Abstract
Great advances have been made in the study of ultra-high energy cosmic rays (UHECR) in the past 2 decades. These include the discovery of the spectral cut-off near $5\times 10^{19}$ eV and ...complex structure at lower energies, as well as increasingly precise information about the composition of cosmic rays as a function of energy. Important improvements in techniques, including extensive surface detector arrays and high resolution air fluorescence detectors, have been instrumental in facilitating this progress. We discuss the status of the field, including the open questions about the nature of spectral structure, systematic issues related to our understanding of composition, and emerging evidence for anisotropy at the highest energies. We review prospects for upgraded and future observatories including Telescope Array, Pierre Auger, and JEM-EUSO, as well as other space-based proposals, and discuss promising new technologies based on radio emission from extensive air showers produced by UHECR.
Previous small-sized studies showed lower thymidylate synthase (TS) expression in adenocarcinoma of the lung, which may explain higher antitumor activity of TS-inhibiting agents such as pemetrexed.
...To quantitatively measure TS gene expression in a large-scale Japanese population (n = 2621) with primary lung cancer, laser-captured microdissected sections were cut from primary tumors, surrounding normal lung tissues and involved nodes.
TS gene expression level in primary tumor was significantly higher than that in normal lung tissue (mean TS/β-actin, 3.4 and 1.0, respectively; P < 0.01), and TS gene expression level was further higher in involved node (mean TS/β-actin, 7.7; P < 0.01). Analyses of TS gene expression levels in primary tumor according to histologic cell type revealed that small-cell carcinoma showed highest TS expression (mean TS/β-actin, 13.8) and that squamous cell carcinoma showed higher TS expression as compared with adenocarcinoma (mean TS/β-actin, 4.3 and 2.3, respectively; P < 0.01); TS gene expression was significantly increased along with a decrease in the grade of tumor cell differentiation. There was no significant difference in TS gene expression according to any other patient characteristics including tumor progression.
Lower TS expression in adenocarcinoma of the lung was confirmed in a large-scale study.
We retrospectively review outcomes of applying boron neutron capture therapy (BNCT) to unresectable advanced or recurrent head and neck cancers. Patients who were treated with BNCT for either local ...recurrent or newly diagnosed unresectable head or neck cancers between December 2001 and September 2007 were included. Clinicopathological characteristics and clinical outcomes were retrieved from hospital records. Either a combination of borocaptate sodium and boronophenylalanine (BPA) or BPA alone were used as boron compounds. In all the treatment cases, the dose constraint was set to deliver a dose <10-12 Gy-eq to the skin or oral mucosa. There was a patient cohort of 62, with a median follow-up of 18.7 months (range, 0.7-40.8). A total of 87 BNCT procedures were performed. The overall response rate was 58% within 6 months after BNCT. The median survival time was 10.1 months from the time of BNCT. The 1- and 2-year overall survival (OS) rates were 43.1% and 24.2%, respectively. The major acute Grade 3 or 4 toxicities were hyperamylasemia (38.6%), fatigue (6.5%), mucositis/stomatitis (9.7%) and pain (9.7%), all of which were manageable. Three patients died of treatment-related toxicity. Three patients experienced carotid artery hemorrhage, two of whom had coexistent infection of the carotid artery. This study confirmed the feasibility of our dose-estimation method and that controlled trials are warranted.
We consider an optimization reformulation approach for the generalized Nash equilibrium problem (GNEP) that uses the regularized gap function of a quasi-variational inequality (QVI). The regularized ...gap function for QVI is in general not differentiable, but only directionally differentiable. Moreover, a simple condition has yet to be established, under which any stationary point of the regularized gap function solves the QVI. We tackle these issues for the GNEP in which the shared constraints are given by linear equalities, while the individual constraints are given by convex inequalities. First, we formulate the minimization problem involving the regularized gap function and show the equivalence to GNEP. Next, we establish the differentiability of the regularized gap function and show that any stationary point of the minimization problem solves the original GNEP under some suitable assumptions. Then, by using a barrier technique, we propose an algorithm that sequentially solves minimization problems obtained from GNEPs with the shared equality constraints only. Further, we discuss the case of shared inequality constraints and present an algorithm that utilizes the transformation of the inequality constraints to equality constraints by means of slack variables. We present some results of numerical experiments to illustrate the proposed approach.
Abstract Objectives In 2002, FDI (World Dental Federation) published a policy advocating that caries be treated by minimal intervention (MI). This MI policy has been accepted worldwide and is taught ...in universities. But acceptance in general dental practice has been slower, especially in Japan where healthcare payment and practice favour drilling and filling. To help disseminate this MI policy into general practice, the Japanese Society of Conservative Dentistry developed an evidence-based clinical guideline for restoring carious permanent teeth in adult patients. Methods The guideline was developed by a committee of nine university clinicians and a librarian. The committee selected the most frequent clinical questions in treating caries and used electronic databases to search and assess the best scientific evidence for each. Members then added their clinical experience and discussed to reach consensus on each question on treating caries with MI policy. Graded recommendations and guidance were made for each clinical question. The provisional guideline was strengthened after review and discussion with university researchers and general practitioners. Results The guideline addresses the 16 most frequent clinical questions in treating adult caries, including restorative methods and how to tackle root caries. Recommendations for treatment using MI policy were developed using the best scientific evidence and consensus of experienced clinicians. Clinical significance The guideline offers a practical expert view of treating caries with the MI policy that incorporates the best scientific evidence, the latest techniques, the most preferable materials and the general consensus of expert clinicians.
Background
The impact of pediatric intensive care unit (PICU) utilization and resource consumption among long-stay patients has not been characterized recently. This study aimed to describe the ...resource consumption and characteristics of long-stay patients in a PICU.
Methods
This was a single-center descriptive cohort study of 1309 patients admitted to a PICU in 2017. The main outcome was ICU length of stay (LOS). Patients were divided into prolonged LOS (PLS) and non-PLS groups if they had an LOS of ≥ 28 or < 28 days, respectively. Two groups were compared to characterize PLS.
Results
Thirty-two (2.4%) patients had a PLS and utilized 33% of PICU bed days. Factors associated with PLS with odds ratio 95% confidence interval (CI) were being a neonate (7.8 2.5–25.4,
p
= <0.001), being an infant (2.9 1.0–9.0,
p
= 0.04), admission for a respiratory ailment (7.3 1.6–44.2,
p
= 0.003), cardiovascular dysfunction (24.1 4.8–152.1,
p
= <0.001), post-cardiac operation (8.0 1.7–50.1,
p
= 0.003), post-cardiopulmonary arrest (22.8 1.7–211.9,
p
= 0.01), and transfer from another facility (4.2 1.8–10.7,
p
= 0.001). PLS patients developed more nosocomial infections and disproportionately received monitoring and therapeutic resources.
Conclusions
A PLS was associated with substantial PICU utilization and complication rates. Future studies should aim to alleviate both institutional and patient-related issues in the affected population harboring possible risk factors for PLS.
Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and ...hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract.
We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögren's syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor.
The median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg per deciliter (5th and 95th percentiles, 136 and 1150), as compared with 51 mg per deciliter (5th and 95th percentiles, 15 and 128) in normal subjects (P<0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. In patients with sclerosing pancreatitis, serum concentrations of immune complexes and the IgG4 subclass of immune complexes were significantly higher before glucocorticoid therapy than after four weeks of such therapy. Glucocorticoid therapy induced clinical remissions and significantly decreased serum concentrations of IgG4, immune complexes, and the IgG4 subclass of immune complexes.
Patients with sclerosing pancreatitis have high serum IgG4 concentrations, providing a useful means of distinguishing this disorder from other diseases of the pancreas or biliary tract.
Thymidine phosphorylase (TP) is often overexpressed in tumours and has a role in tumour aggressiveness and angiogenesis. Here, we determined whether TP increased tumour invasion and whether ...TP-expressing cancer cells stimulated angiogenesis.
Angiogenesis was studied by exposing endothelial cells (HUVECs) to conditioned medium (CM) derived from cancer cells with high (Colo320TP1=CT-CM, RT112/TP=RT-CM) and no TP expression after which migration (wound-healing-assay) and invasion (transwell-assay) were determined. The involvement of several angiogenic factors were examined by RT-PCR, ELISA and blocking antibodies.
Tumour invasion was not dependent on intrinsic TP expression. The CT-CM and RT-CM stimulated HUVEC-migration and invasion by about 15 and 40%, respectively. Inhibition by 10 μM TPI and 100 μM L-dR, blocked migration and reduced the invasion by 50-70%. Thymidine phosphorylase activity in HUVECs was increased by CT-CM. Reverse transcription-polymerase chain reaction revealed a higher mRNA expression of bFGF (Colo320TP1), IL-8 (RT112/TP) and TNF-α, but not VEGF. Blocking antibodies targeting these factors decreased the migration and invasion that was induced by the CT-CM and RT-CM, except for IL-8 in CT-CM and bFGF in RT-CM.
In our cell line panels, TP did not increase the tumour invasion, but stimulated the migration and invasion of HUVECs by two different mechanisms. Hence, TP targeting seems to provide a potential additional strategy in the field of anti-angiogenic therapy.
We compared maternal plasma testosterone and insulin-like peptide 3 (INSL3) concentrations between dams carrying a male versus female fetus from early to late gestation and examined the application ...of maternal hormonal concentrations to fetal gender prediction in dairy and beef cattle. Blood samples were collected from Holstein cows or heifers (N = 31) and Japanese Black beef cows (N = 33) at 1-month intervals at 2 to 8 months of gestation. Fetal gender was confirmed by visual observation of external genitalia of calves just after birth. Plasma testosterone and INSL3 concentrations were determined by enzyme-immunoassay. Fetal genders were judged based on cutoff values of maternal testosterone and INSL3 concentrations (male, if it was ≥ cutoff value; female, if < cutoff value), which we set for each hormone at each gestational month using receiver operating characteristic curves. Plasma testosterone concentrations were higher for dams with a male fetus than those with a female at 4, 5, 7, and 8 months for the dairy cattle (P < 0.05) and at 4, 5, 6, and 8 months for the beef cows (P < 0.05). Plasma INSL3 concentrations were higher for dams with a male fetus than those with a female at 2 and 6 months for the dairy cattle (P < 0.05) and at 4 to 8 months for the beef cows (P < 0.05). The predictive values and detection rates for fetal gender prediction based on maternal testosterone concentrations were 75.8% to 79.3% for dairy cattle at 5 and 7 months and for beef cows at 5 and 6 months, whereas those values by maternal INSL3 concentrations were 71.0% to 72.4% for the dairy cattle at 6 months and beef cows at 4 and 8 months. When multiple time points of testosterone and INSL3 concentrations at several midgestation and late gestation months were considered for fetal gender prediction, predictive values were 89.3% (5–7 months) and 85.7% to 88.0% (4–6, 8 months) for the dairy and beef breeds, respectively. Maternal testosterone and INSL3 concentrations in dams carrying a male fetus were higher than those carrying a female at midgestation and/or late gestation in Holstein and Japanese Black beef cattle. Nearly, 80% accuracy was obtained for fetal gender prediction by a single time point of maternal plasma testosterone concentrations at midgestation. Nearly 90% accuracy for the prediction was obtained when multiple time points of testosterone and INSL3 concentrations from midgestation to late gestation were considered.
Insulin-like peptide 3 (INSL3) is a major secretory product of testicular Leydig cells. The mechanism of acute regulation of INSL3 secretion is still unknown. The present study was undertaken in ...pubertal beef bulls to (1) determine the temporal relationship of pulsatile secretion among LH, INSL3, and testosterone and (2) monitor acute regulation of INSL3 secretion by LH using GnRH analogue and hCG. Blood samples were collected from Japanese Black beef bulls (N = 6) at 15-minute intervals for 8 hours. Moreover, blood samples were collected at −0.5, 0, 1, 2, 3, 4, 5, and 6 hours after GnRH treatment and −0.5, 0, 2, 4, and 8 hours on the day of treatment (Day 0), and Days 1, 2, 4, 8, and 12 after hCG treatment. Concentrations of LH, INSL3, and testosterone determined by EIAs indicated that secretion in the general circulation was pulsatile. The frequency of LH, INSL3, and testosterone pulses was 4.7 ± 0.9, 3.8 ± 0.2, and 1.0 ± 0.0, respectively, during the 8-hour period. Seventy percent of these INSL3 pulses peaked within 1 hour after a peak of an LH pulse had occurred. The mean increase (peak per basal concentration) of testosterone pulses was higher (P < 0.001) than that of INSL3 pulses. After GnRH treatment, LH concentrations increased (P < 0.01) dramatically 1 hour after treatment and remained high (P < 0.05) until the end of sampling, whereas an elevated (P < 0.05) INSL3 concentration occurred at 1, 2, 5, and 6 hours after treatment. Testosterone concentrations increased (P < 0.01) 1 hour after the treatment and remained high until the end of sampling. After hCG treatment, an increase of INSL3 concentration occurred at 2 and 4 hours, and Days 2, 4, and 8 after treatment (P < 0.05), whereas in case of testosterone, concentrations remained high (P < 0.01) until Day 8 after treatment. The increase (maximum per pretreatment concentration) of INSL3 concentrations after injecting GnRH or hCG was much lower (P < 0.001) than that of testosterone. In conclusion, secretion of INSL3 in blood of bulls occurred in a pulsatile manner. We inferred an acute regulation of INSL3 by LH in bulls because INSL3 concentrations increased immediately after endogenous and exogenous LH stimulation. The increase of INSL3 concentrations by LH was much lower than that of testosterone in bulls.
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