Proof-of-Principle Experiment for Testing Strong-Field Quantum Electrodynamics with Exotic Atoms: High Precision X-Ray Spectroscopy of Muonic Neon.

To test bound-state quantum electrodynamics (BSQED) in the strong-field regime, we have performed high precision x-ray spectroscopy of the 5g-4f and 5f- 4d transitions (BSQED contribution of 2.4 and 5.2 eV, respectively) of muonic neon atoms in the low-pressure gas phase without bound electrons. Muonic atoms have been recently proposed as an alternative to few-electron high-Z ions for BSQED tests by focusing on circular Rydberg states where nuclear contributions are negligibly small. We determined the 5g_{9/2}- 4f_{7/2} transition energy to be 6297.08±0.04(stat)±0.13(syst) eV using superconducting transition-edge sensor microcalorimeters (5.2-5.5 eV FWHM resolution), which agrees well with the most advanced BSQED theoretical prediction of 6297.26 eV.

Improved Measurements of Muonic Helium Ground-State Hyperfine Structure at a Near-Zero Magnetic Field.

Muonic helium atom hyperfine structure (HFS) measurements are a sensitive tool to test the three-body atomic system and bound-state quantum electrodynamics theory, and determine fundamental constants of the negative muon magnetic moment and mass. The world's most intense pulsed negative muon beam at the Muon Science Facility of the Japan Proton Accelerator Research Complex allows improvement of previous measurements and testing further CPT invariance by comparing the magnetic moments and masses of positive and negative muons (second-generation leptons). We report new ground-state HFS measurements of muonic helium-4 atoms at a near-zero magnetic field, performed for the first time using a small admixture of CH_{4} as an electron donor to form neutral muonic helium atoms efficiently. Our analysis gives Δν=4464.980(20) MHz (4.5 ppm), which is more precise than both previous measurements at weak and high fields. The muonium ground-state HFS was also measured under the same conditions to investigate the isotopic effect on the frequency shift due to the gas density dependence in He with CH_{4} admixture and compared with previous studies. Muonium and muonic helium can be regarded as light and heavy hydrogen isotopes with an isotopic mass ratio of 36. No isotopic effect was observed within the current experimental precision.

Effect of proton pump inhibitors on the development of hypomagnesemia induced by panitumumab.

Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.

Deexcitation Dynamics of Muonic Atoms Revealed by High-Precision Spectroscopy of Electronic K X Rays.

We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the asymmetric broad profile of the electronic characteristic Kα and Kß x rays together with the hypersatellite K^{h}α x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K- and L-shell hole production and their temporal evolution on the 10-20 fs scale during the muon cascade process.

Non-destructive elemental analysis of a carbonaceous chondrite with direct current Muon beam at MuSIC.

Electron- or X-ray-induced characteristic X-ray analysis has been widely used to determine chemical compositions of materials in vast research fields. In recent years, analysis of characteristic X-rays from muonic atoms, in which a muon is captured, has attracted attention because both a muon beam and a muon-induced characteristic X-ray have high transmission abilities. Here we report the first non-destructive elemental analysis of a carbonaceous chondrite using one of the world-leading intense direct current muon beam source (MuSIC; MUon Science Innovative Channel). We successfully detected characteristic muonic X-rays of Mg, Si, Fe, O, S and C from Jbilet Winselwan CM chondrite, of which carbon content is about 2 wt%, and the obtained elemental abundance pattern was consistent with that of CM chondrites. Because of its high sensitivity to carbon, non-destructive elemental analysis with a muon beam can be a novel powerful tool to characterize future retuned samples from carbonaceous asteroids.

Temporal mapping of photochemical reactions and molecular excited states with carbon specificity.

Photochemical reactions are essential to a large number of important industrial and biological processes. A method for monitoring photochemical reaction kinetics and the dynamics of molecular excitations with spatial resolution within the active molecule would allow a rigorous exploration of the pathway and mechanism of photophysical and photochemical processes. Here we demonstrate that laser-excited muon pump-probe spin spectroscopy (photo-µSR) can temporally and spatially map these processes with a spatial resolution at the single-carbon level in a molecule with a pentacene backbone. The observed time-dependent light-induced changes of an avoided level crossing resonance demonstrate that the photochemical reactivity of a specific carbon atom is modified as a result of the presence of the excited state wavefunction. This demonstrates the sensitivity and potential of this technique in probing molecular excitations and photochemistry.

Self-awareness of fast eating and its impact on diagnostic components of metabolic syndrome among middle-aged Japanese males and females.

OBJECTIVE: The aim of the present study was to examine the association between subjects with self-awareness of fast eating and diagnostic components of metabolic syndrome in Japanese middle-aged male and female. PATIENTS AND METHODS: Subjects consisted of 3208 males (average age 50.6 years) and 2055 females (average age 50.0 years). Associations between subjects with self-awareness of fast eating and multiple components of metabolic syndrome (waist circumference, body mass index [BMI], blood pressure, and related blood sample tests) were evaluated. RESULTS: Significantly more males (57.7%) acknowledged themselves as "fast eater" than females (46.5%). Self-reported fast eaters showed significantly elevated body weight, BMI, and waist circumference in both genders. However, only male self-reported fast eaters showed high levels of blood pressure, fasting blood glucose, uric acid, and low-density lipoprotein (LDL)-cholesterol. CONCLUSION: Fast eating is associated with diagnostic components of metabolic syndrome. The effect of acknowledging themselves as fast eater presents a higher impact on males than on females in the middle-aged Japanese population. The present study indicates that finding subjects with self-awareness of fast eating may lead to the prevention of developing metabolic syndrome.

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1ß and TNF-α.

OBJECTIVE: Excessive mechanical stress on synovial joints causes osteoarthritis (OA) and results in the production of prostaglandin E2 (PGE2), a key molecule in arthritis, by synovial fibroblasts. However, the relationship between arthritis-related molecules and mechanical stress is still unclear. The purpose of this study was to examine the synovial fibroblast response to cyclic mechanical stress using an in vitro osteoarthritis model. METHOD: Human synovial fibroblasts were cultured on collagen scaffolds to produce three-dimensional constructs. A cyclic compressive loading of 40 kPa at 0.5 Hz was applied to the constructs, with or without the administration of a cyclooxygenase-2 (COX-2) selective inhibitor or dexamethasone, and then the concentrations of PGE2, interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), IL-6, IL-8 and COX-2 were measured. RESULTS: The concentrations of PGE2, IL-6 and IL-8 in the loaded samples were significantly higher than those of unloaded samples; however, the concentrations of IL-1ß and TNF-α were the same as the unloaded samples. After the administration of a COX-2 selective inhibitor, the increased concentration of PGE2 by cyclic compressive loading was impeded, but the concentrations of IL-6 and IL-8 remained high. With dexamethasone, upregulation of PGE2, IL-6 and IL-8 was suppressed. CONCLUSION: These results could be useful in revealing the molecular mechanism of mechanical stress in vivo for a better understanding of the pathology and therapy of OA. Cite this article: Bone Joint Res 2014;3:280-8.

High-resolution mapping of a novel genetic locus regulating voluntary physical activity in mice.

Both human beings and animals exhibit substantial inter-individual variation in voluntary physical activity, and evidence indicates that a significant component of this variation is because of genetic factors. However, little is known of the genetic basis underlying central regulation of voluntary physical activity in mammals. In this study, using an F(2) intercross population and interval-specific congenic strains (ISCS) derived from the C57BL/6J strain and a chromosome 13 substitution strain, C57BL/6J-Chr13A/J/NA/J, we identified a 3.76-Mb interval on chromosome 13 containing 25 genes with a significant impact on daily voluntary wheel running activity in mice. Brain expression and polymorphisms between the C57BL/6J and A/J strains were examined to prioritize candidate genes. As the dopaminergic pathway regulates motor movement and motivational behaviors, we tested its function by examining cocaine-induced locomotor responses in ISCS with different levels of activity. The low-activity ISCS exhibited a significantly higher response to acute cocaine administration than the high-activity ISCS. Expression analysis of key dopamine-related genes (dopamine transporter and D1, D2, D3, D4 and D5 receptors) revealed that expression of D1 receptor was higher in the low-activity ISCS than in the high-activity ISCS in both the dorsal striatum and nucleus accumbens. Pathway analysis implicated Tcfap2a, a gene found within the 3.76-Mb interval, involved in the D1 receptor pathway. Using a luciferase reporter assay, we confirmed that the transcriptional factor, Tcfap2a, regulates the promoter activity of the D1 receptor gene. Thus, Tcfap2a is proposed as a candidate genetic regulator of the level of voluntary physical activity through its influence on a dopaminergic pathway.

A mutation in KCNJ11 causing human hyperinsulinism (Y12X) results in a glucose-intolerant phenotype in the mouse.

AIMS/HYPOTHESIS: We identified a mouse with a point mutation (Y12STOP) in the Kcnj11 subunit of the K(ATP) channel. This point mutation is identical to that found in a patient with congenital hyperinsulinism of infancy (HI). We aimed to characterise the phenotype arising from this loss-of-function mutation and to compare it with that of other mouse models and patients with HI. METHODS: We phenotyped an N-ethyl-N-nitrosourea-induced mutation on a C3H/HeH background (Kcnj11 ( Y12STOP )) using intraperitoneal glucose tolerance testing to measure glucose and insulin plasma concentrations. Insulin secretion and response to incretins were measured on isolated islets. RESULTS: Homozygous male and female adult Kcnj11 ( Y12STOP ) mice exhibited impaired glucose tolerance and a defect in insulin secretion as measured in vivo and in vitro. Islets had an impaired incretin response and reduced insulin content. CONCLUSIONS/INTERPRETATION: The phenotype of homozygous Kcnj11 ( Y12STOP ) mice is consistent with that of other Kcnj11-knockout mouse models. In contrast to the patient carrying this mutation homozygously, the mice studied did not have hyperinsulinaemia or hypoglycaemia. It has been reported that HI patients may develop diabetes and our mouse model may reflect this clinical feature. The Kcnj11 ( Y12STOP ) model may thus be useful in further studies of K(ATP) channel function in various cell types and in investigation of the development of hyperglycaemia in HI patients.

The first clinical case of a mutation at residue K185 of Kir6.2 (KCNJ11): a major ATP-binding residue.

BACKGROUND: Closure of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel plays a key role in insulin secretion from the pancreatic beta-cells. Many mutations in KCNJ11 and ABCC8, which respectively encode the pore-forming (Kir6.2) and regulatory (SUR1) subunits of the K(ATP) channel, cause neonatal diabetes. All such mutations impair the ability of metabolically generated ATP to close the channel. Although lysine 185 is predicted to be a major contributor to the ATP-binding site of Kir6.2, no mutations at this residue have been found to cause neonatal diabetes to date. METHODS: We report a 3-year-old girl with permanent neonatal diabetes (PNDM) caused by a novel heterozygous mutation (K185Q) at residue K185 of KCNJ11. The patient presented with marked hyperglycaemia and ketoacidosis at 70 days after birth, and insulin therapy was commenced. RESULTS: Wild-type and mutant K(ATP) channels were expressed in Xenopus oocytes and the effects of intracellular ATP on macroscopic K(ATP) currents in inside-out membrane patches were measured. In the simulated heterozygous state, the K185Q mutation caused a substantial reduction in the ability of MgATP to inhibit the channel. Heterozygous K185Q channels were still blocked effectively by the sulphonylurea tolbutamide. CONCLUSIONS: We report the first clinical case of a PNDM caused by a mutation at K185. Functional studies indicate that the K185Q mutation causes PNDM by reducing the ATP sensitivity of the K(ATP) channel, probably via a reduction in ATP binding to Kir6.2. Based on the experimental data, the patient was successfully transferred to sulphonylurea therapy.

The effect of gantry and collimator angles on leaf limited velocity and position in dynamic multileaf collimator intensity-modulated radiation therapy.

The purpose of the study is to evaluate the limiting velocity (LV) of a multileaf collimator and the leaf position in various collimator and gantry angles. Both leading leaves and trailing leaves began to move with a constant acceleration from 0 to 4 cm s(-1). When the beam hold occurred, the leaf velocity was defined as the leaf LV. Dynamic irradiation was performed at eight gantry angles of every 45 degrees with three different collimator angles. The analysis of the LV and the leaf position was performed with a log file from a leaf motion controller. The mean LVs for Varian Clinac 21EX (21EX) ranged from 2.51 to 3.10 cm s(-1). The mean LVs for Clinac 600C ranged from 2.91 to 3.12 cm s(-1). When only central 5 mm leaves of 21EX moved, LVs were significantly higher than those when all 60 pairs of leaf moved, while the leaf position inconsistencies of the two accelerators were within 1 mm at the leaf velocities from 0.5 to 2.0 cm s(-1). It was recognized that the LV was affected by gravity. This measurement method can be utilized as routine quality assurance for a dynamic multileaf collimator (DMLC) is and easily reproducible.

Mechanism of disopyramide-induced hypoglycaemia in a patient with Type 2 diabetes.

BACKGROUND: Disopyramide, an antiarrhythmia drug, has been reported to cause hypoglycaemia. Pre-existing factors that increase the concentration of the drug in the blood increase the risk of hypoglycaemia. Furthermore, other factors can also increase the risk of hypoglycaemia even when disopyramide levels are in the therapeutic range. It has been proposed that disopyramide-induced hypoglycaemia is caused by inhibition of the pancreatic B-cell K(ATP) channels. CASE REPORT: We report a case of severe disopyramide-induced hypoglycaemia in a 62-year-old woman with Type 2 diabetes taking low-dose glimepiride treatment. She had not experienced hypoglycaemia prior to the start of disopyramide therapy. No further hypoglycaemic episodes occurred following withdrawal of disopyramide therapy. FUNCTIONAL STUDY: Current recordings of K(ATP) channels expressed in Xenopus oocytes showed that at their estimated therapeutic concentrations, disopyramide and glimepiride inhibited K(ATP) channels by about 50-60%. However, when both drugs were applied together, K(ATP) channels were almost completely closed (approximately 95%). Such dramatic inhibition of K(ATP) channels is sufficient to cause B-cell membrane depolarization and stimulate insulin secretion. CONCLUSIONS: Disopyramide therapy is not recommended for patients treated with K(ATP) channel inhibitors.

Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.

BACKGROUND: Regenerating gene type IV (RegIV) is a candidate marker for cancer and inflammatory bowel disease. In this study, its potential as a novel marker for the detection of gastric cancer peritoneal micrometastases was examined. PATIENTS AND METHODS: RegIV mRNA levels in the peritoneal washes of 95 gastric cancer patients and 22 with benign disease were quantified by real-time RT-PCR. To examine whether expression of RegIV enhance tumorigenicity or not, thirty two mice were injected intraperitoneally or subcutaneously with RegIV transfectants of TMK-1 cells, parental TMK-1 cells, or neomycin control transfectants. RESULTS: RegIV expression was markedly higher in patients with peritoneal metastases compared to those without. The level of RegIV mRNA in gastric cancer patients was related to the extent of wall penetration. A cut-off value for RegIV-positive expression was based on an analysis of negative control patients with benign disease, and gastric cancer patients above the cut-off value constituted the micrometastasis (MM+) group. Based on this criteria, 3 out of 43 T1 or T2 cases were MM+ (93% specificity). Among 15 patients with peritoneal dissemination (7 out of 15 cases were positive by cytology), 14 cases were positive for RegIV expression (93% sensitivity), while analysis of carcinoembryonic antigen (CEA) mRNA failed to detect micrometastases in 4 cases (73% sensitivity). Combined analysis of CEA and RegIV improved the accuracy of diagnosis to 100%. The prognosis of RegIV-positive cases was significantly worse than that of RegIV-negative cases. Multivariate analysis using the Cox proportional hazards model suggested that RegIV may be an independent prognostic factor. Stable expression of RegIV significantly enhanced peritoneal metastasis in an animal model of gastric cancer. CONCLUSION: These findings suggest that RegIV mRNA expression has the potential to serve as a novel marker for detecting peritoneal dissemination in gastric cancer.

Hydrogen bonding in sodium alanate: a muon spin rotation study.

We have detected the occurrence of hydrogen bonding involving an interstitial positive muon situated between hydrogen atoms of two independent alanate anions in sodium alanate (NaAlH4). Ti doping, which is known to dramatically improve the hydrogen cycling performance of NaAlH4, reduces the kinetic barrier of the transition of the muon from the muon-dialanate state to a mobile interstitial state. This observation strongly suggests that hydrogen bonding is the primary bottleneck for hydrogen release or uptake in sodium alanate, which might be common to other complex hydrides.

A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.

OBJECTIVES: Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome. METHODS: We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant K(ATP) channels heterologously expressed in Xenopus oocytes. RESULTS: We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell K(ATP) currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities. CONCLUSIONS: We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.

Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress.

This paper reviews recent studies on the role of Nnt (nicotinamide nucleotide transhydrogenase) in insulin secretion and detoxification of ROS (reactive oxygen species). Glucose-stimulated insulin release from pancreatic beta-cells is mediated by increased metabolism. This elevates intracellular [ATP], thereby closing KATP channels (ATP-sensitive potassium channels) and producing membrane depolarization, activation of voltage-gated Ca2+ channels, Ca2+ influx and, consequently, insulin secretion. The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion, which results from a naturally occurring deletion in the Nnt gene. Transgenic expression of the wild-type Nnt gene in C57BL/6J mice rescues the phenotype. Knockdown of Nnt in the insulin-secreting cell line MIN6 with small interfering RNA dramatically reduced Ca2+ influx and insulin secretion. Similarly, mice carrying ENU (N-ethyl-N-nitrosourea)-induced loss-of-function mutations in Nnt were glucose intolerant and secreted less insulin during a glucose tolerance test. Islets isolated from these mice showed impaired insulin secretion in response to glucose, but not to the KATP channel blocker tolbutamide. This is explained by the fact that glucose failed to elevate ATP in Nnt mutant islets. Nnt is a nuclear-encoded mitochondrial protein involved in detoxification of ROS. beta-Cells isolated from Nnt mutant mice showed increased ROS production on glucose stimulation. We hypothesize that Nnt mutations enhance glucose-dependent ROS production and thereby impair beta-cell mitochondrial metabolism, possibly via activation of uncoupling proteins. This reduces ATP production and lowers KATP channel activity. Consequently, glucose-dependent electrical activity and insulin secretion are impaired.

Effect of peroxisome proliferator-activated receptor alpha ligand fenofibrate on K(v) channels in the insulin-secreting cell line HIT-T15.

Ligands for peroxisome proliferator-activated receptors alpha (PPARalpha) are clinically used for the treatment of patients with hyperlipidemia. As we have previously shown, a synthetic ligand of PPARalpha, fenofibrate, has a stimulatory effect on insulin secretion in clonal hamster insulinoma beta-cell line HIT-T15 cells. We have also demonstrated that fenofibrate directly inhibits ATP-sensitive potassium (K(ATP)) channels, an effect independent of PPARalpha. In this study, fenofibrate was shown to be able to reduce voltage-dependent K(+) (K(v)) channel currents in voltage-independent manner. Therefore, fenofibrate may modulate insulin secretion not only via inhibition of K(ATP) channels but also via reduction of the K(v) channel current.

Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography.

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P<0.05). Within the tumour, downregulation of RUNX3 expression ranged from 74.7 to 85.7% in the three groups. The rate of downregulation of RUNX3 of adjacent mucosa was 39.2% (11 in 28 cases) in RB and 47.6% (10 in 21 cases) in RM, which are significantly higher than that of the GCI group (19.5%, 17 in 87 cases). In noncancerous mucosa of the remnant stomach in the RB group, RUNX3 expression decreased more near the anastomosis area. In the RM group, however, there were no significant differences in RUNX3 expression by sampling location. Based on RUNX3 downregulation and clinical features, residual stomach mucosa of the RM group would have a higher potential of gastric carcinogenesis compared to the RB or GCI group. Gastric stump mucosa of the RB group has higher potential especially than other areas of residual stomach mucosa. Measurement of RUNX3 expression and detection of RUNX3 methylation in remnant gastric mucosa may estimate the forward risk of carcinogenesis in the remnant stomach.