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Neurotrophins (NTs) have recently been found to regulate synaptic transmission in the hippocampus. Whole-cell and single-channel recordings from cultured hippocampal neurons revealed a mechanism responsible for enhanced synaptic strength. Specifically, brain-derived neurotrophic factor augmented glutamate-evoked, but not acetylcholine-evoked, currents 3-fold and increased N-methyl-D-aspartic acid (NMDA) receptor open probability. Activation of trkB NT receptors was critical, as glutamate currents were not affected by nerve growth factor or NT-3, and increased open probability was prevented by the tyrosine kinase inhibitor K-252a. In addition, the NMDA receptor antagonist MK-801 blocked brain-derived neurotrophic factor enhancement of synaptic transmission, further suggesting that NTs modulate synaptic efficacy via changes in NMDA receptor function.

The original article [1] mistakenly omitted mention of a grant support source in the Funding sub-section, and would like to acknowledge that the work was also supported by National Key Basic Research Program of China (2013CB530900).

Background Our previous studies of Alzheimer’s disease (AD) suggested that glutamine broadly improves cellular readiness to respond to stress and acts as a neuroprotectant both in vitro and in AD mouse models. We now expand our studies to a second neurodegenerative disease, ataxia-telangiectasia (A-T). Unlike AD, where clinically significant cognitive decline does not typically occur before age 65, A-T symptoms appear in early childhood and are caused exclusively by mutations in the ATM (A-T mutated) gene. Results Genetically ATM-deficient mice and wild type littermates were maintained with or without 4 % glutamine in their drinking water for several weeks. In ATM mutants, glutamine supplementation restored serum glutamine and glucose levels and reduced body weight loss. Lost neurophysiological function assessed through the magnitude of hippocampal long term potentiation was significantly restored. Glutamine supplemented mice also showed reduced thymus pathology and, remarkably, a full one-third extension of lifespan. In vitro assays revealed that ATM-deficient cells are more sensitive to glutamine deprivation, while supra-molar glutamine (8 mM) partially rescued the reduction of BDNF expression and HDAC4 nuclear translocation of genetically mutant Atm −/− neurons. Analysis of microarray data suggested that glutamine metabolism is significantly altered in human A-T brains as well. Conclusion Glutamine is a powerful part of an organism’s internal environment. Changes in its concentrations can have a huge impact on the function of all organ systems, especially the brain. Glutamine supplementation thus bears consideration as a therapeutic strategy for the treatment of human A-T and perhaps other neurodegenerative diseases.

Although neurotrophins are primarily associated with long-term effects on neuronal survival and differentiation, recent studies have shown that acute changes in synaptic transmission can also be produced. In the hippocampus, an area critically involved in learning and memory, we have found that brain-derived neurotrophic factor (BDNF) rapidly enhanced synaptic efficacy through a previously unreported mechanism-increased postsynaptic responsiveness via a phosphorylation-dependent pathway. Within minutes of BDNF application to cultured hippocampal neurons, spontaneous firing rate was dramatically increased, as were the frequency and amplitude of excitatory postsynaptic currents. The increased frequency of postsynaptic currents resulted from the change in presynaptic firing. However, the increased amplitude was postsynaptic in origin because it was selectively blocked by intracellular injection of the tyrosine kinase receptor (Ntrk2/TrkB) inhibitor K-252a and potentiated by injection of the phosphatase inhibitor okadaic acid. These results suggest a role for BDNF in the modulation of synaptic transmission in the hippocampus.

N-type calcium channels are thought to be expressed specifically in neuronal cells and to have a dominant role in the control of neurotransmitter release from sympathetic neurons. But their unitary properties are poorly understood and the separation of neuronal Ca2+ current into components carried by N-type or L-type Ca2+ channels is controversial. Here we show that individual N-type Ca2+ channels in sympathetic neurons can carry two kinetically distinct components of current, one that is rapidly transient and one that is long lasting. The mechanism that gives rise to these two components is unexpected for Ca2+ channels: a test depolarization elicits either a rapidly inactivating, single short burst with an average duration of 40 ms, or sustained, noninactivating channel activity lasting for over 1 s. The switching between inactivating and noninactivating activity is a slow process, the occurrence of each type of unitary kinetic behaviour remaining statistically correlated over several seconds. Variable coupling of inactivation in N-type Ca2+ channels could be an effective mechanism for the modulation of neuronal excitability and synaptic plasticity.

Electrical activity from two identified synaptically coupled mechanosensory interneurons in the abdominal nervous system of the crayfish Orconectes limosus were recorded, and their responses to constant-velocity water-jet stimuli presented from different directions are studied.

We have recorded electrical activity from two identified synaptically coupled mechanosensory interneurons in the abdominal nervous system of the crayfish Orconectes limosus and have studied their responses to constant-velocity water-jet stimuli presented from different directions. The two neurons, the ascending caudal photoreceptor (CPR) and the local directionally selective neuron, responded preferentially to stimuli delivered ipsilaterally to their dendritic input regions. Both neurons featured responses consisting of a phasic excitatory \"on\" response and a tonic depolarizing plateau. The different response components showed various degrees of directional selectivity: The initial \"on\" peak of the response was the least sensitive and the plateau was the most sensitive to stimulus direction. The CPR showed a sharp cut-off in responsiveness to contralateral stimuli, whereas the local directionally selective neuron showed a more gradual decrease in its directional responsiveness. This difference is a consequence of the feed-forward lateral inhibition that the local directionally selective neuron exerts on the CPR and of the threshold for initiation of action potentials in the CPR. A comparison of the spiking response of the CPR with its generator potential shows that the number and frequency of action potentials are a more sensitive indicator of directional preference than the generator potential response. The directional characteristic of the CPR is discussed as a filter matched to a specific spatial aspect of biologically relevant water movements.

ENSO causes climate extremes across and beyond the Pacific basin; however, evidence of ENSO at high southern latitudes is generally restricted to the South Pacific and West Antarctica. Here, the authors report a statistically significant link between ENSO and sea salt deposition during summer from the Law Dome (LD) ice core in East Antarctica. ENSO-related atmospheric anomalies from the central-western equatorial Pacific (CWEP) propagate to the South Pacific and the circumpolar high latitudes. These anomalies modulate high-latitude zonal winds, with El Niño (La Niña) conditions causing reduced (enhanced) zonal wind speeds and subsequent reduced (enhanced) summer sea salt deposition at LD. Over the last 1010 yr, the LD summer sea salt (LDSSS) record has exhibited two below-average (El Niño–like) epochs, 1000–1260 AD and 1920–2009 AD, and a longer above-average (La Niña–like) epoch from 1260 to 1860 AD. Spectral analysis shows the below-average epochs are associated with enhanced ENSO-like variability around 2–5 yr, while the above-average epoch is associated more with variability around 6–7 yr. The LDSSSrecord is also significantly correlated with annual rainfall in eastern mainland Australia. While the correlation displays decadal-scale variability similar to changes in the interdecadal Pacific oscillation (IPO), the LDSSSrecord suggests rainfall in the modern instrumental era (1910–2009 AD) is below the long-term average. In addition, recent rainfall declines in some regions of eastern and southeastern Australia appear to be mirrored by a downward trend in the LDSSSrecord, suggesting current rainfall regimes are unusual though not unknown over the last millennium.

Background We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma. Methods Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate. Results Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above. Conclusions Evidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials.

Abstract Context Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps to limit postprandial glycemic excursions and reduce chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, eg, retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration or bowel obstruction. Data Acquisition We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. Data Synthesis Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs but rarely are associated with pulmonary aspiration. Well-justified recommendations for the periprocedural management of GLP-1RAs (eg, whether to withhold these medications and for how long) are compromised by limited evidence. Important aspects to be considered are (1) their long half-lives, (2) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (ie, in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. Conclusion Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful and represent an important area needing further study to increase patient safety for those treated with GLP-1 RAs.