Characterizing Small-Scale Dynamics of Navier-Stokes Turbulence with Transverse Lyapunov Exponents: A Data Assimilation Approach.

Data assimilation (DA) of turbulence, which involves reconstructing small-scale turbulent structures based on observational data from large-scale ones, is crucial not only for practical forecasting but also for gaining a deeper understanding of turbulent dynamics. We propose a theoretical framework for DA of turbulence based on the transverse Lyapunov exponents (TLEs) in synchronization theory. Through stability analysis using TLEs, we identify a critical length scale as a key condition for DA; turbulent dynamics smaller than this scale are synchronized with larger-scale turbulent dynamics. Furthermore, considering recent findings for the maximal Lyapunov exponent and its relation with the TLEs, we clarify the Reynolds number dependence of the critical length scale.

Single response assessment of transplant-ineligible multiple myeloma: a supplementary analysis of JCOG1105 (JCOG1105S1).

BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with FLT3-internal tandem duplication AML: The JALSG AML209-FLT3-SCT study.

In this phase II multicenter study (JALSG AML209-FLT3-SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) for FLT3-internal tandem duplication (ITD)-positive AML. Newly diagnosed de novo AML patients with FLT3-ITD were enrolled at the achievement of CR1 and received allo-HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17-49) years, 36 (75%) received allo-HSCT at a median of 108 days after CR1. The median follow-up was 1726 days. The primary end-point, 3-year disease-free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%-57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3-year overall survival, post-transplant DFS, and non-relapse mortality rates were 54.2% (95% CI, 39%-67%), 58.3% (95% CI, 41%-72%), and 25.0% (95% CI, 12%-40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006-4.099). Neither FLT3-ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo-HSCT for FLT3-ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Long-Term Effect of Promoting In-Hospital Physical Activity on Postdischarge Patients with Mild Ischemic Stroke.

BACKGROUND: Although there are reports on the promotion of physical activity during hospitalization, there is no evidence that promoting in-hospital physical activity continues over time after discharge. The purpose of this study was to evaluate the long-term effect of promoting in-hospital physical activity on postdischarge physical activity and self-efficacy for physical activity in patients with mild ischemic stroke. METHODS: This was a cross-sectional study of a post hoc analysis of a previous randomized controlled trial. Patients with mild ischemic stroke were divided into the intervention group (in which physical activity was promoted during hospitalization) and a control group. To promote in-hospital physical activity, patients in the intervention group were instructed in the self-monitoring approach. After discharge, we measured physical activity and self-efficacy for physical activity by mailing a questionnaire to the patients. The average number of steps taken was used the index of postdischarge physical activity. RESULTS: The study sample comprised 30 patients, with 13 patients in the intervention group and 17 patients in the control group. There were no significant differences in physical activity values (6176.8 versus 6112.8 steps/day, P = .932) and self-efficacy for physical activity score (66.0 versus 76.0 points, P = .801) between the 2 groups. CONCLUSIONS: This study showed that the promotion of in-hospital physical activity did not appear to increase physical activity and self-efficacy for physical activity in patients with mild ischemic stroke after discharge. Additional study is needed to establish a more specific approach to promote physical activity during hospitalization that will carry over during long-term follow-up.

Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma.

A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal-naïve patients with relapsed or refractory multiple myeloma (RRMM). Patients ≥20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m2 ) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3-week cycle) were followed by maintenance phase (5-week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end-point was 1-year progression-free survival (PFS). Forty-four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow-up of 34.3 months, the 1-year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%-64.3%) and 31.8% (95% CI, 14.2%-51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3-year overall survival (OS) was 70.0% (95% CI, 44.9%-85.4%) in the BD, and 48.8% (95% CI, 25.1%-69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1-year PFS and 3-year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal-naïve RRMM patients. (Clinical trial registration no. UMIN000003135.).

Heart Rate Variability During Early Mobilization in Patients with Acute Ischemic Stroke.

Autonomic dysfunction is one of the predictors of poor outcome in patients with acute ischemic stroke. We compared the heart rate variability (HRV) during early mobilization in patients with or without neurological deterioration (ND). We enrolled 7 acute ischemic patients with ND and 14 without ND and measured their HRV in the rest and mobilization by electrocardiography. There was a significant difference in sympathetic nervous activity during mobilization between the 2 groups. However, no significant differences in blood pressure, heart rate, and parasympathetic nerve activity were observed. In patients with acute ischemic stroke, it is likely that the increase in sympathetic nervous activity during mobilization is associated with ND.

Physical Activity, Physical Function, and Quadriceps Muscle Thickness in Male Patients with Sub-Acute Stroke during Hospitalization: A Pilot Study.

Increasing physical activity (PA) is an important rehabilitation target for patients with sub-acute stroke during hospitalization in order to recover physical function and prevent stroke recurrence. However, the characteristics of low PA in stroke patients during hospitalization who were targets for increased intervention have not been reported. The purpose of this study was to investigate the relationship between the daily number of steps and physical function and quadriceps muscle thickness (QMT) in patients with sub-acute stroke during hospitalization for convalescence rehabilitation. Twenty-nine patients with ischemic or haemorrhagic stroke (mean age, 69 ± 11 years) hospitalized for inpatient convalescent rehabilitation were included. PA was measured using a three-dimensional accelerometer that calculates the daily number of steps taken. Physical function was measured by a short physical performance battery (SPPB; 0-12 points) and the leg motor selectivity score (6 motor stages defined by Brunnstrom), and the QMT of both legs was measured using ultrasonography. PA was significantly correlated with the SPPB score (r = 0.63, p = 0.0002), QMT on the paretic side (r = 0.41, p = 0.02), and QMT on non-paretic side (r = 0.56, p = 0.002). There were no significant effects of the leg motor selectivity score on daily PA (F = 1.37, p = 0.27). In the multiple regression analysis, only the SPPB score showed significant linear regression (ß = 0.44, p = 0.02). PA in male patients with sub-acute stroke during hospitalization was related to physical function and QMT and not with the severity of paresis.

Effect of accelerometer-based feedback on physical activity in hospitalized patients with ischemic stroke: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of accelerometer-based feedback on physical activity in hospitalized patients with ischemic stroke. DESIGN: Randomized controlled trial. SETTING: Acute care hospital. SUBJECTS: A total of 55 patients with ischemic stroke who could walk without assistance were randomly assigned to the intervention group ( n = 27) or the control group ( n = 28). INTERVENTIONS: At the baseline measurement, patients did not receive accelerometer-based feedback. At follow-up, a physical therapist provided instruction on accelerometer-based feedback, discussed physical activity targets and encouraged the patients to walk more until discharge. MAIN MEASURES: The average daily number of steps taken was used as the index of daily hospitalized physical activity. RESULTS: The study sample consisted of 48 patients, of whom 23 patients comprised the intervention group and 25 patients comprised the control group. Although there were no significant differences in physical activity values between the two groups at the baseline measurement, the values in the intervention group at follow-up were significantly higher than those in the control group (5180.5 ± 2314.9 vs. 3113.6 ± 1150.9 steps/day, P = 0.0003). The effect size of physical activity values (Cohen's d = 1.15) at follow-up was large between the two groups. CONCLUSION: Exercise training combined with accelerometer-based feedback effectively increased physical activity in hospitalized patients with ischemic stroke.

Allogeneic Hematopoietic Cell Transplantation for Dyskeratosis Congenita: A Report of 3 Cases.

Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Careful follow-up of patient-specific complications is required after allo-HCT in patients with DKC.

Network analysis of chaotic systems through unstable periodic orbits.

A chaotic motion can be considered an irregular transition process near unstable periodic orbits embedded densely in a chaotic set. Therefore, unstable periodic orbits have been used to characterize properties of chaos. Statistical quantities of chaos such as natural measures and fractal dimensions can be determined in terms of unstable periodic orbits. Unstable periodic orbits that can provide good approximations to averaged quantities of chaos or turbulence are also known to exist. However, it is not clear what type of unstable periodic orbits can capture them. In this paper, a model for an irregular transition process of a chaotic motion among unstable periodic orbits as nodes is constructed by using a network. We show that unstable periodic orbits which have lots of links in the network tend to capture time averaged properties of chaos. A scale-free property of the degree distribution is also observed.

Pisiferdiol restores the growth of a mutant yeast suffering from hyperactivated Ca2+ signalling through calcineurin inhibition.

In the course of our screening program for a new inhibitor of the Ca(2+) signalling pathway using mutant yeast [Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ)], a mouse PP2Cα activator, pisiferdiol, isolated from Chamaecyparis pisifera, was found to alleviate the Ca(2+) signal-mediated growth inhibition. Pisiferdiol showed growth inhibition activity against the mpk1Δ strain compared with the cnb1Δ strain and induced Li(+) sensitivity to the wild-type strain, indicating that it suppresses the calcineurin pathway in the yeast. However, the Li(+) sensitivity to ptc1Δ strain by pisiferdiol was diminished. Pisiferdiol showed growth restored activity in the zds1Δ strain without immunophilins Fkb1p or Cph1p, and in the pmc1Δ strain. It inhibited calcineurin-induced expression in the reporter gene assay and decreased the protein expression (Western blots) of calcineurin (Cnb1p) in addition to a decrease of Swe1p and phosphorylation of Cdc28p in the mutant yeast. These results showed that pisiferdiol could suppress indirectly the action of calcineurin and restored the growth inhibition of the mutant yeast through Ptc1p activation.

A case of traumatic intrapleural foreign body with progressive supranuclear palsy removed by thoracoscopic surgery.

Traumatic intrathoracic foreign bodies are said to occur in many cases when the patient himself/herself is aware of the trauma. However, at the time of injury, the patient may sometimes be accompanied by loss of consciousness. We report a case of traumatic intrathoracic foreign body that was difficult to diagnose due to loss of consciousness at the time of injury. A 51-year-old female was brought to our emergency department with a fall trauma due to loss of consciousness while bathing. The head computed tomography and electrocardiogram showed no abnormalities, and the laceration of approximately 3 cm in length was found on the left side thorax, and it was sutured and the patient was sent home. Four days later, she returned to our hospital with a complaint of left anterior chest pain, and chest X-ray showed a left degree pneumothorax and mediastinal emphysema. She underwent semi-emergency thoracoscopic removal of the foreign body, and was discharged from the hospital on the fourth postoperative day. She had progressive supranuclear palsy, and her memory at the time of injury was not clear due to loss of consciousness caused by central autonomic neuropathy, and she also had dementia, making it difficult to interview her. She had no thoracic symptoms, and the glass fragment that had strayed into the thoracic cavity was not exposed outside the body, making the diagnosis difficult at the time of initial examination. When a patient with loss of consciousness is difficult to interview at the time of injury, it is advisable to perform an imaging examination appropriate for the site of injury, taking into consideration the presence of foreign bodies.

Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation.

Relapsed leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a significant challenge, with the re-emergence of the primary disease being the most frequent cause of death. Human leukocyte antigen (HLA)-DPB1 mismatch occurs in approximately 70% of unrelated allo-HSCT cases, and targeting mismatched HLA-DPB1 is considered reasonable for treating relapsed leukemia following allo-HSCT if performed under proper conditions. In this study, we established several clones restricted to HLA-DPB1*02:01, -DPB1*04:02, and -DPB1*09:01 from three patients who underwent HLA-DPB1 mismatched allo-HSCT using donor-derived alloreactive T cells primed to mismatched HLA-DPB1 in the recipient's body after transplantation. A detailed analysis of the DPB1*09:01-restricted clone 2A9 showed reactivity against various leukemia cell lines and primary myeloid leukemia blasts, even with low HLA-DP expression. T cell receptor (TCR)-T cells derived from clone 2A9 retained the ability to trigger HLA-DPB1*09:01-restricted recognition and lysis of various leukemia cell lines in vitro. Our study demonstrated that the induction of mismatched HLA-DPB1 specific T cell clones from physiologically primed post-allo-HSCT alloreactive CD4+ T cells and the redirection of T cells with cloned TCR cDNA by gene transfer are feasible as techniques for future adoptive immunotherapy.

Collective bending motion of a two-dimensionally correlated bowl-stacked columnar liquid crystalline assembly under a shear force.

Stacked teacups inspired the idea that columnar assemblies of stacked bowl-shaped molecules may exhibit a unique dynamic behavior, unlike usual assemblies of planar disc- and rod-shaped molecules. On the basis of the molecular design concept for creating higher-order discotic liquid crystals, found in our group, we synthesized a sumanene derivative with octyloxycarbonyl side chains. This molecule forms an ordered hexagonal columnar mesophase, but unexpectedly, the columnar assembly is very soft, similar to sugar syrup. It displays, upon application of a shear force on solid substrates, a flexible bending motion with continuous angle variations of bowl-stacked columns while preserving the two-dimensional hexagonal order. In general, alignment control of higher-order liquid crystals is difficult to achieve due to their high viscosity. The present system that brings together higher structural order and mechanical softness will spark interest in bowl-shaped molecules as a component for developing higher-order liquid crystals with unique mechanical and stimuli-responsive properties.

Autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia is safe but poses challenges for long-term maintenance of molecular remission: Results of the Auto-Ph17 study.

Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34+ cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission.

Discovery of novel and potent CRTH2 antagonists.

High throughput screening of our chemical library for CRTH2 antagonists provided a lead compound 1a. Initial optimization of the lead led to the discovery of a novel, potent and orally bioavailable CRTH2 antagonist 17.

Therapeutic potential of ASP3258, a selective phosphodiesterase 4 inhibitor, on chronic eosinophilic airway inflammation.

We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-α production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an α(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α(2) - adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

Design of discotic liquid crystal enabling complete switching along with memory of homeotropic and homogeneous alignment over a large area.

The alignment control of discotic columnar liquid crystals (LCs), featuring a low motility of the constituent molecules and thus having a large viscosity, is a challenging task. Here we show that triphenylene hexacarboxylic ester, when functionalized with hybrid side chains consisting of alkyl and perfluoroalkyl groups in an appropriate ratio, gives a hexagonal columnar (Colh) LC capable of selectively forming large-area uniform homeotropic or homogeneous alignments, upon cooling from its isotropic melt or upon application of a shear force at its LC temperature, respectively. In addition to the alignment switching ability, each alignment state remains persistent unless the LC is heated to its melting temperature. In situ X-ray diffraction analysis under the application of a shear force, together with polarized optical microscopy observations, revealed how the columnar assembly is changed during the alignment-switching process. The remarkable behavior of the discotic LC is discussed in terms of its rheological properties.

A pitfall in hemoglobin A1c measurement with high performance liquid chromatography method in the diagnosis of onset of fulminant type 1 diabetes mellitus.

We showed a case with the onset of fulminant type 1 diabetes mellitus (FT1DM) whose HbA1c could not be measured with HPLC method. We think that the reason why his HbA1c was not be detected was associated with the presence of labile hemoglobin A1c (LHbA1c). These result mean that it is possible that LHbA1c can bring about a pitfall on HPLC method in diagnosis of onset of FT1DM.