The ionotropic glutamate receptor NMDA is allosterically modulated by glycine, a coagonist, its presence is an absolute requirement for receptor activation. The transport of glycine in glutamatergic ...synapse is carried out by glycine transporter-1 (GlyT1), a Na+/Cl--dependent carrier molecule. The primary role of GlyT1 is to maintain glycine concentrations below saturation level at postsynaptic NMDA receptors. Several isoforms of GlyT1 (a-e) have been identified, which are expressed both in glial and neuronal cell membranes. GlyT1 operates bidirectionally: it decreases synaptic glycine concentration when operates in normal mode and releases glycine from glial cells as operates in a reverse mode. It is expected that non-transportable, non-competitive inhibitors of GlyT1 may have therapeutic value in CNS disorders characterized by hypofunctional NMDA receptor-mediated glutamatergic neurotransmission. Accordingly, GlyT1 inhibitors exhibited antipsychotic profile in a number of animal tests. The first promising in vitro and in vivo experiments with glycine itself, and its N-methyl analogue, sarcosine, had initiated the syntheses of potential GlyT1 inhibitors with more complex structures, in which, however, the glycine or sarcosine moiety had always been incorporated. Those attempts led to the development of two compounds, ALX-5407 and Org-24461 with high inhibitory potency; however, none of which is now considered as a drug candidate due, most probably, to safety and/or pharmacokinetic issues. More recently, several structurally new series of highly potent inhibitors with no aminomethylcarboxy group have also been discovered. Some of them might be expected to fulfill all requirements for clinical development. The new generation of GlyT1 inhibitors may represent a novel treatment of patients suffering from schizophrenia and/or other neuropathological conditions.
Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the
N-methyl-
d-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of ...Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (±)-2,3-dihydro-5,6-dimethoxy-2-1-(phenylmethyl)-4-piperidinylmethyl-1
H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C
12H
21N·HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.
Purpose
To evaluate the mutagen sensitivity phenotype on the risk of second primary cancer (SPC) in patients with head and neck squamous cell carcinoma (HNSCC), and to estimate the long-term rate of ...SPC and the outcome with SPC.
Methods
A survey was made regarding SPC among 124 younger (≤ 50 years) adults with HNSCC who were enrolled in a pretreatment mutagen sensitivity investigation during 1996–2006. Mutagen sensitivity was assessed by exposing lymphocytes to bleomycin in vitro and quantifying the bleomycin-induced chromatid breaks per cell (b/c). Patients were classified as hypersensitive (> 1 b/c) or not hypersensitive (≤ 1 b/c).
Results
Mean follow-up time for all patients was 68 months (range: 5–288 months), and the 15-year cancer-specific survival was 15%. Twenty patients (16%) developed a SPC (15-year estimated rate: 41%), and half of them was hypersensitive. The crude rate of SPC for hypersensitive (
n
= 65) or not hypersensitive (
n
= 59) patients were 15 and 17%, respectively (
p
= 0.4272). The 15-year estimated rate of SPC for hypersensitive and not hypersensitive patients was 36 and 48%, respectively (
p
= 0.3743). Gender, UICC stages, anatomical sites of index cancer did not prove to be a significant risk factor for SPC. Forty-five percent of SPC developed after the 10-year follow-up. The 3‑year cancer-specific survival was 23% with SPC.
Conclusion
According to our findings, mutagen hypersensitivity was not associated with an increased SPC risk in HNSCC patients. Patients are at a lifelong risk of developing a SPC. Survival with SPC is very poor.
A new method is presented in this paper which analyses the scattered light of individual aerosol particles simultaneously at two different wavelengths in order to retrieve information on the particle ...type. We show that dust-like particles, such as volcanic ash, can be unambiguously discriminated from water droplets on a single-particle level. As a future application of this method, the detection of volcanic ash particles should be possible in a humid atmosphere in the presence of cloud droplets. The characteristic behaviour of pure water's refractive index can be used to separate water droplets and dust-like particles which are commonly found in the micrometre size range in the ambient air. The low real part of the water's refractive index around 2700–2800 nm results in low scattered light intensities compared to e.g. the visible wavelength range, and this feature can be used for the desired particle identification. The two-wavelength measurement set-up was theoretically and experimentally tested and studied. Theoretical calculations were done using Mie theory. Comparing the ratio of the scattered light at the two wavelengths (visible-to-IR (infrared), R value) for water droplets and different dust types (basalt, andesite, African mineral dust, sand, volcanic ash, pumice) showed at least 9-times-higher values (on average 70 times) for water droplets than for the dust types at any diameter within the particle size range of 2–20 μm. The envisaged measurement set-up was built up into a laboratory prototype and was tested with different types of aerosols. We generated aerosols from the following powders, simulating dust-like particles: cement dust, ISO 12103-1 A1 Ultrafine Test Dust and ash from the 2012 eruption of the Etna volcano. Our measurements verified the theoretical considerations; the median experimental R value is 8–21 times higher for water than for the "dust" particles.
The objective of this study was to study how the outflow of 3Hpurines is altered during a brief period of ischemic-like conditions in superfused hippocampal slices and to show whether it is regulated ...by P2 purinoceptors and the nitric oxide (NO) pathway. The outflow of 3Hpurines increased in response to 5 min of combined hypoxia/hypoglycemia. High performance liquid chromatography analysis verified the efflux of 3Hadenosine-triphosphate, 3Hadenosine-diphosphate, 3Hadenosine-monophosphate, 3Hadenosine, 3Hinosine, and 3Hhypoxanthine in response to ischemic-like conditions. The P2 receptor antagonists suramin and pyridoxal-phosphate-6-azophenyl-2'-4'-disulphonic-acid-tetrasodium (PPADS) reduced significantly the 3Hpurine efflux evoked by ischemic-like conditions, showing that P2 purinoceptors are involved in the initiation of purine outflow. The NO synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME) attenuated significantly the 3Hpurine outflow, evoked by ischemic-like conditions, while 7-nitroindazole (7-NI) caused only a mild decrease in the outflow. The NO donor sodium nitroprusside increased significantly the basal efflux of 3Hpurines. In summary, a brief period of combined hypoxia/hypoglycemia induced the efflux of ATP in addition to the outflow of other purines. Since P2 receptor antagonists decreased the 3Hpurine outflow evoked by ischemic-like conditions we propose that ATP, acting on P2 purinoceptors, is responsible for further efflux of purines after ischemic-like period. It seems likely that NO is also involved in the regulation of purine outflow, since inhibition of NO production attenuated the 3Hpurine outflow, evoked by ischemic-like conditions, while exogenous NO facilitated the basal outflow.
Cloud condensation nuclei counter (CCNC) measurements performed at 14 locations around the world within the European Integrated project on Aerosol Cloud Climate and Air Quality interactions (EUCAARI) ...framework have been analysed and discussed with respect to the cloud condensation nuclei (CCN) activation and hygroscopic properties of the atmospheric aerosol. The annual mean ratio of activated cloud condensation nuclei (NCCN) to the total number concentration of particles (NCN), known as the activated fraction A, shows a similar functional dependence on supersaturation S at many locations – exceptions to this being certain marine locations, a free troposphere site and background sites in south-west Germany and northern Finland. The use of total number concentration of particles above 50 and 100 nm diameter when calculating the activated fractions (A50 and A100, respectively) renders a much more stable dependence of A on S; A50 and A100 also reveal the effect of the size distribution on CCN activation. With respect to chemical composition, it was found that the hygroscopicity of aerosol particles as a function of size differs among locations. The hygroscopicity parameter κ decreased with an increasing size at a continental site in south-west Germany and fluctuated without any particular size dependence across the observed size range in the remote tropical North Atlantic and rural central Hungary. At all other locations κ increased with size. In fact, in Hyytiälä, Vavihill, Jungfraujoch and Pallas the difference in hygroscopicity between Aitken and accumulation mode aerosol was statistically significant at the 5 % significance level. In a boreal environment the assumption of a size-independent κ can lead to a potentially substantial overestimation of NCCN at S levels above 0.6 %. The same is true for other locations where κ was found to increase with size. While detailed information about aerosol hygroscopicity can significantly improve the prediction of NCCN, total aerosol number concentration and aerosol size distribution remain more important parameters. The seasonal and diurnal patterns of CCN activation and hygroscopic properties vary among three long-term locations, highlighting the spatial and temporal variability of potential aerosol–cloud interactions in various environments.
Though the environmental conditions of the Weddell Sea region and Dronning Maud Land are still relatively stable compared to the fast-changing Antarctic Peninsula, we may suspect pronounced effects ...of global climate change for the near future (Thompson et al., 2011). Reducing the uncertainties in climate change modeling requires a better understanding of the aerosol optical properties, and for this we need accurate data on the aerosol refractive index (RI). Due to the remoteness of Antarctica only very few RI data are available from this region (Hogan et al., 1979; Virkkula et al., 2006; Shepherd et al., 2018). We calculate the real refractive index of natural atmospheric aerosols from number size distribution measurements at the German coastal Antarctic station Neumayer III. Given the high average scattering albedo of 0.992 (Weller et al., 2013), we assumed that the imaginary part of the RI is zero. Our method uses the overlapping size range (particle diameter D between 120 and 340 nm) of a scanning mobility particle sizer (SMPS), which sizes the particles by their electrical mobility, and a laser aerosol spectrometer (LAS), which sizes the particles by their optical scattering signal at the 633 nm wavelength.
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