Abstract Although levodopa is the current “gold standard” for treatment of Parkinson's disease, there has been disputation on whether AMPA receptor antagonists can be used as adjuvant therapy to ...improve the effects of levodopa. Systemic administration of levodopa, the precursor of dopamine, increases brain dopamine turnover rate and this elevated turnover is believed to be essential for successful treatment of Parkinson's disease. However, long-term treatment of patients with levodopa often leads to development of dyskinesia. Therefore, drugs that feature potentiation of dopamine turnover rate and are able to reduce daily levodopa dosages might be used as adjuvant in the treatment of patients suffering from Parkinson's disease. To investigate such combined treatment, we have examined the effects of two non-competitive AMPA receptor antagonists, GYKI-52466 and GYKI-53405, alone or in combination with levodopa on dopamine turnover rate in 6-hydroxydopamine-lesioned striatum of the rat. We found here that repeated administration of levodopa, added with the peripheral DOPA decarboxylase inhibitor carbidopa, increased dopamine turnover rate after lesioning the striatum with 6-hydroxydopamine. Moreover, combination of levodopa with GYKI-52466 or GYKI-53405 further increased dopamine turnover enhanced by levodopa administration while the AMPA receptor antagonists by themselves failed to influence striatal dopamine turnover. We concluded from the present data that potentiation observed between levodopa and AMPA receptor antagonists may reflect levodopa-sparing effects in clinical treatment indicating the therapeutic potential of such combination in the management of Parkinson's disease.
The new portable ice nucleation chamber (PINC) developed by the Institute for Atmospheric and Climate Sciences of ETH Zurich was operated during two campaigns PINC II and III at the high alpine ...research station Jungfraujoch situated at 3580 m a.s.l., in March and June 2009, respectively. During this time of the year, a high probability of Saharan Dust Events (SDE) at the Jungfraujoch has been observed. We used an impactor with a cutoff size of 1 km aerodynamic diameter and operated the system at -31 C and relative humidities of 127% and 91% with respect to ice and water, respectively in order to investigate the contribution of deposition freezing to mixed-phase clouds and also to look at the number concentration of ice nuclei (IN) during a SDE. The average IN concentration during PINC II was 8 particles per liter whereas during PINC III, the average number concentration was higher up to 14 particles per liter. Two SDEs were detected on 15 and 16 June 2009. Our measurements show that the SDEs had IN number concentration up to several hundreds per liter. We found the best correlation between the number concentration of the larger particle fraction measured by an optical particle counter and the IN number concentration during a Saharan Dust Event. This correlation factor is higher for particles larger than 0.5 km meaning that a higher concentration of larger particles induced higher IN number concentration. No correlation could be found between the black carbon mass concentration and the variations in IN number concentration.
A new method has been developed to investigate corticostriatal glutamatergic influence on
3Hdopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices ...containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with
3Hdopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of
3Hdopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of
3Hdopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate–dopamine–GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.
Atmospheric aerosol particles are able to act as cloud condensation nuclei (CCN) and are therefore important for the climate and the hydrological cycle, but their properties are not fully understood. ...Total CCN number concentrations at 10 different supersaturations in the range of SS = 0.12-1.18% were measured in May 2008 at the remote high alpine research station, Jungfraujoch, Switzerland (3580 m asl.). In this paper, we present a closure study between measured and predicted CCN number concentrations. CCN predictions were done using number size distribution (scanning particle mobility sizer, SMPS) and bulk chemical composition data (aerosol mass spectrometer, AMS, and multi-angle absorption photometer, MAAP) in a simplified Koehler theory. The predicted and the measured CCN concentrations agree very well and are highly correlated. A sensitivity study showed that the temporal variability of the chemical composition at the Jungfraujoch can be neglected for a reliable CCN prediction, whereas it is important to know the mean chemical composition. The exact bias introduced by using a too low or too high hygroscopicity parameter for CCN prediction was further quantified and shown to be substantial for the lowest supersaturation. Despite the high average organic mass fraction (45%) during the measurement campaign, there was no indication that the surface tension was substantially reduced at the point of CCN activation. A comparison between hygroscopicity tandem differential mobility analyzer (HTDMA), AMS/MAAP, and CCN derived Kappa values showed that HTDMA measurements can be used as a chemical composition proxy for CCN predictions if no suitable chemical composition data are available.
Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with super(3)Hserotonin ( super(3)H5-HT), superfused, and the electrically induced efflux of ...radioactivity was determined. The nonselective 5-HT receptor agonist 5-carboxamido-tryptamine (5-CT; 0.001 to 1 mu M) inhibited the electrically stimulated super(3)H5-HT overflow from raphe nuclei slices (IC sub(50) of 3.34 plus or minus 0.37 nM). This effect of 5-CT on super(3)H5-HT overflow was antagonized by the 5-HT sub(7) receptor antagonist SB-258719 (10 mu M) and the 5-HT sub(1B/1D) antagonist SB-216641 (1 mu M), the IC sub(50) values for 5-CT in the presence of SB-258719 and SB-216641 were 94.23 plus or minus 4.84 and 47.81 plus or minus 4.66 nM. The apparent pA sub(2) values for SB-258719 and SB-216641 against 5-CT were 6.43 and 7.12, respectively. The inhibitory effect of 5-CT on super(3)H5-HT overflow was weakly antagonized by 10 mu M of WAY-100635, a 5-HT sub(1A) receptor antagonist (IC sub(50) 6.65 plus or minus 0.56 nM, apparent pA sub(2) 4.99). The antagonist effect of SB-258719 (10 mu M) on 5-CT-evoked super(3)H5-HT overflow inhibition was also determined in the presence of 1 mu M SB-216641 or 1 mu M SB-216641 and 10 mu M WAY-100635, and additive interactions were found between the antagonists of 5-HT sub(7) and 5-HT sub(1) receptor subtypes. Addition of the Na super(+) channel blocker tetrodotoxin (1 mu M) in the presence of SB-216641 (1 mu M) and WAY-100635 (10 mu M) attenuated the inhibitory effect of 5-CT on KCl-induced super(3)H5-HT overflow. These findings indicate that 5-CT inhibits super(3)H5-HT overflow from raphe nuclei slices of the rat by stimulation of 5-HT sub(7) and 5-HT sub(1B/1D) receptors, whereas the role of 5-HT sub(1A) receptors in this inhibition is less pronounced. They also suggest that 5-HT sub(7) receptors are probably not located on serotonergic neurons and thus may serve as heteroreceptors in regulation of 5-HT release in the raphe nuclei. 5-CT (0.1 mu M) also inhibited super(3)Hglutamate release, and SB-258719 (10 mu M) suspended this effect. We therefore speculated that the axon terminals of the glutamatergic cortico-raphe neurons may possess 5-HT sub(7) receptors that inhibit glutamate release, which consequently leads to decreased activity of serotonergic neurons. The postulated glutamatergic-serotonergic interaction in the raphe nuclei was further evidenced by the finding that N-methyl-d-aspartate and AMPA enhanced super(3)H5-HT release.
Black carbon (BC) mass, size distribution and mixing state in sub-micron aerosols were characterized from late February to March 2007 using a single particle incandescence method at the high alpine ...research station Jungfraujoch (JFJ), Switzerland (46.33 degree N, 7.59 degree E, 3580 m a.s.l.). JFJ is a ground based location, which is at times exposed to continental free tropospheric air. A median mass absorption coefficient (MAC) of 10.2 plus or minus 3.2 m super(2) g super(− 1) at lambda = 630 nm was derived by comparing single particle incandescence measurements of black carbon mass with continuous measurements of absorption coefficient. This value is comparable with other estimates at this location. The aerosols measured at the site were mostly well mixed and aged during transportation via the free troposphere. Pollutant sources were traced by air mass back trajectories, trace gases concentrations and the mass loading of BC. In southeasterly wind directions, mixed or convective weather types provided the potential to vent polluted boundary layer air from the southern Alpine area and industrial northern Italy, delivering enhanced BC mass loading and CN concentrations to the JFJ. The aerosol loadings at this site were also significantly influenced by precipitation, which led to the removal of BC from the atmosphere. Precipitation events were shown to remove about 65% of the BC mass from the free tropospheric background reducing the mean loading from 10 plus or minus 5 ngm super(− 3) to 4 plus or minus 2 ngm super(− 3). Overall, 40 plus or minus 15% of the observed BC particles within the detectable size range were mixed with large amounts of non-refractory materials present as a thick coating around the BC core. The growth of particle size into the accumulation mode was positively linked with the degree of BC mixing, suggesting the important role of condensable materials in increasing particle size as well as enhancing BC mixing state. It is the first time that BC mass, size distribution and mixing state are reported in the free troposphere over Europe. These ground based measurements also provide the first temporal study of BC in the European free troposphere quantitatively measured by single particle methods. At the present time there is only limited information of BC and its mixing state in the free troposphere, especially above Europe. The results reported in this paper provide an important constraint on modelled representation of BC.
The objective of this study was to study how the outflow of super(3)Hpurines is altered during a brief period of ischemic-like conditions in superfused hippocampal slices and to show whether it is ...regulated by P sub(2) purinoceptors and the nitric oxide (NO) pathway. The outflow of super(3)Hpurines increased in response to 5 min of combined hypoxia/hypoglycemia. High performance liquid chromatography analysis verified the efflux of super(3)Hadenosine-triphosphate, super(3)Hadenosine-diphosphate, super(3)Hadenosine-monophosphate, super(3)Hadenosine, super(3)Hinosine, and super(3)Hhypoxanthine in response to ischemic-like conditions. The P sub(2) receptor antagonists suramin and pyridoxal-phosphate-6-azophenyl-2'-4'-disulphonic-acid-tetrasodium (PPADS) reduced significantly the super(3)Hpurine efflux evoked by ischemic-like conditions, showing that P sub(2) purinoceptors are involved in the initiation of purine outflow. The NO synthase inhibitor N-nitro-L-arginine-methyl-ester (l-NAME) attenuated significantly the super(3)Hpurine 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 super(3)Hpurines. In summary, a brief period of combined hypoxia/hypoglycemia induced the efflux of ATP in addition to the outflow of other purines. Since P sub(2) receptor antagonists decreased the super(3)Hpurine outflow evoked by ischemic-like conditions we propose that ATP, acting on P sub(2) 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 super(3)Hpurine outflow, evoked by ischemic-like conditions, while exogenous NO facilitated the basal outflow.
This sensor detects volcanic ash particles and distinguishes them from cloud droplets. Operated on an airplane, this detector can quantify the exposure to hazardous refractory ash and the in-situ ...measurement is not biased by the presence of cloud particles. A volcanic eruption emits a significant amount of hazardous ash particles into the air. If the event is strong enough, the volcanic ash plume can reach high altitudes and can be a serious security risk for airplanes. We have developed a new prototype aerosol sensor for the reliable detection of volcanic ash. The envisaged application is the employment of this new technique on board of passenger aircraft. It allows in-situ monitoring of the airplane's exposure to volcanic ash. The challenge of this development is the requirement that the sensor can distinguish cloud droplets (or ice crystals) from the hazardous refractory ash particles. At aviation altitudes, water droplets and ice crystals are often present in the particle size region of the ash (1-20 micrometer) and their concentrations can reach the levels that are considered as the limits of the different volcanic ash contamination zones. Therefore, it is crucial that the sensor can differentiate between volcanic ash and water or ice particles. The sensor measures the scattered light intensities from individual particles outside of the airplane cabin through a glass window. The desired discrimination is achieved with two lasers operating at different wavelengths. Ash concentrations (in terms of number and mass) are derived, and the exposure of the airplane is recorded and transmitted in real time to the pilot. The volcanic ash detector was tested in the laboratory with various test aerosols and micrometer-sized water droplets. Then, ground-based outdoor measurements were conducted and the instrument response to mineral dust (a surrogate for volcanic ash) and natural cloud droplets (and ice crystals) was investigated. In a next step, this new technique will be tested in summer 2016 on-board of a research aircraft.
In a series of smog chamber experiments, the cloud condensation nuclei (CCN) activity of secondary organic aerosol (SOA) generated from ozonolysis of β-caryophyllene was characterized by determining ...the CCN derived hygroscopicity parameter, κCCN , from experimental data. Two types of CCN counters, operating at different temperatures, were used. The effect of semi-volatile organic compounds on the CCN activity of SOA was studied using a thermodenuder. Overall, SOA was only slightly CCN active (with κCCN in the range 0.001-0.16), and in dark experiments with no OH scavenger present, κCCN decreased when particles were sent through the thermodenuder (with a temperature up to 50 °C). SOA was generated under different experimental conditions: In some experiments, an OH scavenger (2-butanol) was added. SOA from these experiments was less CCN active than SOA produced in experiments without an OH scavenger (i.e. where OH was produced during ozonolysis). In other experiments, lights were turned on, either without or with the addition of HONO (OH source). This led to the formation of more CCN active SOA. SOA was aged up to 30 h through exposure to ozone and (in experiments with no OH scavenger present) to OH. In all experiments, the derived κCCN consistently increased with time after initial injection of β-caryophyllene, showing that chemical ageing increases the CCN activity of β-caryophyllene SOA. κCCN was also observed to depend on supersaturation, which was explained either as an evaporation artifact from semi-volatile SOA (only observed in experiments lacking light exposure) or, alternatively, by effects related to chemical composition depending on dry particle size. Using the method of Threshold Droplet Growth Analysis it was also concluded that the activation kinetics of the SOA do not differ significantly from calibration ammonium sulphate aerosol for particles aged for several hours.
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