Differential induction of helper and killer T cells from isolated CD4+CD8+ thymocytes in suspension culture

Thymocytes of T cell receptor transgenic mice with nonselecting and RAG-2^−/− backgrounds were developmentally arrested at the CD4⁺CD8⁺ stage before positive selection. These thymocytes underwent lineage commitment upon transient stimulation with a combination of ionomycin, a calcium ionophore, and phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, in suspension culture. The effective drug doses were limited within narrow ranges and much lower than those which induce proliferation of mature T cells. The doses corresponded to those which inhibit glucocorticoid-induced apoptosis in these thymocytes. CD4 lineage commitment required longer duration, higher intensity of the stimulation, or both, than CD8 lineage commitment. Functional helper T cells (Th1 and Th2) were induced from the CD4 lineage-committed cells upon secondary stimulation with a combination of ionomycin and PMA followed by lymphokine treatment. Cytotoxic T cells were induced from the CD8 lineage-committed cells upon incubation with concanavalin A and irradiated splenic dendritic cells, but not with the combination of ionomycin and PMA. These results indicate that positive selection is mimicked by the pharmacological stimulation in the absence of other cell types, but that final maturation of CD8 T cells may require a different signal.     

Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index

Aims/IntroductionTo investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD).Materials and MethodsThe subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25–30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected.ResultsThe median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (β = 0.340, P = 0.004) and the age at examination (β = −0.288, P = 0.012) according to the multiple regression analysis.ConclusionsThe average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination.     

Psoas muscle size,possible sarcopenia and frailty,and long-term survival in elderly patients after isolated surgical aortic valve replacement for aortic stenosis

PurposeThis study investigated the use of psoas muscle area index (PAI) as an indicator of mortality risk in relation to survival in elderly patients after isolated surgical aortic valve replacement (SAVR) for aortic valve stenosis (AS).MethodsBetween January 2005 and March 2015, 140 patients with AS, aged ≥ 70 years, and with preoperative abdominal computed tomography scans, underwent elective, primary, isolated SAVR. PAI showed the ratio of the psoas muscle cross-sectional area at the fourth lumbar vertebral level to body surface area, and PAI less than the gender-specific lowest 20th percentile we called “low PAI” for the purposes of this study. Patients were classified as low PAI (n = 29) or normal PAI (n = 111).ResultsThe mean age in the low-PAI group was significantly older than in the normal-PAI group (81.0 vs. 77.3 years; p = 0.001). The mean follow-up was 4.25 years. The low-PAI group had a lower survival rate than the normal-PAI group at 1 year (89.7 ± 5.7% vs. 96.3 ± 1.8%), at 3 years (71.6 ± 9.3% vs. 91.5 ± 2.7%), and overall (53.0 ± 13.4% vs. 76.0 ± 5.6%; p = 0.039). The prognostic factors of mortality included low PAI (hazard ratio 2.95; 95% confidence interval 1.084–8.079; p = 0.034).ConclusionsPAI was associated with reduced overall survival after isolated SAVR in elderly people. PAI measurement may help to predict patient risks.     

Epstein-Barr Virus-positive Intestinal Diffuse Large B-cell Lymphoma in a Japanese Patient with Celiac Disease: First Reported Case and a Literature Review

A 60-year-old Japanese woman was diagnosed with celiac disease (CeD) and treated with a gluten-free diet. For five years, she had a good clinical course. However, she complained of inappetence and nausea. Colonoscopy revealed ulcerative tumors in the terminal ileum. A histological examination of biopsy specimens from the ulcerative tumor showed diffuse infiltration of large atypical lymphocytes. Immunohistologically, the atypical lymphoid cells were positive for cluster of differentiation (CD)10 and CD20. Many Epstein-Barr virus-encoded small RNA (EBER)-positive atypical lymphocytes were detected by in situ hybridization. This represents the first reported case of Epstein-Barr virus-positive intestinal diffuse large B-cell lymphoma complicated with CeD.     

Endovascular Treatment for Lower-extremity Arterial Thrombosis in a Patient with Congenital Afibrinogenemia and a History of Bleeding Complications

Congenital afibrinogenemia is a rare autosomal recessive blood disorder that accompanies thrombotic complications and is associated with bleeding tendency. The management of these opposing complications remains a challenge. Endovascular treatment (EVT) for peripheral arterial thrombosis has not been described in previous studies. A 57-year-old man with congenital afibrinogenemia developed back pain and left lower leg pain. The cause of the pain was confirmed to be renal infarction and lower extremity arterial thrombosis by Doppler ultrasound and contrast-enhanced computed tomography. He was treated with EVT for the lower extremity arterial thrombosis, leading to an excellent short-term improvement without bleeding.     

Mural vegetation in left ventricular apex caused by Staphylococcus aureus

A 77-year-old male on chronic haemodialysis was admitted for repeated episodes of stroke and a high fever. The patient’s blood culture was positive for Staphylococcus aureus and echocardiogram results revealed moderate mitral valve regurgitation, small masses in the left atrial appendage and a 20-mm mobile, spherical structure attached to the apical cavity of the left ventricle. Surgery was conducted to successfully excise these masses and pathological investigation confirmed the diagnosis of infective endocarditis. The attachment of mobile, spherical vegetation to the apex of the left ventricle is a rare manifestation of infective endocarditis.     

Zr- and Ce-doped Li6Y(BO3)3 electrolyte for all-solid-state lithium-ion battery

The ionic conductivity of Li₆Y(BO₃)₃ (LYBO) was enhanced by the substitution of tetravalent ions (Zr⁴⁺ and Ce⁴⁺) for Y³⁺ sites through the formation of vacancies at the Li sites, an increase in compact densification, and an increase in the Li⁺-ion conduction pathways in the LYBO phase. As a result, the ionic conductivity of Li_5.875Y_0.875Zr_0.1Ce_0.025(BO₃)₃ (ZC-LYBO) reached 1.7 × 10⁻⁵ S cm⁻¹ at 27 °C, which was about 5 orders of magnitude higher than that of undoped Li₆Y(BO₃)₃. ZC-LYBO possessed a large electrochemical window and was thermally stable after cosintering with a LiNi_1/3Mn_1/3Co_1/3O₂ (NMC) positive electrode. These characteristics facilitated good reversible capacities in all-solid-state batteries for both NMC positive electrodes and graphite negative electrodes via a simple cosintering process.

Ionic conductivity of Li₆Y(BO₃)₃ (LYBO) is enhanced by the substitution of tetravalent ions through an increase in the conduction pathways etc. Zr,Ce-doped LYBO can be used as an electrolyte for all-solid-state batteries via a cosintering process.     

Solution-phase synthesis of oligodeoxyribonucleotides using the H-phosphonate method with N-unprotected 5′-phosphite monomers

Recent advances in nucleic acid therapeutics increase the requirements for developing efficient methods for the chemical synthesis of oligodeoxyribonucleotides (ODNs). In this study, we report a new approach for the solution-phase synthesis of ODNs using the H-phosphonate method with N-unprotected 5′-phosphite monomers. The 5′-phosphite monomers are synthesized in a single step from unprotected 2′-deoxyribonucleosides using 5′-O-selective phosphitylation and can be applied to the synthetic cycle of the H-phosphonate method. We synthesized four kinds of 5′-phosphite monomers and then optimized the conditions for the condensation between the 3′-hydroxy groups of the 5′-phosphite monomers and the H-phosphonate monoesters. As a result of various investigations, solution-phase synthesis of trithymidine diphosphate (TTT) and tetramers containing four kinds of nucleobases was achieved according to the procedure consisting of repeated condensation, deprotection, and purification using simple extraction or precipitation.

A new strategy for a solution-phase synthesis of oligodeoxyribonucleotides with 5′-phosphite monomers synthesized in a single step from unprotected 2′-deoxyribonucleosides.     

Comparison of endoscopic ultrasound-guided choledochoduodenostomy and endoscopic retrograde cholangiopancreatography in first-line biliary drainage for malignant distal bile duct obstruction: A multicenter randomized controlled trial

Introduction:In patients with malignant distal bile duct obstruction and normal gastrointestinal anatomy, endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) is indicated when endoscopic retrograde cholangiopancreatography (ERCP) fails. The ERCP drainage route passes through the tumor, whereas the EUS-CDS route does not. Therefore, EUS-CDS is expected to have a longer stent patency than ERCP. However, for first-line biliary drainage, it remains unclear whether EUS-CDS or ERCP is superior in terms of stent patency. To reduce the frequency of highly adverse events (AEs) such as bile peritonitis or stent migration following EUS-CDS, we developed an antimigration metal stent with a thin delivery system for tract dilatation. This study is designed to assess whether EUS-CDS with this novel stent is superior to ERCP with a traditional metal stent in terms of stent patency when the two techniques are used for first-line drainage of malignant distal biliary obstruction.Methods/design:This study is a multicenter single-blinded randomized controlled trial (RCT) involving 95 patients in four tertiary centers. Patients with malignant distal biliary obstruction that is unresectable or presents a very high surgical risk and who pass the inclusion and exclusion criteria will be randomized to EUS-CDS or ERCP in a 1:1 proportion. The primary endpoint is the stent patency rate 180 days after stent insertion. Secondary outcomes include the rates of technical success, clinical success, technical success in cases not requiring fistulous-tract dilation (only EUS-CDS group), procedure-related AEs, re-intervention success, patients receiving post-drainage chemotherapy, procedure time, and overall survival time.Discussion:If EUS-CDS is superior to ERCP in terms of stent patency and safety for the first-line drainage of malignant distal biliary obstruction, it is expected that the first-line drainage method will be changed from ERCP to EUS-CDS, and that interruption of chemotherapy due to stent dysfunction can be avoided.Trial registration:University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), ID: UMIN000041343. Registered on August 6, 2020. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047201Version number: 1.2, December 7, 2020.     

Exacerbation of Established Collagen-Induced Arthritis in Mice Treated with An Anti—T Cell Receptor Antibody

Objective. To investigate the effect of T cell depletion on established collagen-induced arthritis (CIA) in mice, using monoclonal antibodies (MAb) to T cell receptor α/β (TCRα/β). In addition, experiments using anti-CD3 MAb were performed for comparison. Methods. CIA was induced in male DBA/1 mice by immunizing them twice with bovine type II collagen (CII). The arthritis score and anti-CII antibody titers were examined serially. Proportions of T cells were determined by fluorescence-activated cell sorter (FACS) analysis on spleen cells or peripheral blood cells. Results. When anti-TCRα/β MAb was injected on the day of CII priming, no arthritis was detected in association with depressed anti-CII antibody titers. Unexpectedly, however, when MAb was given after arthritis was established, a rapid exacerbation of arthritis was observed, which resulted in ankylosis of most joints. Anti-CII antibody titers were not affected. The addition of anti-TCRγ/δ MAb had no effect on the augmented arthritis. T cell depletion by anti-CD3 MAb during established CIA also caused an enhancement of arthritis, which was, however, weak and only transient. FACS analysis revealed that the early improvement of arthritis after the transient augmentation seen in the mice treated with anti-CD3 MAb paralleled the early recovery of α/β T cells in the periphery. Conclusion. The present results support the concept that α/β T cells, in general, may play a regulatory role in the clinical course of murine CIA after disease onset. Therefore, caution is recommended when using intensive T cell—targeted therapy in patients with rheumatoid arthritis.