Selective Pharmacophore Models of Dopamine D1 and D2 Full Agonists Based on Extended Pharmacophore Features

This study is focused on the identification of structural features that determine the selectivity of dopamine receptor agonists toward D₁ and D₂ receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor (the Ser residues in TM5 and the Asp in TM3), a directional aromatic feature in the ligand, a feature with large positional tolerance representing the positively charged nitrogen in the ligand, and sets of excluded volumes reflecting the shapes of the receptors. The sets of D₁ and D₂ ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. The robustness of the models in discriminating actives from inactives was tested against four ensembles of conformations generated by using different established methods and different force fields. The reasons for the selectivity can be attributed to both geometrical differences in the arrangement of the features, e.g., different tilt angels of the π system, as well as shape differences covered by the different sets of excluded volumes. This work provides useful information for the design of new D₁ and D₂ agonists and also for comparative homology modeling of D₁ and D₂ receptors. The approach is general and could therefore be applied to other ligand–protein interactions for which no experimental protein structure is available.     

Optimization of high-resolution continuous flow analysis for transient climate signals in ice cores

Over the past two decades, continuous flow analysis (CFA) systems have been refined and widely used to measure aerosol constituents in polar and alpine ice cores in very high-depth resolution. Here we present a newly designed system consisting of sodium, ammonium, dust particles, and electrolytic meltwater conductivity detection modules. The system is optimized for high-resolution determination of transient signals in thin layers of deep polar ice cores. Based on standard measurements and by comparing sections of early Holocene and glacial ice from Greenland, we find that the new system features a depth resolution in the ice of a few millimeters which is considerably better than other CFA systems. Thus, the new system can resolve ice strata down to 10 mm thickness and has the potential of identifying annual layers in both Greenland and Antarctic ice cores throughout the last glacial cycle.     

A novel image cytometric method for quantitation of immunohistochemical staining of cytoplasmic antigens

A novel method was developed to evaluate the acrosomal status of mammalian spermatozoa. The method is based on the ability of the lectin Pisum sativum agglutinin (PSA) to bind specifically to glycoproteins of the acrosomal matrix released during the acrosome reaction. The amount of released acrosomal content is proportional to the fraction of spermatozoa that underwent acrosome reaction. The released glycoproteins present in the supernatant separated from the cells were detected via an ELISA-like assay. The authors suggest that one of these glycoproteins might be the acrosin as identified by anti-acrosin antibodies, using Western blot analysis. The new method (demonstrated here with ram and bull spermatozoa) correlates well with the results obtained by conventional methods. Its advantages are simplicity, objectiveness, rapidity, and low cost. In addition, many samples can be processed in parallel. The method can be used in experimental as well as clinical applications.     

Occupational allergic contact dermatitis in a patient with a positive patch test to tin

The case of a 69-year-old man with liver cirrhosis, thrombocytopenia, unstable angina, and a history of previous coronary artery bypass grafting (CABG) is presented. The patient under-went successful repeat CABG through lateral thoracotomy on the beating heart without extracorporeal circulatory support.     

The beta-lactamases of Moraxella (Branhamella) catarrhalis isolated from Danish children

Two distinct beta-lactamases have been isolated from Moraxella catarrhalis: the stronger acting BRO-1 enzyme and the weaker acting BRO-2. Several reports have noted an effect of penicillin and ampicillin on infections caused by M. catarrhalis in spite of the presence of beta-lactamase production. The purpose of this work was to charaterize the beta-lactamases of M. catarrhalis isolated from Danish children regarding type and susceptibility, and to relate these findings to the eradication of beta-lactamases-producing strains by use of antibiotic treatment with penicillin or ampicillin. MICs for penicillin V, ampicillin, cefuroxime and amoxicillin/clavulanic acid (2:1) were determined in 70 strains of M. catarrhalis: 46 strains from children with lower respiratory tract infection (LRTI) and 24 strains from respiratory healthy children, beta-lactamase production was found in 59 strains. The BRO-1 enzyme was identified by isoelectric focusing in 55 strains (93.2%) and BRO-2 in 3 strains (5.1%); in 1 strain no isoelectric bands were produced. All strains were susceptible to cefuroxime and amoxicillin/clavulanic acid, and non-beta-lactamase-producing strains were susceptible to penicillin and ampicillin. For the beta-lactamase-producing strains, MIC50 of penicillin was 8.0 micrograms/ml, while MIC50 of ampicillin was 1.0 microgram/ml and MIC90 of ampicillin was 2.0 micrograms/ml. M. catarrhalis was more often eradicated from the children who received antibiotic treatment with penicillin or ampicillin than from those who did not receive any treatment, indicating an in vivo effect of penicillin and ampicillin in spite of the beta-lactamase production.     

Injuries among domestic waste collectors

In a recent paper [R.R. Holson, J.F. Bowyer, P. Clausing, B. Gough, Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion, Brain Res. 739 (1996) 301-307] we reported that methamphetamine-stimulated striatal dopamine release declined rapidly over the first eight hours following microdialysis probe insertion. This decline was strictly a function of time post-probe implantation, and not due to tolerance or desensitization. To further examine this phenomenon, we subjected rats to three brief pulses of several DA-releasing compounds at 2, 4 and 6 h post-probe insertion, and compared these results to those caused by a single pulse 6 h post-insertion, or in some cases to pulses given more than 24 h post-insertion. We found that when buproprion, a dopamine reuptake blocker, was infused briefly into the striatum via the microdialysis probe, there was a pronounced drop in the amount of dopamine released at 6 h vs. 2 h post-insertion; this drop was not due to repeated exposure, since dopamine release at 6 h post-insertion was the same for a single pulse, or when preceded by two earlier pulses. Twenty-four hours later, buproprion-stimulated dopamine release was still lower, but did not appear to drop further thereafter. Potassium-stimulated dopamine release, on the other hand, dropped rapidly over the first 8 h post-insertion, and this decline continued throughout the 24-32 h interval post-insertion. Similarly, a single i.p. injection of 0.5 mg/kg haloperidol released three times as much dopamine when given two compared to six hours post-implantation. Both bupropion- and potassium-stimulated dopamine release were accompanied by declines in extracellular DOPAC concentrations, and these declines were the same 2 or 26 h post-insertion. In contrast, haloperidol exposure increased extracellular DOPAC, and this haloperidol-stimulated DOPAC increase was also greatly attenuated at 6 compared to 2 h post-insertion. We conclude that there is a general decline over time post-probe implantation in the ability of the striatal dopamine system to release dopamine, and perhaps to increase dopamine synthesis, in response to pharmacological challenges.     

The fundamentals of average local variance--Part I: Detecting regular patterns.

The method of average local variance (ALV) computes the mean of the standard deviation values derived for a 3 x 3 moving window on a successively coarsened image to produce a function of ALV versus spatial resolution. In developing ALV, the authors used approximately a doubling of the pixel size at each coarsening of the image. They hypothesized that ALV is low when the pixel size is smaller than the size of scene objects because the pixels on the object will have similar response values. When the pixel and objects are of similar size, they will tend to vary in response and the ALV values will increase. As the size of pixels increase further, more objects will be contained in a single pixel and ALV will decrease. The authors showed that various cover types produced single peak ALV functions that inexplicitly peaked when the pixel size was 1/2 to 3/4 of the object size. This paper reports on work done to explore the characteristics of the various forms of the ALV function and to understand the location of the peaks that occur in this function. The work was conducted using synthetically generated image data. The investigation showed that the hypothesis originally proposed in is not adequate. A new hypothesis is proposed that the ALV function has peak locations that are related to the geometric size of pattern structures in the scene. These structures are not always the same as scene objects. Only in cases where the size of and separation between scene objects are equal does the ALV function detect the size of the objects. In situations where the distance between scene objects are larger than their size, the ALV function has a peak at the object separation, not at the object size. This work has also shown that multiple object structures of different sizes and distances in the image provide multiple peaks in the ALV function and that some of these structures are not implicitly recognized as such from our perspective. However, the magnitude of these peaks depends on the response mix in the structures, complicating their interpretation and analysis. The analysis of the ALV Function is, thus, more complex than that generally reported in the literature.     

Comparison Of Volatile Organic Compounds From Processed Paper And Toners From Office Copiers And Printers: Methods,Emission Rates,And Modeled Concentrations

The emission of volatile organic compounds (VOC) from nine toner powders and eleven types of processed paper from photocopying machines (6), laser (3) and matrix printers (21, and one carbonless copy fm has been measured. A total of 61 VOC from toner powders were identified by heating (185 °C) the powder for three minutes for thermal desorption and by gas chromatography followed by the use of low and high resolution EI and CI mass spectrometry. VOC from processed paper were analyzed by headspace sampling on Tenax TA from nylon bags. Thirty-one VOC with a wide range of volatility and persistency were identified from processed paper. The total VOC emission from the various types of paper differed substantially. Using the field and laboratory emission cell (FLEC), the calculated initial emission rate of styrene was 5 μg m^?2h^?1 from a freshly processed paper The VOC emission from machines and the processed paper can be reduced by proper choice of o m e equipment. However, an evaluation should consider all potential pollutants.