Deliberate self-poisoning in Australian adolescents is increased on school days.

Deliberate self-poisoning (DSP) in adolescents is increasing dramatically. Life at school is one of the most important life influences for this age group. This study aimed to investigate whether the frequency of DSP is higher during school term compared to holidays and whether this difference has become greater over time. This is an ecological study using Poisons Information Centre (PIC) data for all DSPs in 10-19 year olds from New South Wales, Tasmania and Australian Capital Territory that occurred between 2005 and 2018. For each call, the date of the poisoning was assigned as 'term' or 'holiday'. To control for population growth, calls were expressed as per 100,000 of the population per day. Multivariable Poisson regression was performed to investigate the combined impact of various predictors (state, sex, year, holiday/term, day of week, age) on call number. 26,432 calls were included in the analysis (73.6% female, 24.1% male and 2.3% unknown). Poisson regression showed significant effects for all predictors, with an increased likelihood of DSP during the school term compared with holidays and on Monday-Thursday compared with Saturday but only during the school term. DSP doubled between 2012 and 2017 and the disparity between DSP that occurs during term vs. holiday increased over that time frame. We conclude that some of the increase in DSP is likely due to school-specific stressors, hence the school environment is the ideal setting for self-harm prevention initiatives.

Controlled beat-wave Brillouin scattering in the ionosphere.

Stimulated Brillouin scattering experiments in the ionospheric plasma using a single electromagnetic pump wave have previously been observed to generate an electromagnetic sideband wave, emitted by the plasma, together with an ion- acoustic wave. Here we report results of a controlled, pump and probe beat-wave driven Brillouin scattering experiment, in which an ion-acoustic wave generated by the beating of electromagnetic pump and probe waves, results in electromagnetic sideband waves that are recorded on the ground. The experiment used the EISCAT facility in northern Norway, which has several high power electromagnetic wave transmitters and receivers in the radio frequency range. An electromagnetic pump consisting of large amplitude radio waves with ordinary (O) or extraordinary (X) mode polarization was injected into the overhead ionosphere, along with a less powerful probe wave, and radio sideband emissions observed on the ground clearly show stimulated Brillouin emissions at frequencies agreeing with, and changing with, the pump and probe frequencies. The experiment was simulated using a numerical full-scale model which clearly supports the interpretation of the experimental results. Such controlled beat-wave experiments demonstrate a way of remotely investigating the ionospheric plasma parameters.

Collisionless shock acceleration in the corona of an inertial confinement fusion pellet with possible application to ion fast ignition.

Two-dimensional particle-in-cell simulations are used to explore collisionless shock acceleration in the corona plasma surrounding the compressed core of an inertial confinement fusion pellet. We show that an intense laser pulse interacting with the long scale-length plasma corona is able to launch a collisionless shock around the critical density. The nonlinear wave travels up-ramp through the plasma reflecting and accelerating the background ions. Our results suggest that protons with characteristics suitable for ion fast ignition may be achieved in this way. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

New criteria for efficient Raman and Brillouin amplification of laser beams in plasma.

Raman or Brillouin amplification of a laser beam in plasma has long been seen as a way to reach multi-PW powers in compact laser systems. However, no significant plasma-based Raman amplification of a laser pulse beyond 0.1 TW has been achieved in nearly 20 years, and only one report of Brillouin amplification beyond 1 TW. In this paper, we reveal novel non-linear criteria for the initial seed pulse that will finally open the door to efficient Raman and Brillouin amplification to petawatt powers and Joule-level energies. We show that the triple product of the coupling constant [Formula: see text], seed pulse duration [Formula: see text] and seed pulse amplitude a for the Raman seed pulse (or [Formula: see text] for Brillouin) must exceed a specific minimum threshold for efficient amplification. We also analyze the plasma-based Raman and Brillouin amplification experiments to date, and show that the seed pulses used in nearly all experiments are well below our new threshold, which explains the poor efficiency obtained in them. Finally, we analyze a recent Brillouin amplification experiment that used increased seed pulse power to obtain Joule-level amplification, and find excellent agreement with our theory.

Desvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects.

CONTEXT: Desvenlafaxine is used to treat major depression. Desvenlafaxine is also the active metabolite of venlafaxine. Venlafaxine overdose can cause serotonin toxicity, seizures and cardiovascular effects, but there is limited information on desvenlafaxine overdose. OBJECTIVE: We aimed at investigating the clinical effects and complications from desvenlafaxine overdose. MATERIALS AND METHODS: This was a retrospective observational study of desvenlafaxine overdoses over a six-year period. Demographic details, dose and timing of the overdose, together with clinical effects, treatment and complications were extracted from a local hospital network database or the medical records of patients following hospital admission with a desvenlafaxine overdose. RESULTS: There were 182 cases of desvenlafaxine overdose included in the study. From the 182 cases, 75 were desvenlafaxine (± alcohol) only ingestions and 107 included one or more co-ingested drugs. In single-agent desvenlafaxine ingestions, median age was 25 years (range: 13-68 years) with a median ingested dose of 800 mg (range: 250-3500 mg; interquartile range (IQR): 600-1400 mg), and 54/75 (72%) were female. The Glasgow Coma Score (GCS) was 15 in 68/74 (92%) patients, 13-14 in 5/74 (7%), and was seven in one patient following aspiration. Mild hypertension (systolic blood pressure [BP] > 140-180 mmHg) occurred in 23/71 patients (32%), and tachycardia occurred in 29/74 (39%) patients. There were no abnormal QT intervals and no QRS >120 m s. Serotonin toxicity was diagnosed by the treating physician in 7/75 (9%) patients, but only one of these met the Hunter Serotonin Toxicity Criteria. None of the 75 patients who took desvenlafaxine only (± alcohol) had seizures, were admitted to intensive care or died. In comparison, the 107 patients taking desvenlafaxine in overdose with other medications developed more pronounced toxicity. Generalised seizures occurred in 5/107 (5%), but in three of these cases co-ingestants were possible proconvulsants. Fifteen patients had a GCS ≤9 and none had an abnormal QT or QRS. Severe effects appeared to be associated with coingestants. CONCLUSION: Desvenlafaxine overdose causes minor effects with mild hypertension and tachycardia. The risk of seizures or serotonin toxicity is low.

Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio.

Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.

Backward wave cyclotron-maser emission in the auroral magnetosphere.

In this Letter, we present theory and particle-in-cell simulations describing cyclotron radio emission from Earth's auroral region and similar phenomena in other astrophysical environments. In particular, we find that the radiation, generated by a down-going electron horseshoe distribution is due to a backward-wave cyclotron-maser emission process. The backward wave nature of the radiation contributes to upward refraction of the radiation that is also enhanced by a density inhomogeneity. We also show that the radiation is preferentially amplified along the auroral oval rather than transversely. The results are in agreement with recent Cluster observations.

Annexin A6 is a scaffold for PKCα to promote EGFR inactivation.

Protein kinase Cα (PKCα) can phosphorylate the epidermal growth factor receptor (EGFR) at threonine 654 (T654) to inhibit EGFR tyrosine phosphorylation (pY-EGFR) and the associated activation of downstream effectors. However, upregulation of PKCα in a large variety of cancers is not associated with EGFR inactivation, and factors determining the potential of PKCα to downregulate EGFR are yet unknown. Here, we show that ectopic expression of annexin A6 (AnxA6), a member of the Ca(2+) and phospholipid-binding annexins, strongly reduces pY-EGFR levels while augmenting EGFR T654 phosphorylation in EGFR overexpressing A431, head and neck and breast cancer cell lines. Reduced EGFR activation in AnxA6 expressing A431 cells is associated with reduced EGFR internalization and degradation. RNA interference (RNAi)-mediated PKCα knockdown in AnxA6 expressing A431 cells reduces T654-EGFR phosphorylation, but restores EGFR tyrosine phosphorylation, clonogenic growth and EGFR degradation. These findings correlate with AnxA6 interacting with EGFR, and elevated AnxA6 levels promoting PKCα membrane association and interaction with EGFR. Stable expression of the cytosolic N-terminal mutant AnxA6(1-175), which cannot promote PKCα membrane recruitment, does not increase T654-EGFR phosphorylation or the association of PKCα with EGFR. AnxA6 overexpression does not inhibit tyrosine phosphorylation of the T654A EGFR mutant, which cannot be phosphorylated by PKCα. Most strikingly, stable plasma membrane anchoring of AnxA6 is sufficient to recruit PKCα even in the absence of EGF or Ca(2+). In summary, AnxA6 is a new PKCα scaffold to promote PKCα-mediated EGFR inactivation through increased membrane targeting of PKCα and EGFR/PKCα complex formation.

Cancer cell metabolism.

Although the generation of a distinctive metabolic profile is a well-known aspect of cancer, the significance of these adaptations and their potential for exploitation for anticancer therapy has not been fully appreciated until recently. Many oncogenic changes known to affect intracellular signaling pathways play an active role in mediating these metabolic changes, which, in turn, function to support cancer cell growth and replication. In this chapter, we discuss the most current findings in cancer cell metabolism in terms of their impact on tumor cell growth as well as their potential for identifying new targets for therapeutic intervention.

Production of picosecond, kilojoule, and petawatt laser pulses via Raman amplification of nanosecond pulses.

Raman amplification in plasma has been promoted as a means of compressing picosecond optical laser pulses to femtosecond duration to explore the intensity frontier. Here we show for the first time that it can be used, with equal success, to compress laser pulses from nanosecond to picosecond duration. Simulations show up to 60% energy transfer from pump pulse to probe pulse, implying that multikilojoule ultraviolet petawatt laser pulses can be produced using this scheme. This has important consequences for the demonstration of fast-ignition inertial confinement fusion.

Prognostic impact of electrocardiographic signs in patients with Type 2 diabetes and cardiovascular disease: results from the PROactive study.

AIMS: Although a resting electrocardiograph is broadly applied in clinical practice for evaluating patients with Type 2 diabetes and cardiovascular disease, the independent prognostic relevance of electrocardiographic signs has not thoroughly been examined. METHODS: Baseline 12-lead electrocardiographs available in 5231 of the 5238 participants of the PROactive trial were analysed for heart rate, heart rate corrected QT-interval, presence of atrial fibrillation/flutter, left axis deviation, right and left bundle branch block. The association of electrocardiographic signs with total mortality, the principal secondary composite endpoint (death, myocardial infarction and stroke) and serious adverse heart failure events was examined by Cox-regression analysis. RESULTS: Two hundred and twenty-three (4.3%) patients showed atrial fibrillation/flutter, 213 (4.1%) patients had right bundle branch block, 111 (2.1%) patients had left bundle branch block and 706 (13.5%) patients had left axis deviation. Mean cQT-interval was 418 ms (± 25 ms) and mean heart rate was 72/min (± 14/min). In multivariate adjusted analyses, heart rate and cQT-interval were significantly associated with mortality, the composite secondary endpoint and heart failure, whereas right and left bundle branch blocks were significantly associated with heart failure only. Left axis deviation was associated with heart failure and atrial fibrillation/flutter was associated with mortality and heart failure in univariate but not multivariate analyses. CONCLUSION: Easily assessable electrocardiographic signs such as heart rate, cQT-interval and bundle branch blocks were predictive for adverse outcome independently of multiple risk factor adjustment and should be considered in clinical care.

Dust-acoustic shock waves due to strong correlation among arbitrarily charged dust.

The nonlinear propagation of the dust-acoustic (DA) waves in a strongly coupled dusty plasma containing strongly correlated arbitrarily (positively or negatively) charged dust and weakly correlated Boltzmann electrons and ions has been investigated by employing the generalized hydrodynamic model and the reductive perturbation method. It has been shown that the strong correlation among the charged dust is a source of dissipation and is responsible for the formation of the DA shock waves in such a strongly coupled dusty plasma. It has also been found that the DA shock waves with positive (negative) potential are formed for positively (negatively) charged dust. The basic features of such DA shock waves have been identified. It has been suggested that a laboratory experiment be performed to test the theory presented here.

Cyclotron maser radiation from an inhomogeneous plasma.

Cyclotron maser radiation is important in both laboratory devices such as gyrotrons and in space physics applications to phenomena such as auroral kilometric radiation. To understand the behavior, especially in the latter case where there is generally a localized region of instability, requires an understanding of how such instabilities behave in an inhomogeneous plasma. Here we consider, for simplicity, a simple ring distribution of electrons in either a step function variation of magnetic field or a continuous gradient. In each case we show that there can exist localized regions of instability from which waves, growing in time, can be radiated outwards.

Efficiency and energy spread in laser-wakefield acceleration.

The theoretical limits on efficiency and energy spread of the laser-wakefield accelerator are investigated using a one-dimensional model. Modifications, both of the wakefield due to the electron bunch, and of the laser pulse shape due to the varying permittivity of the plasma, are described self-consistently. It is found that a short laser pulse gives a higher efficiency than a long laser pulse with the same initial energy. Energy spread can be minimized by optimizing bunch length and bunch charge such that the variation of the accelerating force along the length of the bunch is minimized. An inherent trade-off between energy spread and efficiency exists.

A systematic review describing the prognosis of chronic fatigue syndrome.

AIM: To perform a systematic review of studies describing the prognosis of chronic fatigue (CF) and chronic fatigue syndrome (CFS) and to identify occupational outcomes from such studies. METHOD: A literature search was used to identify all studies describing the clinical follow-up of patients following a diagnosis of CF or CFS. The prognosis is described in terms of the proportion of individuals improved during the period of follow-up. Return to work, other medical illnesses and death as outcomes are also considered, as are variables which may influence prognosis. RESULTS: Twenty-eight articles met the inclusion criteria and, for the 14 studies of subjects meeting operational criteria for CFS, the median full recovery rate was 5% (range 0-31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8-63%). Less fatigue severity at baseline, a sense of control over symptoms and not attributing illness to a physical cause were all associated with a good outcome. Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome. CONCLUSIONS: Full recovery from untreated CFS is rare. The prognosis for an improvement in symptoms is less gloomy. This review looks at the course of CF/CFS without systematic intervention. However, there is increasing evidence for the effectiveness of cognitive behavioural and graded exercise therapies. Medical retirement should be postponed until a trial of such treatment has been given.

Molecular mechanisms of tumor invasion and metastasis: an integrated view.

As tumors progress to increased malignancy, cells within them develop the ability to invade into surrounding normal tissues and through tissue boundaries to form new growths (metastases) at sites distinct from the primary tumor. The molecular mechanisms involved in this process are incompletely understood but those associated with cell-cell and cell-matrix adhesion, with the degradation of extracellular matrix, and with the initiation and maintenance of early growth at the new site are generally accepted to be critical. This article discusses current knowledge of molecular events involved in these various processes. The potential role of adhesion molecules (eg. integrins and cadherins) has undergone a major transition over the last ten years, as it has become apparent that such molecules play a major role in signaling from outside to inside a cell, thereby controlling how a cell is able (or not) to sense and interact with its local environment. Similarly the roles of proteolytic enzymes and their inhibitors (eg. matrix metalloproteinases and TIMPs) have also expanded as it has become apparent that they not only have the abilities to break down the components of the extracellular matrix but also are involved in the release of factors which can affect the growth of the tumor cells positively or negatively. Recent work has highlighted the importance of the later, post-extravasational stages of metastasis, where adhesion and proteolysis are now known to play a role along with other processes such as apoptosis, dormancy, growth factor-receptor interactions and signal transduction. Recent work has also demonstrated that not only the immediate cellular microenvironment, in terms of specific cell-cell and cell-matrix interactions, but also the extended cellular microenvironment, in terms of vascular insufficiency and hypoxia in the primary tumor, can modify cellular gene expression and enhance metastasis. Mechanisms of metastasis appear to involve a complex array of genetic and epigenetic changes many of which appear to be specific both for different types of tumors and for different sites of metastasis. Our improved understanding of the expanded roles of the individual molecules involved has resulted in a mechanistic blurring of the previously described discrete stages of the metastatic process.

Role of parallel flow in the improved mode on the STOR-M tokamak.

A novel feature of the H-mode induced by compact torus injection on the STOR-M tokamak is observed. There is almost no change in the radial electric field profiles during and after the L-H transition. The usual hypothesis of the E x B shear stabilization mechanism is therefore unlikely to play a role in this transition. A new mechanism of the stabilization of microinstabilities by parallel flow is suggested as the plausible cause for the transition to this improved regime.

Tolerability of ibuprofen, aspirin and paracetamol for the treatment of cold and flu symptoms and sore throat pain.

This double-blind randomised study compared the tolerability of ibuprofen (up to 1.2 g daily), aspirin and paracetamol (both up to 3 g daily) for up to seven days, in patients with mild to moderate pain resulting from cold/flu symptoms or sore throat (CF/ST) (n = 2,815). The main outcome was the rate of significant adverse events (SGAE). Rates of SGAE for ibuprofen, aspirin and paracetamol were respectively 12.0%, 15.7% and 12.3%. Ibuprofen was significantly better tolerated than aspirin (p = 0.02) and had comparable tolerability with paracetamol. The latter was also true for total digestive system events and for abdominal pain and dyspepsia. In conclusion, in patients with CF/ST, ibuprofen used at over-the-counter doses is as well tolerated as paracetamol and much better tolerated than aspirin.

Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors.

Hypoxia exists in most human and rodent solid tumors and has been shown to correlate with poor survival in carcinoma of the cervix, carcinoma of the head and neck, and soft tissue sarcoma. It exists both chronically, due to the poorly organized vasculature of solid tumors, and acutely, due to fluctuations in blood flow. It has been found that tumors that are more hypoxic are more likely to metastasize in humans and in rodent models, and it has been demonstrated that exposure of tumor cells to hypoxia in vitro can transiently enhance their metastatic potential when they are reinjected i.v. into mice. The purpose of the present study was to determine whether experimentally imposed hypoxic stress in vivo, either chronic or acute, affects the process of spontaneous metastasis in tumor-bearing mice. We exposed mice bearing KHT tumors to low oxygen conditions (5-7% O(2) breathing) daily during tumor growth in an attempt to induce additional chronic (2 h/day) and acute (12 x 10 min/day) hypoxia in their tumors. By monitoring tumor pO(2) levels over the course of treatment, we demonstrated that these treatments produce acute and chronic hypoxia within the tumor tissue. The acute but not the chronic hypoxia treatment significantly increased the number of spontaneous microscopic lung metastases in the mice by a factor of about 2, and the results suggest that this effect was due to the changes induced in the primary tumor. This study describes a novel method for studying the effects of hypoxia in solid tumors and demonstrates that acute and chronic hypoxia can have different effects on tumor cell behavior in vivo.