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.     

Gamma knife radiosurgery cured hydrocephalus in non-hemorrhagic brain stem arteriovenous malformation

A 13-year-old boy, with a history of intermittent headache and transient diplopia, was found to have non-hemorrhagic cerebral arteriovenous malformation in the midbrain tegmental region associated with hydrocephalus. Gamma knife radiosurgery was performed at 16 Gy with 75% marginal dose. Posttreatment course was uneventful. Follow-up MR imaging at one year after the treatment revealed complete disappearance of the abnormal vascular flow voids. The size of each ventricle at the treatment and at one year after treatment were as follows; 60.2 cc and 20.9 cc in the lateral ventricles, 3.7 cc and 2.7 cc in the third ventricle. The hydrocephalus might be caused by obstructive mechanism but mostly by high venous pressure due to the shunt blood flow. The goal of treatment for hydrocephalus should be nidus obstruction and normalizing the vascular flow.     

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.     

Wound,pressure ulcer and burn guidelines – 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.     

Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice

The accumulation of abnormal prion protein (PrP^Sc) produced by the structure conversion of PrP (PrP^C) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the structure of PrP^C and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrP^Sc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrP^Sc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00903-9) contains supplementary material, which is available to authorized users.