Observation of the Exotic 0_{2}

We report here the first observation of the 0_{2}^{+} state of ^{8}He, which has been predicted to feature the condensatelike α+^{2}n+^{2}n cluster structure. We show that this state is characterized by a spin parity of 0^{+}, a large isoscalar monopole transition strength, and the emission of a strongly correlated neutron pair, in line with theoretical predictions. Our finding is further supported by the state-of-the-art microscopic α+4n model calculations. The present results may lead to new insights into clustering in neutron-rich nuclear systems and the pair correlation and condensation in quantum many-body systems under strong interactions.

Probing the Symmetry Energy with the Spectral Pion Ratio.

Many neutron star properties, such as the proton fraction, reflect the symmetry energy contributions to the equation of state that dominate when neutron and proton densities differ strongly. To constrain these contributions at suprasaturation densities, we measure the spectra of charged pions produced by colliding rare isotope tin (Sn) beams with isotopically enriched Sn targets. Using ratios of the charged pion spectra measured at high transverse momenta, we deduce the slope of the symmetry energy to be 42

Fragmentation of Single-Particle Strength around the Doubly Magic Nucleus

Spectroscopic factors of neutron-hole and proton-hole states in ^{131}Sn and ^{131}In, respectively, were measured using one-nucleon removal reactions from doubly magic ^{132}Sn at relativistic energies. For ^{131}In, a 2910(50)-keV γ ray was observed for the first time and tentatively assigned to a decay from a 5/2^{-} state at 3275(50) keV to the known 1/2^{-} level at 365 keV. The spectroscopic factors determined for this new excited state and three other single-hole states provide first evidence for a strong fragmentation of single-hole strength in ^{131}Sn and ^{131}In. The experimental results are compared to theoretical calculations based on the relativistic particle-vibration coupling model and to experimental information for single-hole states in the stable doubly magic nucleus ^{208}Pb.

Current status of integrating oncology and palliative care in Japan: a nationwide survey.

BACKGROUND: Palliative care (PC) is increasingly recognized as essential for oncology care, and several academic societies strongly recommend integrating oncology and palliative care (IOP) in daily practice. Similarly, the Japanese government encouraged the implementation of IOP through the Cancer Control Act of 2007; however, its detailed progress remains unclear. Therefore, this cross-sectional nationwide survey was conducted to investigate the current status and hospital executive physicians' perception of IOP. METHODS: The questionnaire was developed based on IOP indicators with international consensus. It was distributed to executive physicians at all government-designated cancer hospitals (DCHs, n = 399) and matched non-DCHs (n = 478) in November 2017 and the results were compared. RESULTS: In total, 269 (67.4%) DCHs and 259 (54.2%) non-DCHs responded. The number of PC resources in DCHs was significantly higher than those in non-DCHs (e.g., full-time PC physicians and nurses, 52.8% vs. 14.0%, p < 0.001; availability of outpatient PC service ≥3 days per week, 47.6% vs. 20.7%, p < 0.001). Routine symptom screening was more frequently performed in DCHs than in non-DCHs (65.1% vs. 34.7%, p < 0.001). Automatic trigger for PC referral availability was limited (e.g., referral using time trigger, 14.9% vs. 15.3%, p = 0.700). Education and research opportunities were seriously limited in both types of hospitals. Most executive physicians regarded IOP as beneficial for their patients (95.9% vs. 94.7%, p = 0.163) and were willing to facilitate an early referral to PC services (54.7% vs. 60.0%, p < 0.569); however, the majority faced challenges to increase the number of full-time PC staff, and < 30% were planning to increase the staff members. CONCLUSIONS: This survey highlighted a considerable number of IOP indicators met, particularly in DCHs probably due to the government policy. Further efforts are needed to address the serious research/educational gaps.

Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up.

BACKGROUND: A predisposition to exacerbations is being recognized as a distinct phenotype with "previous exacerbations" representing the strongest clinical factor associated with future exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, "past exacerbation status" must be included as a confounding factor. OBJECTIVE: This study aimed to characterize the clinical and biomarker features associated with asthma exacerbations in severe asthma. METHODS: We evaluated clinical parameters from 105 severe asthmatics yearly for 3 years, as well as their exacerbation status. We classified the subjects into 3 groups: (i) consistent non-exacerbators (CNE, subjects who did not experience any exacerbation over the 3-year period); (ii) consistent frequent exacerbators (CFE, subjects with frequent exacerbation, defined as those who had 2 or more exacerbations within 1 year, throughout the 3-year period); and (iii) intermittent exacerbators (IE). We conducted multivariate analysis for comparisons among the groups for multiple factors, including several Th2-related biomarkers, in addition to the "past exacerbation status." RESULTS: Thirty-nine subjects were classified as CNE, 15 as CFE, and 51 as IE. Frequent exacerbations in the previous year predicted exacerbations for the following year (P < .001). Among the several Th2-related biomarkers, only FeNO was associated with exacerbation status. When we analysed the data after the second visit, the impact of FeNO on predicting future exacerbation remained significant, even after considering the exacerbation status during the first year (P < .05). CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of FeNO has a significant potential to predict future asthma exacerbation, which is independent of the "past exacerbation history."

Extraction of the Landau-Migdal Parameter from the Gamow-Teller Giant Resonance in

The key parameter to discuss the possibility of the pion condensation in nuclear matter, i.e., the so-called Landau-Migdal parameter g^{'}, was extracted by measuring the double-differential cross sections for the (p,n) reaction at 216 MeV/u on a neutron-rich doubly magic unstable nucleus, ^{132}Sn with the quality comparable to data taken with stable nuclei. The extracted strengths for Gamow-Teller (GT) transitions from ^{132}Sn leading to ^{132}Sb exhibit the GT giant resonance (GTR) at the excitation energy of 16.3±0.4(stat)±0.4(syst) MeV with the width of Γ=4.7±0.8 MeV. The integrated GT strength up to E_{x}=25 MeV is S_{GT}^{-}=53±5(stat)_{-10}^{+11}(syst), corresponding to 56% of Ikeda's sum rule of 3(N-Z)=96. The present result accurately constrains the Landau-Migdal parameter as g^{'}=0.68±0.07, thanks to the high sensitivity of the GTR energy to g^{'}. In combination with previous studies on the GTR for ^{90}Zr and ^{208}Pb, the result of this work shows the constancy of this parameter in the nuclear chart region with (N-Z)/A=0.11 to 0.24 and A=90 to 208.

Telomere length determined by the fluorescence in situ hybridisation distinguishes malignant and benign cells in cytological specimens.

BACKGROUND: Telomeres are tandem repeats of TTAGGG at the end of eukaryotic chromosomes that play a key role in preventing chromosomal instability. The aim of the present study is to determine telomere length using fluorescence in situ hybridisation (FISH) on cytological specimens. METHODS: Aspiration samples (n = 41) were smeared on glass slides and used for FISH. RESULTS: Telomere signal intensity was significantly lower in positive cases (cases with malignancy, n = 25) as compared to negative cases (cases without malignancy, n = 16), and the same was observed for centromere intensity. The difference in DAPI intensity was not statistically significant. The ratio of telomere to centromere intensity did not show a significant difference between positive and negative cases. There was no statistical difference in the signal intensities of aspiration samples from ascites or pleural effusion (n = 23) and endoscopic ultrasound-guided FNA samples from the pancreas (n = 18). CONCLUSIONS: The present study revealed that telomere length can be used as an indicator to distinguish malignant and benign cells in cytological specimens. This novel approach may help improve diagnosis for cancer patients.

Multiple skin cancers in patients with mycosis fungoides after long-term ultraviolet phototherapy.

Phototherapy is a useful noninvasive therapy, but it can induce cutaneous malignant tumours, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). We report on a 79-year-old man who had long-standing mycosis fungoides for 40 years, which had been treated with psoralen ultraviolet A therapy for 37 years at a dose of approximately 5000 J/cm2 . Approximately 6 years before presentation, numerous types of cutaneous malignancies, including actinic keratosis, BCC and SCC, had begun to develop all over the patient's body. We hypothesized that he was experiencing a pathogenesis similar to patients with xeroderma pigmentosum (XP), and we therefore assessed his DNA repair capacity. Based on these investigations, the patient was eventually diagnosed as non-XP, even though we detected that his DNA repair capacity was slightly lower than that of normal controls, which may have led to the skin cancers. We speculate that multiple skin malignancies can be induced by long-term phototherapy in patients with slightly impaired DNA repair capacity.

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Candidate Resonant Tetraneutron State Populated by the

A candidate resonant tetraneutron state is found in the missing-mass spectrum obtained in the double-charge-exchange reaction ^{4}He(^{8}He,^{8}Be) at 186 MeV/u. The energy of the state is 0.83±0.65(stat)±1.25(syst) MeV above the threshold of four-neutron decay with a significance level of 4.9σ. Utilizing the large positive Q value of the (^{8}He,^{8}Be) reaction, an almost recoilless condition of the four-neutron system was achieved so as to obtain a weakly interacting four-neutron system efficiently.

DNA hypermethylation of extracellular matrix-related genes in human periodontal fibroblasts induced by stimulation for a prolonged period with lipopolysaccharide derived from Porphyromonas gingivalis.

OBJECTIVES AND BACKGROUND: The involvement of DNA methylation in periodontal disease is not clear. Lipopolysaccharide (LPS) derived from Porphyromonas gingivalis is involved in the progression of periodontal disease. We recently developed an in vitro model of LPS infection in human periodontal fibroblast cells (HPdLFs) for a prolonged period. In this study, we examined genome-wide analysis of DNA methylation in HPdLFs stimulated with LPS derived from P. gingivalis for a prolonged period. We noted the hypermethylation of extracellular matrix (ECM)-related genes and examined whether hypermethylation affected their transcription levels. MATERIAL AND METHODS: HPdLFs were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum. The culture was repeated, alternating 3 d with LPS derived from P. gingivalis and 3 d without LPS for 1 mo. Untreated samples were used as controls. DNA was analyzed using the human CpG island microarray. Quantitative methylation-specific polymerase chain reaction was carried out to confirm reproducibility of the microarray data. The expression levels of mRNA of the selected ECM-related genes from the data were analyzed by quantitative reverse transcription-polymerase chain reaction. RESULTS: We found 25 ECM-related genes with hypermethylation at the CpG island of the promoter region, which exhibited a fourfold greater hypermethylation than controls. Among these genes, hypermethylation of nine ECM-related genes, FANK1, COL4A1-A2, 12A1 and 15A1, LAMA5 and B1, MMP25, POMT1 and EMILIN3, induced a significantly downregulated expression of their mRNA. CONCLUSION: These results indicate that LPS derived from P. gingivalis may cause DNA hypermethylation of some ECM-related genes followed by downregulated expression of their transcriptional levels.

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.

BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.

Development of a particle nanoimprinting technique by core-shell particles.

We developed a particle nanoimprinting technique assisted by the array of core-shell particles. Core-shell particles composed of a solid core of polystyrene and a soft shell were prepared by soap-free emulsion polymerization and subsequently seeded polymerization. By the Langmuir-Blodgett method, particles were arranged into a closely packed 2D array over the water surface and transferred onto a polystyrene (PS) substrate at a regular interval. The PS substrate was heated up above its glass transition temperature (Tg) by either UV irradiation using a high-pressure Hg lamp or heat treatment in a temperature-controlled incubator. It could be observed that a nanopatterned indented surface was formed through the denting of particles into the PS substrate (particle nanoindenting). By the detachment of particles from the substrate by ultrasonication in ethanol, nanoholes were produced over the surface (particle nanoimprinting). The depth and the wall of nanoholes and their interval were tunable by the shell thickness and the 2D packing ratio of core-shell particle monolayers. The contact angle decreased from 70 degrees of the pristine particle monolayer to 13 degrees by the particle nanoindenting, and again increased to 50 degrees by detaching the particles from the substrate to create the nanoholes. The use of nanoholes as zepto-litter volume vessels enabled us to produce and arrange nanocrystals, such as NaCl and CaCO3 (zepto-reactor).

Pharmacokinetic modelling of serum and bronchial concentrations for clarithromycin and telithromycin, and site-specific pharmacodynamic simulation for their dosages.

WHAT IS KNOWN AND OBJECTIVE: Clinical pharmacokinetic profiles of clarithromycin and telithromycin in bronchopulmonary sites have not been fully characterized. This study aimed to describe in more detail the pharmacokinetics of the two macrolides in epithelial lining fluid (ELF) of human bronchi and to evaluate their pharmacodynamic target attainment at this site. METHODS: Previously reported drug concentration data for serum and ELF were simultaneously fitted to a three-compartment pharmacokinetic model using nonmem program. The model parameter estimates were used for site-specific pharmacodynamic simulation. RESULTS AND DISCUSSION: Population mean parameters for clarithromycin were as follows: distribution volumes of central, peripheral and ELF compartments (V1 /F, V2 /F and V3 /F) = 204·7, 168·9 and 67·1 L; clearance (CL/F) = 34·4 L/h; absorption rate constant (Ka ) = 0·680 1/h; transfer rate constants connecting compartments (K12 , K21 , K13 and K31  = 0·0193, 0·434, 0·667 and 0·260 1/h, respectively). Mean parameters for telithromycin were as follows: V1 /F, V2 /F and V3 /F = 370·3, 290·3 and 213·8 L; CL/F = 89·5 L/h; Ka  = 0·740 1/h; K12 , K21 , K13 and K31  = 0·0026, 1·044, 0·758 and 0·158 1/h, respectively. Using these parameters, the mean ELF/serum ratio in the area under drug concentration-time curve (AUC) was 7·80 for clarithromycin and 8·05 for telithromycin. Clarithromycin achieved a ≥ 90% probability of attaining a pharmacodynamic target [AUC/minimum inhibitory concentration (MIC) = 100] in ELF against bacterial isolates for which MICs were ≤0·5 and ≤1 mg/L for twice-daily doses of 250 and 500 mg, respectively. For telithromycin, once-daily doses of 600 and 800 mg achieved a ≥90% probability in ELF against Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis isolates but not Haemophilus influenzae isolates. WHAT IS NEW AND CONCLUSION: These results should provide a better understanding of the bronchial pharmacokinetics of clarithromycin and telithromycin, while also providing useful information about their dosages for respiratory tract infections based on site-specific pharmacodynamic evaluation. Further studies in a large number of patients are needed to confirm our findings and clarify their therapeutic implications.

Cervical intervertebral disc disease in 307 small-breed dogs (2000-2021): Breed-characteristic features and disc-associated vertebral instability.

OBJECTIVE: To evaluate the breed-characteristic features of cervical intervertebral disc disease (C-IVDD) and associated vertebral instability in small-breed dogs and to present the concept of intervertebral disc degeneration and associated instability stage, method of diagnosis, treatment and outcomes. ANIMALS: In total, 307 client-owned dogs with C-IVDD treated with spinal cord decompression with or without vertebral stabilization (2000-2021). METHODS: Information on age, sex, affected sites, stabilized sites, diagnostic methods for vertebral instability and outcomes were retrieved. The patient's age, affected sites (cranial vs caudal discs), and frequency of vertebral stabilization were compared in six CD and five NCD breed. Multivariable analyses of the chondrodystrophic (CD) vs non-CD (NCD) groups, and vertebral stabilization (dogs stabilized vs dogs not stabilized) were performed. RESULTS: In total, 222 (72.3%) and 77 (25.1%) were CD and NCD breeds, respectively. Vertebral instabilities were diagnosed based on the survey radiographs with computed tomography/magnetic resonance imaging (n = 2), dynamic myelography (n = 29), intraoperative spinal manipulation (n = 11) or second surgery in dogs with persistent postoperative paraspinal pain (n = 3). Of these dogs, 295 (96.1%) recovered (median follow-up: 8.5 [range, 1-119] months). Significant differences in age, affected sites and frequency of stabilization were noted among the breeds. Older age and frequent vertebral stabilization were the associated factors for the NCD breed dogs. Male dogs, caudal discs affected (C5-T1) and the NCD breed dogs were risk factors for the dogs with vertebral stabilization. CONCLUSION: Vertebral stabilization is indicated for small-breed dogs with cervical disc-associated vertebral instability.

Rapid hippocampal network adaptation to recurring synchronous activity--a role for calcineurin.

Neuronal networks are thought to gradually adapt to altered neuronal activity over many hours and days. For instance, when activity is increased by suppressing synaptic inhibition, excitatory synaptic transmission is reduced. The underlying compensatory cellular and molecular mechanisms are thought to contribute in important ways to maintaining normal network operations. Seizures, due to their massive and highly synchronised discharging, probably challenge the adaptive properties of neurons, especially when seizures are frequent and intense - a condition common in early childhood. In the experiments reported here, we used rat and mice hippocampal slice cultures to explore the effects that recurring seizure-like activity has on the developing hippocampus. We found that developing networks adapted rapidly to recurring synchronised activity in that the duration of seizure-like events was reduced by 42% after 4 h of activity. At the same time, the frequency of spontaneous excitatory postsynaptic currents in pyramidal cells, the expression of biochemical biomarkers for glutamatergic synapses and the branching of pyramidal cell dendrites were all dramatically reduced. Experiments also showed that the reduction in N-methyl-D-aspartate receptor subunits and postsynaptic density protein 95 expression were N-methyl-D-aspartate receptor-dependent. To explore calcium signaling mechanisms in network adaptation, we tested inhibitors of calcineurin, a protein phosphatase known to play roles in synaptic plasticity and activity-dependent dendrite remodeling. We found that FK506 was able to prevent all of the electrophysiological, biochemical, and anatomical changes produced by synchronised network activity. Our results show that hippocampal pyramidal cells and their networks adapt rapidly to intense synchronised activity and that calcineurin play an important role in the underlying processes.

CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.

We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.