigate the predictors of PACE in noncardiac surgery. We retrospectively analyzed 723 patients who were scheduled for elective noncardiac surgery and underwent preoperative examinations including 12-lead electrocardiography, transthoracic echocardiography, and blood test. PACE was defined as cardiac death, non-fatal myocardial infarction, unstable angina, congestive heart failure, arrhythmia attack that needs emergency treatment (rapid atrial fibrillation, ventricular tachycardia, and bradycardia), acute pulmonary embolism, asystole, pulseless electrical activity, or stroke during 30 days after surgery. PACE occurred in 54 (7.5%) of 723 patients. High-risk operation (11% vs. 3%, p = 0.003) was more often seen, left ventricular ejection fraction (LVEF) (55 ± 8% vs. 60 ± 7%, p = 0.001) and preoperative hemoglobin level (11.8 ± 2.2 g/dl vs. 12.7 ± 2.0 g/dl, p = 0.001) were lower in patients with PACE compared to those without PACE. By multivariate logistic regression analysis, high-risk operation (odds ratio (OR): 7.05, 95% confidence interval (CI) 2.16–23.00, p = 0.001), LVEF (OR 1.06, every 1% decrement, 95% CI 1.03–1.09, p = 0.001), and preoperative hemoglobin level (OR 1.22, every 1 g/dl decrement, 95% CI 1.07–1.39, p = 0.003) were identified as independent predictors of PACE. Receiver operating characteristic analysis demonstrated that LVEF of 58% (sensitivity = 80%, specificity = 61%, area under the curve (AUC) = 0.723) and preoperative hemoglobin level of 12.2 g/dl (sensitivity = 63%, specificity = 64%, AUC = 0.644) were optimal cut-off values for predicting PACE. High-risk operation, reduced LVEF, and reduced preoperative hemoglobin level were independently associated with PACE in patients undergoing noncardiac surgery. [ABSTRACT FROM AUTHOR]

Background: Subdiaphragmatic abscesses are sometimes caused by intraabdominal infections. We report a case of endoscopic ultrasound-guided transgastric drainage.Case Presentation: A 75-year-old Asian man was referred to our hospital for treatment for upper gastrointestinal bleeding. On admission, blood tests showed a marked inflammatory response, and abdominal computed tomography showed free air in the abdominal cavity and a left subdiaphragmatic abscess. Therefore, the patient was diagnosed with an intraabdominal abscess associated with a perforated duodenal ulcer. Because he did not have generalized peritonitis, fasting and antibiotic treatment were the first therapies. However, because of the strong pressure on the stomach associated with the abscess and difficulty eating, we performed endoscopic ultrasound-guided transgastric drainage. After treatment, the inflammatory response resolved, and food intake was possible. The patient's condition remains stable.Conclusions: Drainage is the basic treatment for subdiaphragmatic abscesses; however, percutaneous drainage is often anatomically difficult, and surgical drainage is common. We suggest that our success with endoscopic ultrasound-guided transgastric drainage in this patient indicates that this approach can be considered in similar cases and that it can be selected as a minimally invasive treatment method. [ABSTRACT FROM AUTHOR]

Background: Xanthogranulomatous cholecystitis (XGC) is a rare inflammatory gallbladder disease which is difficult to diagnose and treat; XGC may be confused with gallbladder cancer. The present study aimed to evaluate the clinical and radiological features and surgical outcomes, with the aim to determine the appropriate treatment approaches for XGC. Methods: This retrospective study analyzed the clinical characteristics, intraoperative findings, and postoperative outcomes of 31 patients (2.0%) who were diagnosed with XGC based on histopathological findings among 1513 patients who underwent cholecystectomy at our hospital between January 2010 and July 2019. Results: Preoperative ultrasonography and computed tomography findings indicated acute cholecystitis, chronic cholecystitis, and suspicious XGC in 26 (83.9%) patients with thickening of the gallbladder wall and suspicious gallbladder cancer in 5 (16.1%) patients. Abdominal pain and jaundice were observed in 18 (58.1%) patients and 5 (16.1%) patients, respectively. Biliary drainage before surgery was performed in 21 (67.7%) patients. Laparoscopic cholecystectomy, which was performed in 23 (74.2%) patients, was converted to open cholecystectomy in 12 (52.2%) of these 23 patients. Among the patients with other diseases treated during the study period, laparoscopic cholecystectomy was performed in 1377 patients and converted to open surgery in 71 (5.2%) patients. Five patients with suspicious gallbladder cancer underwent open surgery. In these patients, intraoperative frozen section analysis was useful in distinguishing between XGC and gallbladder cancer and was important in avoiding unnecessarily extended surgery. Conclusion: Laparoscopic cholecystectomy for XGC is possible, but often difficult due to severe inflammation. The frequency of conversion to open surgery is higher in patients with XGC than those with other forms of cholecystitis. XGC may resemble gallbladder cancer based on the diagnostic imaging findings, and intraoperative frozen section analysis is essential to avoid unnecessarily extended surgery. [ABSTRACT FROM AUTHOR]

An 87-year-old man complaining of abdominal distention was referred to our hospital. Plain radiograph and enhanced computed tomography (CT) showed a dilated sigmoid colon with a coffee bean sign, leading to the diagnosis of sigmoid volvulus. Based on symptoms and the CT and laboratory test findings, we initially treated the patient with endoscopic reduction, resulting in successful reduction of the sigmoid volvulus with widespread presumed mucosal ischemia. Due both to the lack of emerging symptoms suggesting colon perforation and to the laboratory test findings after endoscopic reduction, we treated the patient without further urgent surgical intervention. Two months later, the patient underwent successful elective laparoscopic surgery with a redundant sigmoid colon resection and a functional end-to-end anastomosis. He has been well without any events for 20 months. Conservative treatment with careful observation should be taken into consideration in the treatment of sigmoid volvulus with mild to moderate ischemia after endoscopic reduction. [ABSTRACT FROM AUTHOR]

Background: Thrombosis of the internal jugular vein occasionally occurs in association with long-term placement of a central venous catheter; however, such complications rarely involve calcification within the blood vessels. We report a case of calcification and abscess formation around a central venous catheter tip.Case Presentation: Our patient was an 84-year-old Asian woman who developed a fever that had started approximately 5 months after the placement of a central venous catheter. At the time of presentation, blood tests showed a marked inflammatory response, and chest computed tomography showed a high absorption area and air density around the catheter tip. Therefore, the patient was diagnosed with abnormal intravascular calcification and a deep neck abscess associated with long-term central venous catheter placement. The initial plan was to administer antibiotics and remove the central venous catheter. However, central venous catheter removal was deemed difficult due to the calcification and therefore required an incision. Because of the patient's advanced age and dementia, her family requested antibiotic treatment only. Following antibiotic treatment, the patient's inflammatory response normalized, and her fever resolved. The treatment was discontinued, and the patient's condition gradually stabilized.Conclusions: Catheter-related complications of central venous catheter placement include vascular occlusion, extravasation of the infusion, and infection. However, abnormal calcification in the blood vessels is extremely rare, and there has been only one case report of a neonate with central venous catheter-related vascular calcification in Japan. The etiology of intravascular calcification is considered to be related to the infusion content and the infusion rate of high caloric infusions and blood products. The incidence of complications associated with long-term central venous catheter placement is expected to increase with the increasing aging of the population and advances in chemotherapy. The report of the clinical course of this rare case adds to the body of knowledge in this area. [ABSTRACT FROM AUTHOR]