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Arrival time of particles in an extensive air shower (EAS) is a key physical parameter to determine its direction. EAS direction is useful for studies of anisotropy and composition of cosmic rays, and search for multi-TeV γ-rays sources. Accurate timing may be used to search exotic phenomena such as production of new particles at extremely high energies available during early stages of development of EAS and also for detecting sub-relativistic hadrons in EAS. Time to digital converters (TDCs) are used to perform this task. Traditional TDCs operate in the START-STOP mode with limited dynamic range and single-hit capability. With the advent of high luminosity collider LHC, need for TDCs with large dynamic range, multi-hit capability and TRIGGERED mode of operation became necessary. A 32 channel TDC was designed for the GRAPES-3 experiment on a CAMAC platform around TDC32, an ASIC developed by micro-electronics group at CERN, Geneva. Four modules were operated in the GRAPES-3 experiment. Here, we present details of the circuit design and their performance over several years. The multi-hit feature of this device was used to study the time structure of particles in the EAS on time scale of ~1 μs. The distribution of time intervals in the multi-hit data shows an exponential profile with a time constant of ~370 ns. These delayed particles are likely to be neutrons produced in the EAS core that were recorded in the scintillator detectors following the relativistic EAS front.

The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor alpha (ERalpha), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERalpha and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERalpha signaling, a heregulin-1beta induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERalpha signaling. This interplay between ERalpha and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, the present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance.

The objective was to compare the epidemiology and outcome of healthcare- (HA-) and community-associated (CA-) MRSA bacteraemia. A 10-year retrospective study of MRSA bacteraemia was carried out. Episodes were classified according to established criteria. Molecular typing was performed on a subset of isolates. Of 197 MRSA bacteraemia episodes, 178 (90.4%) were classified as HA-MRSA and 19 (9.6%) as CA-MRSA. All-cause 7- and 30-day mortality rates were similar in the HA and CA-MRSA bacteraemia groups; however, 1-year mortality was higher in the HA-MRSA bacteraemia group (48.3% vs 21.1% [p = 0.023]). Thirty-day all-cause mortality was significantly lower if empiric antimicrobial therapy included agent(s) to which the isolate tested susceptible, compared with patients receiving "inactive" therapy (19% vs 35.1% [p = 0.011]). The majority of MRSA bacteraemia episodes were caused by clones known to circulate in the community. All-cause mortality is as high in HA- as in CA-MRSA bacteraemia. Thirty-day mortality was significantly reduced if the patient received an antibiotic with activity against the MRSA isolate.

Histone deacetylase inhibitors (HDACi) inhibit the growth of cancer cells, and combinations of HDACi with established chemotherapeutics can lead to synergistic effects. We have investigated effects of PXD101 (HDACi in phase II clinical trials) in combination with 5-fluorouracil, on tumour cell proliferation and apoptosis both in vitro and in vivo. HCT116 cells were studied using proliferation and clonogenic assays. Synergistic inhibition of proliferation and clonogenicity was determined by incubation with PXD101 and 5-fluorouracil, and analysis using CalcuSyn™ software. The effect of combining PXD101 and 5-fluorouracil on apoptosis was examined in vitro using PARP-cleavage and TUNEL. Finally, the effectiveness of combining PXD101 and 5-fluorouracil in vivo was tested using both HT-29 and HCT116 xenograft models. Synergistic inhibition of proliferation and clonogenicity was obtained when HCT116 cells were incubated with PXD101 and 5-fluorouracil. 5-fluorouracil combined with PXD101 also increased DNA fragmentation and PARP cleavage in HCT116 cells. Incubation with PXD101 down regulated thymidylate synthase expression in HCT116 cells. In vivo studies, using mouse HT29 and HCT116 xenograft models, showed improved reductions in tumour volume compared to single compound, when PXD101 and 5-fluorouracil were combined. PXD101 and 5-fluorouracil synergistically combine in their anti-tumour effects against colon cancer cells in vitro and show enhanced activity when combined in vivo. Based on the results presented herein, a rationale for the use of PXD101 and 5-fluorouracil in combination in the clinic has been demonstrated.

Stripe or yellow rust of wheat, caused by Puccinia striiformis f. sp. tritici, is an important disease in many wheat-growing regions of the world. A number of major genes providing resistance to stripe rust have been used in breeding, including one gene that is present in the differential tester Carstens V. The objective of this study was to locate and map a stripe rust resistance gene transferred from Carstens V to Avocet S and to use molecular tools to locate a number of genes segregating in the cross Savannah/Senat. One of the genes present in Senat was predicted to be a gene that is present in Carstens V. For this latter purpose, stripe rust response data from both seedling and field tests on a doubled haploid population consisting of 77 lines were compared to an available molecular map for the same lines using a non-parametric quantitative trait loci (QTL) analysis. Results obtained in Denmark suggested that a strong component of resistance with the specificity of Carstens V was located in chromosome arm 2AL, and this was consistent with chromosome location work undertaken in Australia. Since this gene segregated independently of Yr1, the only other stripe rust resistance gene known to be located in this chromosome arm, it was designated Yr32. Further QTLs originating from Senat were located in chromosomes 1BL, 4D, and 7DS and from Savannah on 5B, but it was not possible to characterize them as unique resistance genes in any definitive way. Yr32 was detected in several wheats, including the North American differential tester Tres.

Studies of the effect of fertilisation stress, harvest time, machine sorting, storage time, peeling and blanching of potatoes (Solarium tuberosum L.) were carried out. Mechanical impact by sorting before storage did not have a significant effect on hardness of pre-peeled potatoes. Potato hardness decreased significantly with the storage time for raw potatoes following an exponential function. Treatment of potatoes in a damage drum for 5 minutes (36 drops from 35 cm) increased the subsurface hardening, production of brick-like cells and deposition of suberin. Potato hardness throughout the whole potatoes increased with blanching time by blanching at 85 and 95 °C. It was concluded that development of potato hardiness occur because of two mechanisms. That is: 1) wound healing by periderm formation with deposition of suberin and: 2) activation of methyl esterase activity by blanching and subsequent crosslinking of demethoxylated pectin by calcium ions, respectively.

A case report of a patient with a large pulmonary arteriovenous fistula and valvar pulmonary stenosis is presented. The fistula was diagnosed prenatally and its effect on in utero cardiovascular growth and development documented. Due to concerns about massive intrapulmonary shunting potentially causing profound cyanosis after delivery, an EXIT (EX-utero Intrapartum Treatment) procedure was used to transfer the infant from placental to extracorporeal membrane oxygenation (ECMO) support. Severe pulmonary microvascular disease resulted in prohibitive pulmonary hypertension despite surgical ligation of the fistula. Prenatal and postnatal hemodynamic assessments of the fistula are presented and are compared to the pathologic findings.

Background Health care worker (HCW) colonization with methicillin resistant Staphylococcus aureus (MRSA) is a documented cause of hospital outbreaks and contributes to ongoing transmission. At Royal Perth Hospital (RPH) it had been anecdotally noted that the increasing prevalence of EMRSA-15 appeared to be associated with increased HCW colonization compared with Aus2/3-EMRSA. Hence we compared HCW colonization rates during outbreaks of EMRSA-15 and Aus2/3-EMRSA at a single institution. Methods We performed a retrospective review of EMRSA-15 and Aus2/3-EMRSA outbreaks from 2000–2009 at RPH, a quaternary hospital in Western Australia. Outbreak files were reviewed and relevant data extracted. Results Ten EMRSA-15 outbreaks were compared with seven Aus2/3 outbreaks. The number of patients colonized was similar between EMRSA-15 and Aus2/3-EMRSA outbreaks (median 7 [range 3–20] and 11 [5–26], respectively; P = 0.07) but the number of HCWs colonized was significantly higher in EMRSA-15 outbreaks compared to Aus2/3-EMRSA outbreaks (median 4 [range 0–15] and 2 [1-3], respectively; P = 0.013). The percentage of HCWs colonized was also higher in EMRSA-15 outbreaks versus Aus2/3-EMRSA outbreaks (median 3.4% [range 0–5.5%] and 0.81% [0.56–2.2%], respectively; P = 0.013). Conclusions This study demonstrates a higher level of HCW colonization during EMRSA-15 outbreaks compared with Aus2/3-EMRSA outbreaks. This finding suggests that MRSA vary in their ability to colonize HCWs and contribute to outbreaks. MRSA type should be determined during outbreaks and future research should investigate the mechanisms by which EMRSA-15 contributes to increased HCW colonization.

A method for plant regeneration via organogenesis in pea (Pisum sativum) using nodal thin cell layer segments has been developed.From 10 to 12 days old sterile pea seedlings, nodal expiants were excised from which leaves and axillary buds were removed. Shoot regeneration was consistently obtained from liquid cultures where the expiants were floated on the medium. Shoots could be harvested after two weeks and thereafter up to ten weeks and no important effect of the cultivar (Bodil, Puget, Rondo and Trille) used could be observed as far as shooting capacity was concerned.Rooting frequency of the regenerated shoots was cultivar dependent. Plantlets were obtained within 7 weeks after expiant excision. Agrobacterium tumefaciens carrying a disarmed Tiplasmid and a binary vector containing the ß-glucuronidase reporter gene, were used in cocultivation experiments on pea nodal expiants in order to obtain transgenic shoots.

A previously healthy 18-year-old male, following appendectomy developed post-anaesthetic hyperthermia (42.1° C) with an elevation of serum creatine kinase and activated partial thromboplaslin time. Repeated arterial blood gases were normal. Cooling and anti-pyretic medication did not control the fever. In contrast, sodium dantrolene appeared effective in lowering the patient’s temperature and normalizing the vital signs, both acutely and over the following three days. Subsequent muscle biopsy revealed a normal contracture response to caffeine alone or in the presence ofhalothane. However, the muscle had a larger than normal potentiation of evoked twitch tension in the presence of caffeine and halothane. Electrophoresis of the muscle revealed a marked increase of an unidentified low molecular weight protein. The patient’s clinical course, and the results of the muscle studies, sugest that an abnormality of skeletal muscle, other than that seen in the classic malignant hyperthermia syndrome may result in anaesthesia-related hyperthermia.

Observations of waves exhibiting an often complex frequency banding related to the electron gyrofrequency were first reported in 19701. Later observations2–5 showed that the spectral content of these electrostatic electron cyclotron harmonic waves is highly variable6,7, including single frequency emissions between the electron gyrofrequency Ωe and its first harmonic, multiple bands between consecutive harmonics of Ωe, and emissions in a single band far above the electron gyrofrequency8–10. These observations have led theorists to investigate both the linear instability which generates the waves11–15 and various wave–particle14,16 and wave–wave17–18 interactions in which they may be involved. The consensus seems to be that at least two plasma components with different temperatures are required to destablilize electron cyclotron harmonic waves. We adopt this view here and test our present knowledge of electron cyclotron harmonic instabilities against the observed reality. To do this we use simultaneous observations of wave spectra and electron distribution functions, available in the GEOS 1 data from 25 August 1977 (see ref. 15). From these we present the wave event and then use the measured particle fluxes to derive a model distribution function, providing the input to a computer program which solves the plasma dispersion relation. From the computed temporal growth rates and group velocities, the total amplification of waves which are unstable within a limited volume of space is estimated.

The trapezoidal rule with deferred corrections using uncentered end formulas is shown to converge. While the proof technique is more specialized than the standard asymptotic expansion approach, it has some advantages. In addition to providing a more complete theoretical justification for current implementations of deferred corrections with the trapezoidal rule, the approach given here will hopefully apply for several other discretization methods.

The quadrupole hyperfine interaction of111Cd in Cd, In, Sn, and of67Zn,69Ge in Zn was measured with high accuracy using TDPAC and TDPAD methods; in addition the systems117In in Cd and In, and113Sn in Cd were investigated. The temperature dependence of the electric field gradienteq(T) can be reproduced by the simple relationeq(T)/eq(0)=1—B⋅T 3/2 over a range of temperatures from a few K up to the melting point. A comparison with other experiments was carried out to test the universality of this empirical relation. In particular, high precision NQR experiments on Ga, In and Sb strongly support this relation. It is discussed whether lattice vibrations can explain the observed temperature variation or whether the experimental data indicate the need for a new description. Some new ideas suggesting a basically different model are given.

On the basis of low pressure spark discharges a new type of a particle accelerator as been developed. It produces pulsed ion as well as electron beams of high intensities in a gas atmosphere at pressures of the order of 1 mbar. The method was used to produce in hydrogene at particle energies of about 70 keV an electron beam with a current density of more than 106 A/cm2 at 140 A total current. It is shown that magnetic confinement by the pinch effect takes place in the discharge. Discharge times smaller than 5 ns and spark frequencies up to 2 MHz can be obtained.

Natural noise bands, a persistent feature of the Earth's magnetosphere, have been identified for the first time, using novel techniques on the recently launched Geos I satellite. It is argued that these waves, in the electron cyclotron harmonic mode, are radiated incoherently by suprathermal electrons.

Carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-Epoxide) in the temporal lobe were measured in five epileptic patients undergoing unilateral temporal lobectomy. The patients had been under CBZ treatment from 6 months to 6 years and all were in steady state at the time of operation. The brain tissue concentration of CBZ in all patients was higher than the plasma concentration; the brain/plasma ratio ranged from 1.4--1.6. Brain/plasma ratios of CBZ-Epoxide ranged from 0.6--1.5. The ratio for CBZ was similar in patients treated with CBZ alone or in combination with other anticonvulsants, but for the CBZ-Epoxide a higher ratio was found in patients on combined treatment. The results may mean that other antiepileptic drugs, too, can influence the brain concentration of an active metabolite, which could have a bearing on the enhanced therapeutic effect often seen on combining CBZ treatment with other antiepileptic drugs.

Mossbauer spectra in α-Fe2O3 were measured below and above the Morin temperature following the reaction56Fe(d, p)57Fe. Within high accuracy, shift, quadrupole splitting, and Debye-Waller-factor are found to be the same as corresponding radioactive source data, whereas the magnetic field is lower by 10 kG. It follows that 10−7 s after the nuclear reaction essentially all excited recoils are at normal lattice sites with nearest neighbors being undisturbed. The deviation in magnetic field cannot be explained by a rise in temperature.

The characteristic features of a parallel-plate avalanche counter are described. Using extremely thin foils as electrodes this counter can be designed as a large area transmission detector for the measurement ofd E/ds of ionizing particles. A telescope consisting of three parallel-plate avalanche counters was used for the measurement of the polarization of fast neutrons employingn-α scattering as analysing reaction. The experimental methods of these measurements are discussed.

POLARISATION requirements and wave number matching dictate that a nonlinear interaction involving three electromagnetic waves that propagate in a magnetoactive plasma must necessarily be two-dimensional if one of the waves propagates parallel to the external magnetic field B0. We report here what we believe to be the first observation of a three wave interaction of this kind. Our experiment involved the production of a whistler mode wave (k3, ω3) (referred to as WMW) through the interaction of two beams of high frequency electromagnetic waves (k1, ω1) and (k2, ω2), propagating somewhat above the local plasma frequency ωp. The resonance condition for the interaction are If ω1,2 > ωp and ω3 is sufficiently small compared with the electron gyrofrequency ωe (ωe < ωp), the high frequency beams must be directed1 almost at right angles to B0 (Fig. 1 inset). The strength of the coupling of the beams is determined by two factors: first, the magnitude of the matrix element for the interaction; and second, the time in which a stationary state is established as a result of the convection of the WMW packet across the finite interaction region of width, l. An expression2,3 for the steady-state amplitude, E3 of the electric field of the WMW, can be obtained in terms of the amplitudes E1 and E2 of the beams where where e and m are the charge and mass of the electron, respectively, c the speed of light, μ, the refractive index for the WMW, and other symbols are as defined previously.

The supersonic solar wind possesses a variety of simple small scale (

WE present here observations of electron-cyclotron harmonic (ECH) waves occurring in the vicinity of the geomagnetic equator at 6.6 Earth's radii, and discuss their relevance to the morphology of electron distributions (with energies below 500 eV) observed simultaneously1.

Electron cyclotron harmonic (ECH) instabilities just outside the plasmapause and at frequencies near the cold upper hybrid frequency are a common feature of the Earth's magnetosphere. These waves which have virtually no magnetic component, are believed to have an important role in the generation of weak diffuse aurora1,2. They are able to interact strongly with electrons in the hundred eV to several keV energy range which can result in pitch angle scattering and precipitation on magnetic field lines which map down into the auroral zone. On the dayside magnetosphere these waves can exhibit large amplitude variations of 30–40 dB and can also exist at steady amplitudes on time scales of the order of tens of seconds. Here we seek an explanation for the sporadic nature of such instabilities by performing linear stability calculations and extending the technique used in the accompanying paper3.