Regional Absolute Quantification of the Neurochemical Profile of the Canine Brain: Investigation by Proton Nuclear Magnetic Resonance Spectroscopy and Tissue Extraction

The purpose of this study was to characterize the neurochemical profiles of various parts of the canine brain using proton nuclear magnetic resonance spectroscopy, tissue extraction, and external simulated phantom concentration quantification. The occipital, frontal, and temporal lobes, thalami, cerebellar cortices, and spinal cords of five pure bred adult beagles were collected, and heavy water solutions for the nuclear magnetic resonance sample were prepared using the methanol–chloroform–water extraction method. The metabolite concentrations in canine brain tissues were measured and compared with those found in human and rat brain tissues. In addition, the cross peaks of Lac, Glu/Gln, and mIns were identified using two-dimensional correlation spectroscopy in the canine frontal cortex. The present study demonstrated the absolute quantification of canine neuronal parts using in vitro high-resolution magnetic resonance spectroscopy, with tissue extraction used to accurately measure metabolite concentrations, thus providing valuable metabolic information regarding the various canine neuronal regions.     

Response time and vendor–assembler relationship in a supply chain

Relationships between an assembler and a vendor in a supply chain are investigated in two-period models when the assembler wants to reduce response time by incentive systems. The assembler may offer myopic or farsighted incentive contracts to the vendor, under short-term or long-term relationships. Incentive schemes, effort levels, and expected payoffs under different perspectives and relationships are examined. We find that a farsighted assembler provides the vendor with a higher incentive than a myopic assembler in the first period. A long (short)-term relationship is preferred if the value of farsightedness under a long-term relationship is greater (less) than the switching option value under a short-term relationship. We propose several sufficient conditions regarding which perspectives and relationships are preferred.     

Efficient prediction of the quality factors of micromechanical resonators

A high quality factor (Q-factor) is one of the major requirements of high-performance resonators. An understanding of the dissipation mechanism is crucial for maximizing the quality factor by reducing the energy loss. Thermoelastic damping has been well-known as the important intrinsic dissipation that affects the quality factor of micro-resonators. In this study, a finite element formulation based on the weak form of fully coupled thermoelastic problems is suggested. The coupled thermoelastic equation usually leads to a large-size complex eigenvalue problem, which is very massive and time-consuming to solve. Therefore, we also applied the model order reduction (MOR) scheme to this coupled multiphysical problem in order to achieve computational efficiency. The present approach is validated by comparing the numerical results and analytical solutions.     

Metabolism and excretion of 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3,5-dihydropyrrolo[3,2-d]-pyrimidin-4-one (SK3530) in rats

The in vitro and in vivo metabolism of a novel PDE 5 inhibitor, SK3530, was investigated in rats. Bile, plasma, feces, urine and liver samples were collected and analyzed using a high-performance liquid chromatography (HPLC) system equipped with ultraviolet (UV), mass spectrometric and radioactivity detectors. After a single oral administration, the mean radiocarbon recovery was 92.32+/-6.26%, with 91.25+/-6.25 and 1.07+/-0.21% in the feces and urine, respectively. The biliary excretion of radioactivity for the first 24 h period was approximately 38.82%, suggesting that SK3530 is cleared by hepatobiliary excretion. In vitro incubation of SK3530 with rat and human liver microsomes resulted in the formation of twelve and ten metabolites, respectively. SK3530 was extensively metabolized to twenty different metabolites, including three glucuronide and three sulfate conjugates in rats. The structures of these metabolites were elucidated based on MSn spectral analyses. Six major metabolic pathways were identified in the rat: N-dealkylation and oxidation of the hydroxyethyl moiety; N,N-deethylation and hydroxylation of the piperazine ring; hydroxylation of the propyl group and sulfate conjugation. An additional metabolite due to aromatic hydroxylation was also identified in hepatic microsomes.     

Determination of plasma topiramate concentration using LC-MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers

A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.     

An inhibitory compound against the interaction between G alpha(s) and the third intracellular loop region of serotonin receptor subtype 6 (5-HT6) disrupts the signaling pathway of 5-HT6

Serotonin receptor subtype 6 (5-HT(6)) is a neurotransmitter receptor, which is involved in various brain functions such as memory and mood. It mediates signaling via the interaction with a stimulatory G-protein. Especially, the third intracellular loop (iL3) of 5-HT(6) and the alpha subunit of stimulatory G protein (G alpha(s)) are responsible for the signaling process of 5-HT(6). Chemical compounds that could inhibit the interaction between the iL3 region of 5-HT(6) and G alpha(s) were screened from a chemical library consisted of 5,600 synthetic compounds. One of the identified compounds bound to G alpha(s) and effectively blocked the interaction between G alpha(s) and the iL3 region of 5-HT(6). The identified compound was further shown to reduce the serotonin-induced accumulation of cAMP in 293T cells transformed with 5-HT(6) cDNA. It also lowered the Ca(2+) efflux induced by serotonin in cells expressing 5-HT(6) and chimeric G alpha(s5/q). These results indicate that the interaction between the iL3 of 5-HT(6) and G alpha(s) can be exploited for screening of regulatory compounds against the signaling pathway of 5-HT(6).     

Imaging features of small (≤ 3 cm) pancreatic solid tumors on gadoxetic-acid-enhanced MR imaging and diffusion-weighted imaging: an initial experience

Objective

The objective was to determine imaging features that distinguish small (≤3cm) solid pancreatic adenocarcinoma, neuroendocrine tumor (NET) and solid pseudopapillary tumor (SPT) on gadoxetic-acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighed imaging (DWI).

Materials and methods

Twenty-four adenocarcinomas, 10 NETs and 8 SPTs were retrospectively included. Two radiologists analyzed morphologic features, signal intensity of the tumors on MR images including DWI (b=800) and dynamic enhancement pattern with consensus. Tumor-to-parenchyma ratio and tumor apparent diffusion coefficients (ADCs) were quantitatively assessed.

Results

All adenocarcinomas had an ill-defined margin and irregular shape, and more frequently had pancreatic duct dilatation compared with other tumors (P<.05). All SPTs and all but one of the adenocarcinomas (95.8%) had no arterial enhancement with progressively increased enhancement, whereas seven NETs (70%) had arterial enhancement with progressively decreased enhancement (P<.01). The mean value of tumor-to-parenchyma ratio on arterial and portal phases was significantly higher for NETs, and the mean value of tumor ADCs was significantly lower for SPTs than for other tumors (P<.05).

Conclusions

Gadoxetic-acid-enhanced MRI may aid in differentiation between small adenocarcinomas, NETs and SPTs based on morphologic features with dynamic enhancement pattern in adenocarcinomas, dynamic enhancement pattern with tumor-to-parenchyma ration on arterial and portal phases in NETs, and dynamic enhancement pattern with lower ADC value in SPTs.