Comparison of in Silico,Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ1 Receptor Ligands Designed for Positron Emission Tomography

The imaging of σ₁ receptors in the brain by fluorinated radiotracers will be used for the validation of σ₁ receptors as drug targets as well as for differential diagnosis of diseases in the central nervous system. The biotransformation of four homologous fluorinated PET tracers 1′‐benzyl‐3‐(ω‐fluoromethyl to ω‐fluorobutyl)‐3H‐spiro[2]benzofuran‐1,4′‐piperidine] ([¹⁸F] 1 – 4 ) was investigated. In silico studies using fast metabolizer (FAME) software, electrochemical oxidations, in vitro studies with rat liver microsomes, and in vivo metabolism studies after application of the PET tracers [¹⁸F] 1 – 4 to mice were performed. Combined liquid chromatography and mass spectrometry (HPLC–MS) analysis allowed structural identification of non‐radioactive metabolites. Radio‐HPLC and radio‐TLC provided information about the presence of unchanged parent radiotracers and their radiometabolites. Radiometabolites were not found in the brain after application of [¹⁸F] 2 – 4 , but liver, plasma, and urine samples contained several radiometabolites. Less than 2 % of the injected dose of [¹⁸F] 4 reached the brain, rendering [¹⁸F] 4 less appropriate as a PET tracer than [¹⁸F] 2 and [¹⁸F] 3 . Compounds [¹⁸F] 2 and [¹⁸F] 3 possess the most promising properties for imaging of σ₁ receptors in the brain. High σ₁ affinity (K_i=0.59 nm ), low lipophilicity (logD_7.4=2.57), high brain penetration (4.6 % of injected dose after 30 min), and the absence of radiometabolites in the brain favor the fluoroethyl derivative [¹⁸F] 2 slightly over the fluoropropyl derivative [¹⁸F] 3 for human use.     

Quantitative in vivo 1H spectroscopic imaging of metabolites in the early postnatal mouse brain at 17.6 T

Object  Early postnatal brain maturation is closely connected to local changes of metabolite levels. Spatially resolved in vivo ¹H NMR spectroscopic imaging is applied to follow absolute changes of brain metabolites in early postnatal mouse brain. Materials and methods  A short echo time semi LASER (localization by adiabatic selective refocusing) chemical shift imaging (CSI) sequence incorporating weighted k-space averaging was implemented at high magnetic field (17.6 T). In vivo measurements were carried out on postnatal days 5, 8, 12, 16, and 20. In vivo relaxation times T ₁ and T ₂ were measured using variable repetition times or a CPMG sequence, respectively, combined with LASER single voxel localization. Results  Spectra were obtained with a spatial resolution of (1 × 1) mm² in a 1.5 mm slice as early as postnatal day 5. Maturational changes of absolute metabolite concentrations of major metabolites were calculated in four different brain regions. A significant increase of N-acetylaspartate (NAA), total creatine (tCr), and glutamate/glutamine (Glx) concentration was paralleled by a decrease of taurine (Tau) concentration with age (P < 0.05). Differences between brain regions were found for NAA, tCr, and Tau (P < 0.05). Furthermore, in vivo T ₁ and T ₂ of the four major brain metabolites in adult mice are reported. Conclusion  The implemented semi LASER CSI sequence allows following regional changes of metabolite levels. It is suitable for investigation of local differences in brain metabolism and development.     

Evaluation of hydrogen and methanol fuel cell performance of sulfonated diels alder poly(phenylene) membranes

Hydrogen fuel cell performance of sulfonated diels alder poly(phenylene) (SDAPP) with IECs ≥ 1.8 meq g⁻¹ is comparable to Nafion 212 under fully humidified conditions at 80 °C. However, as relative humidity is reduced, performance loss is substantial for SDAPP when compared to Nafion 212. This loss can be attributed to the large drop in proton conductivity in SDAPP as relative humidity is reduced; the proton conductivity of SDAPP with an IEC of 2.3 meq g⁻¹ dropped from 0.117 S cm⁻¹ to 0.001 S cm⁻¹ as the relative humidity was reduced from 100% to 25% at 80 °C. Methanol fuel cell experiments using 3 M methanol result in a 60 mV performance improvement at 25 mA cm⁻² when using SDAPP with an IEC of 1.2 meq g⁻¹ instead of Nafion 212. This improvement is due to lower methanol permeability of SDAPP (1.4 meq g⁻¹) over Nafion 212, with SDAPP films having methanol permeabilities less than 25% of Nafion 212.     

Characterisation of Escherichia coli O157 strains from humans, cattle and pigs in the North-West Province, South Africa

Escherichia coli O157 strains cause diseases in humans that result from the consumption of food and water contaminated with faeces of infected animals and/or individuals. The objectives of this study were to isolate and characterise E. coli O157 strains from humans, cattle and pigs and to determine their antibiotic resistant profiles as well as detection of virulence genes by PCR. Eight hundred faecal samples were analysed for typical E. coli O157 and 76 isolates were positively identified as E. coli O157 strains. 16S rRNA sequence data were used to confirm the identity of the isolates. Susceptibility profiles to 9 antibiotics were determined and the multiple antibiotic resistant (MAR) patterns were compiled. A large proportion (52.6%-92.1%) of the isolates from pigs, cattle and humans were resistant to tetracycline, sulphamethoxazole and erythromycin. Thus the phenotype Smx-T-E (sulphamethozaxole-tetracycline-erythromycin) was present in most of the predominant MAR phenotypes obtained. Cluster analysis of antibiotic resistances revealed a closer relationship between isolates from pig and human faeces than cattle and humans. PCR were performed to amplify STEC virulence and tetracycline resistance gene fragments. A tetB gene fragment was amplified among the isolates. Eighteen (60%) of the isolates possessed the hlyA gene and 7(23.3%) the eae gene while only 5(16.7%) possessed both genes. Although shiga toxin genes were detected in the E. coli O157:H7 positive control strain none of the isolates that were screened possessed these genes. In a related study we reported that the prevalence of E. coli O157 was higher in pigs than cattle and humans. A high market demand for pork and beef in South Africa amplifies the risk that diseased animals pose to human health. This highlighted the need for proper hygiene management to reduce the prevalence of E. coli O157 in farm animals and prevent the spread from animals to humans.     

Cylindrical Silicon-on-Insulator Microdosimeter: Design, Fabrication and TCAD Modeling

A novel silicon-on-insulator (SOI) microdosimeter has been designed and fabricated using planar processing techniques to realise a device with a micron-scale well-defined sensitive volume. Cylindrical structures were employed to allow for an improved definition of the average chord length of the sensitive volume over that of previous elongated parallelepiped solid-state detector designs. The structures were manufactured on individual silicon mesas situated on top of a buried oxide insulating layer. The mesa design eliminated lateral charge diffusion. Two kinds of test structures were designed with sensitive region widths of 2 mum and 10 mum. In addition, an array of 900 cylindrical diodes was fabricated to increase the charge collection statistics. TCAD (Technology Computer Aided Design) modeling of the electrostatic potential and electric field profile of the cylindrical microdosimeter was carried out to obtain 3D potential and electric field profiles. The modeling revealed a radial electric field within the cylindrical-shaped sensitive volume with a 1/r dependence. While the electric field at the core of the cylindrical microdosimeter was not sufficiently high to induce avalanche signal multiplication, the higher electric field at the core should still assist in the measurement of low linear-energy transfer (LET) events.     

Pyryliumverbindungen,XXV. Quantenchemische Berechnungen zur Valenzisomerisierung von 2-Amino-2H-pyran und -thiopyran

Pyrylium Compounds. XXV. Quantum Chemical Calculations Concerning the Valence Isomerization of 2-Amino-2H-pyran and -thiopyran The equilibrium 2-amino-2H-pyran 6 ⇌ 5-amino-2,4-dien-1-one 7 was investigated using the semi-empirical MINDO/3 and MNDO methods. In accordance with experimental findings for the substituted derivatives 1/2a–d , the introduction of a methyl group into the position 3 of 6 or the exchange of oxygen by sulfur shifts the equilibrium towards the cyclic structures 8 and 10 , respectively. Polar solvents, the influence of which was estimated applying the reaction field approach as well as the solvaton theory, and entropy effects are calculated to favour the ring-open valence isomer 7 . These results also correspond to experimental results.     

Access to ambulatory care for American Indians and Alaska Natives; the relative importance of personal and community resources

The debate on health care reform in the United States has been greatly influenced by various national studies showing a strong relationship between lack of public or private health care coverage and inadequate access to health services. There is also much concern about deficiencies in the availability and delivery of services to certain population groups--especially for those living in the most remote and sparsely populated areas of the country. However, national studies have generally not demonstrated that the use of health services is strongly associated with urban/rural residence or the supply of medical providers. In this study, we show that national studies can obscure the problems of certain population groups including American Indians and Alaska Natives. Using data from the 1987 National Medical Expenditure Survey, the findings show that the availability of medical providers as well as place of residence were strongly associated with the use of health care by American Indians and Alaska Natives. Although American Indians and Alaska Natives included in this study were eligible to receive health care free of charge from the Indian Health Service (IHS), financial factors were also significantly associated with use due to the use of services other than those provided or sponsored by IHS. Also, the results show that while geographic and supply factors have only modest effects on the average travel time to medical providers for the U.S. population as a whole, travel times are dramatically longer for American Indians and Alaska Natives living in rural areas and where there are few medical providers. In addition, there appear to be fewer hospitalizations in areas where there are IHS outpatient services. We conclude by discussing the need for health care reform to take into account the diversity of a large country such as the U.S., and the special needs of population groups that are usually not adequately represented in national studies.     

Problems with the language modula-2

One of the first tasks of the working groups producing a Modula-2 standard has been to identify problems with the language defined by N. Wirth. This paper reports on the major problems with the language. These occur in the areas of type coercions and casts, scope, strings, the module SYSTEM , dynamic storage management and opaque types. Some familiarity with the language Modula-2 is assumed.