Uptake Index Research Articles

Transplacental permeability of hydrophilic physiological substances determined by fetus uptake index method

Transplacental permeability of hydrophilic physiological substances determined by fetus uptake index method

IN VIVO METHODS TO STUDY UPTAKE OF NANOPARTICLES INTO THE BRAIN

Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques various parameters can be determined after drug administration, including the blood to brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods. Keywords: Nanoparticles,CNS,Visualization,Transcytosis,Parameters,uptake mechanism.

β-Alanine and l-histidine transport across the inner blood-retinal barrier: Potential involvement in l-carnosine supply

The supply of l-carnosine, a bioactive dipeptide of β-alanine and l-histidine, to the retina across the blood-retinal barrier (BRB) was studied. The in vivo and in vitro studies revealed low uptake activities for [3H]Gly-Sar, a representative dipeptide, suggesting that l-carnosine transport plays only a minor role at the BRB. The in vivo study using rats showed approximately 18- and 23-fold greater retinal uptake indexes (RUI) for [3H]β-alanine and [3H]l-histidine compared with that of a paracellular marker, respectively. The RUI of [3H]β-alanine was taurine- and γ-aminobutyric acid-sensitive, and the in vitro uptake by TR-iBRB2 cells showed time- concentration- and temperature-dependent [3H]β-alanine uptake, suggesting that a carrier-mediated process was involved in β-alanine transport across the inner BRB. [3H]β-Alanine uptake was inhibited by taurine and β-guanidinopropionic acid, suggesting that taurine transporter (TAUT/SLC6A6) is responsible for the influx transport of β-alanine across the inner BRB. Regarding l-histidine, the l-leucine-sensitive RUI of [3H]l-histidine was identified, and the in vitro [3H]l-histidine uptake by TR-iBRB2 cells suggested that a carrier-mediated process was involved in l-histidine transport across the inner BRB. The inhibition profile suggested that L-type amino acid transporter (LAT1/SLC7A5) is responsible for the influx transport of l-histidine across the inner BRB. These results show that the influx transports of β-alanine and l-histidine across the inner BRB is carried out by TAUT and LAT1, respectively, suggesting that the retinal l-carnosine is supplied by enzymatic synthesis from two kinds of amino acids transported across the inner BRB.

Image quality of myocardial perfusion-gated studies: effect of ingestion of different fat content in the reduction of extra-myocardial abdominal signal

Myocardial perfusion-gated-SPECT (MP-gated-SPECT) imaging often shows radiotracer uptake in abdominal organs. This accumulation interferes frequently with qualitative and quantitative assessment of the infero-septal region of myocardium. The objective of this study is to evaluate the effect of ingestion of different fat content on the reduction of extra-myocardial uptake and to improve MP-gated-SPECT image quality. In this study, 150 patients (65 ± 18 years) who were referred for MP-gated-SPECT underwent a 1-day-protocol including imaging after stress (physical or pharmacological) and resting conditions. All patients gave written informed consent. Patients were subdivided into five groups: GI, GII, GIII, GIV and GV. In the first four groups, patients ate two chocolate bars with different fat content. Patients in GV – control group (CG) – had just water. Uptake indices (UI) of myocardium (M)/liver(L) and M/stomach–proximal bowel(S) revealed lower UI of M/S at rest in all groups. Both stress and rest studies using different food intake indicate that patients who ate chocolate with different fat content showed better UI of M/L than the CG. The UI of M/L and M/S of groups obtained under physical stress are clearly superior to that of groups obtained under pharmacological stress. These differences are only significant in patients who ate high-fat chocolate or drank water. The analysis of all stress studies together (GI, GII, GIII and GIV) in comparison with CG shows higher mean ranks of UI of M/L for those who ate high-fat chocolate. After pharmacological stress, the mean ranks of UI of M/L were higher for patients who ate high- and low-fat chocolate. In conclusion, eating food with fat content after radiotracer injection increases, respectively, the UI of M/L after stress and rest in MP-gated-SPECT studies. It is, therefore, recommended that patients eat a chocolate bar after radiotracer injection and before image acquisition.

Synthesis and evaluation of 11C-labeled naphthalene derivative as a novel non-peptidergic probe for the β-secretase (BACE1) imaging in Alzheimer's disease brain

As a first trial for in vivo imaging of β-secretase (BACE1) in Alzheimer's disease brain, we applied a novel non-peptidergic small molecule which has high affinity to the enzyme, naphthalene-1-carboxylic acid (3'-chloro-4'-fluoro-4-piperazin-1-yl-biphenyl-3-yl)amide (NCFB) into positron emission tomography (PET) probe. In the current study, N-(11)C-methylated compound of NCFB, [(11)C]Me-NCFB was synthesized and evaluated for the visualization of BACE1 in brain. BACE1 inhibitory constant was measured by FRET assay. [(11)C]Me-NCFB was synthesized from NCFB with [(11)C]methyl triflate. To evaluate properties of [(11)C]Me-NCFB, log P value, stability in mouse plasma and brain uptake index were measured. The biodistribution in 6-week-old ddY mice was also studied. BACE1 inhibitory constant showed an affinity of Me-NCFB to the enzyme (IC50=2.3 ± 0.80 μM). [(11)C]Me-NCFB was synthesized in a 3.0% ± 0.55% decay-corrected radiochemical yield. [(11)C]Me-NCFB showed high lipophilicity, high stability in mouse plasma and blood-brain barrier (BBB) permeability. Injected to 6-week-old ddY mice, [(11)C]Me-NCFB penetrated BBB and was retained in the brain (0.79% ± 0.22% ID/g at 2 min and 0.75% ± 0.08% ID/g at 60 min after injection, respectively), moreover, rapid blood clearance was observed. [(11)C]Me-NCFB could have a potential as a PET probe for the imaging of BACE1 in the brain.

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg⁻¹·min⁻¹, Ex-4-low; n = 5) or high (0.9 pmol·kg⁻¹·min⁻¹, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg⁻¹·min⁻¹ between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg⁻¹·min⁻¹), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver.

Increase in left liver lobe function after preoperative right portal vein embolisation assessed with gadolinium-EOB-DTPA MRI

To prospectively evaluate the early development of regional liver function after right portal vein embolisation (PVE) with Gd-EOB-DTPA-enhanced MRI in patients scheduled for extended right hemihepatectomy. Ten patients who received a PVE before an extended hemihepatectomy were examined before and 14days after PVE using Gd-EOB-DTPA-enhanced MRI of the liver. In these sequences representative region of interest measurements were performed in the embolised right (RLL) and the non-embolised left liver lobe (LLL). The volume as well as hepatic uptake index (HUI) was calculated independently for each lobe. Relative enhancement 14days after PVE decreased in the RLL and increased significantly in the LLL (P < 0.05). Average hepatic uptake index (HUI) for RLL was significantly lower 14days after PVE than before PVE (P < 0.05) and significantly higher for LLL (P < 0.05). A significant shift of contrast uptake from the right to the left liver lobe can be depicted as early as 14days after right PVE by using Gd-EOB-DTPA-enhanced MRI, which could reflect the redirected portal venous blood flow and the rapid utilisation of a hepatic functional reserve. • Preoperative portal vein embolisation (PVE) is widely performed before right-sided hepatic resection. • PVE increases intravenous contrast medium uptake in the left lobe of liver. • The hepatic uptake index for the left liver lobe increases rapidly after PVE. • Left liver lobe function increase may be visualised by Gd-EOB-DTPA-enhanced MRI.

A New Method to Determine Central Wavelength and Optimal Bandwidth for Predicting Plant Nitrogen Uptake in Winter Wheat

Plant nitrogen (N) uptake is a good indicator of crop N status. In this study, a new method was designed to determine the central wavelength, optimal bandwidth and vegetation indices for predicting plant N uptake (g N m−2) in winter wheat (Triticum aestivum L.). The data were collected from the ground-based hyperspectral reflectance measurements in eight field experiments on winter wheat of different years, eco-sites, varieties, N rates, sowing dates, and densities. The plant N uptake index (PNUI) based on NDVI of 807 nm combined with 736 nm was selected as the optimal vegetation index, and a linear model was developed with R2 of 0.870 and RMSE of 1.546 g N m−2 for calibration, and R2 of 0.834, RMSE of 1.316 g N m−2, slope of 0.934, and intercept of 0.001 for validation. Then, the effect of the bandwidth of central wavelengths on model performance was determined based on the interaction between central wavelength and bandwidth expansion. The results indicated that the optimal bandwidth varies with the changes of the central wavelength and with the interaction between the two bands in one vegetation index. These findings are important for prediction and diagnosis of plant N uptake more precise and accurate in crop management.

The effects of body condition score and nutrition of triplet-bearing ewes in late pregnancy

At day 128 (P128) of pregnancy, triplet-bearing Romney ewes were allocated to either a ‘Control’ or ‘ad-libitum’ (‘Adlib’) nutritional regimen until P142. Both nutritional regimens included ewes of body condition score (BCS): 2.0, 2.5 and 3.0. During the nutritional period the post grazing masses were 807.9±58.5 and 1254±61.1kgDM/ha for the Control and Adlib regimens respectively. At P142 Control ewes had lighter (P<0.05) live weight and lower (P<0.05), condition score and backfat depths than Adlib ewes. Neither ewe nutritional regimen nor BCS affected (P>0.05) lamb live weight or indices of colostrum uptake. There was no effect (P>0.05) of ewe nutritional regimen on lamb survival. Lambs born to BCS2.5 ewes had lower survival (P<0.05) than BCS3.0 lambs and BCS3.0 lambs tended (P=0.09) to have greater survival than BCS2.0 lambs. BCS3.0 ewes weaned a greater total weight of lamb (P<0.05) than BCS2.5 ewes. There were no (P<0.05) interactions between ewe nutritional regimen and BCS for any of the lamb traits measured. In conclusion, the data indicates triplet-bearing ewes can be managed under controlled grazing conditions with post grazing masses of approximately 800kgDM/ha to day 142 of pregnancy without affecting lamb performance. The present study also suggests farmers should aim to have their triplet-bearing ewes at a body condition score of 3.0 prior to late pregnancy to achieve higher levels of performance.

Validation of nigrostriatal positron emission tomography measures: Critical limits

Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells. Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001). Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

Involvement of Organic Anion-Transporting Polypeptides in the Hepatic Uptake of Dioscin in Rats and Humans

The objective of this study was to clarify the mechanism underlying hepatic uptake of dioscin (diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside), an herbal ingredient with antihepatitis activity, in rats and humans. The liver uptake index (LUI) in vivo, perfused rat liver in situ, rat liver slices, isolated rat hepatocytes, and human organic anion-transporting polypeptide (OATP)-transfected cells in vitro were used to evaluate hepatic uptake of dioscin. Values of 11.9% ± 1.6% and 15.0% ± 0.9% of dose for uptake of dioscin were observed by LUI in vivo and perfused rat livers in situ, respectively. The time course of dioscin uptake by rat liver slices was temperature-dependent. Uptake of dioscin by rat liver slices and isolated rat hepatocytes was inhibited significantly by Oatp modulators, such as ibuprofen (Oatp1a1 inhibitor), digoxin (Oatp1a4 substrate), and glycyrrhizic acid (Oatp1b2 inhibitor), but not by TEA or p-aminohippurate. Uptake of dioscin in rat hepatocytes and OATP1B3-human embryonic kidney (HEK) 293 cells indicated a saturable process with a Km of 3.75 ± 0.51 μM and 2.08 ± 0.27 μM, respectively. (-)-Epigallocatechin gallate, cyclosporin A, rifampicin, and telmisartan inhibited transport of dioscin in OATP1B3-HEK293 cells. However, transcellular transport of dioscin in OATP1B1- or OATP1B1/multidrug resistance-associated protein 2-Madin-Darby canine kidney strain II cells was not observed. These results indicate that hepatic uptake of dioscin is involved in OATP1B3 in humans, and multiple Oatps might participate in this process in rats.

Rat Brain-Uptake Index for Phenylethylamine and Various Monomethylated Derivatives

Phenylethylamine and its monomethylated derivatives p-methylphenylethylamine, α-methylphenylethylamine, phenylethylamine itself, N-methylphenylethylamine, o-methylphenylethylamine, and β-methylphenylethylamine, readily cross the blood-brain barrier showing a brain-uptake index (%) ± SD (water considered 100 %), of 108 ± 11, 98 ± 14, 83 ± 6, 78 ± 11, 62 ± 7 and 56 ± 6, respectively (injection of tritiated water and 100 μg standard amine, which was measured by gas-liquid chromatography). Similar brain-uptake index values (determined by double isotope counting) were obtained for phenylethylamine and α-methylphenylethylamine (amphetamine) after the injection of tritiated water and C(14)-labeled amine (either 3 μg or when added 100 μg standard compound), suggesting that they entered the brain via passive diffusion. Accordingly, both amines distributed rather evenly in the various rat brain areas examined: uptake index (%) ± SD (double isotope counting; non-, and diluted labeled amine) for phenylethylamine (89 ± 8 and 78 ± 7, 83 ± 9 and 86 ± 9, 96 ± 6 and 84 ± 7) and for α-methylphenylethylamine (88 ± 11 and 87 ± 9, 93 ± 14 and 87 ± 11, 97 ± 12 and 87 ± 9) for the cerebellum, frontal cortex, and striatum, respectively. These results will aid a greater understanding of the pharmacological and behavioral effects observed after the administration of phenylethylamine and methylphenylethylamine derivatives.

Zinc fractionation in the rhizosphere of wheat (Triticum aestivumL.) plant in soils treated with sewage sludge

Rhizosphere is a microbiosphere and has quite different chemical, physical and biological properties from bulk soils. A greenhouse experiment was performed to compare fractionation of Zinc (Zn) between rhizosphere and bulk soils amended with sewage sludge (1% w/w of sewage sludge to soil). Fractions of Zn were determined in two subsamples (rhizosphere and bulk soils). The results indicated concentration of Zn-fractions (except carbonates-associated) in the rhizosphere soils were significantly (p<0.05) different from concentrations of Zn-fractions in the bulk soils. Also, results revealed that significant correlation (p<0.05) between Zn associated with iron-manganese and yield and uptake indices in the rhizosphere and bulk soils were found. The results of this research illustrated that rhizosphere is a small zone but important environmental zone in soils with quite different properties.

735 – Adherence to the baltic sea diet is associated with lower prevalence of elevated depressive symptoms

Introduction Recently, Baltic Sea Diet Score (BSDS) was developed based on the Baltic Sea Dietary Pyramid. The association between Baltic Sea Diet Score and prevalence of depressive symptoms has not been studied earlier, though diet including fish and whole grain products may be preventive for depression. Objectives and aims We assessed whether adherence to Baltic Sea Diet is associated with a decreased prevalence of depressive symptoms. Methods The population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study included 2682 Finnish men aged 42-60 years. Diet was assessed by a 4-d food record and depressive symptoms with the 18-item Human Population Laboratory Depression Scale. Those who scored five or more were considered to have elevated depressive symptoms. The BSDS was calculated according to the quartiles of consumption of each score component. For healthy considered foods (fruits and berries, vegetables, wholegrain products, ratio of polyunsaturated fatty acids to saturated fatty acids and fish) the quartiles were coded 0-3 points (lowest quartile was coded as 0, etc.). For meat and total fat scores were opposite. Alcohol was coded 1 point ( Results Altogether 228 (8.5%) men had depressive symptoms. In a multivariable model, after adjustments for age, energy intake, smoking, marital status, socio-economic status, maximal oxygen uptake and body mass index, men in the highest v. lowest BSDS quartile were 40% more likely to be non-depressed (OR 0.60, 95% CI 0.39, 0.93, p=0.02). Conclusions Adherence to Baltic Sea diet may be associated with lowered level of depression.

Inorganic mercury (Hg2+) uptake by different plankton fractions of Andean Patagonian lakes (Argentina)

The species composition and the size structure of natural planktonic food webs may provide essential information to understand the fate of mercury and, in particular, the bioaccumulation pattern of Hg2+ in the water column of lake ecosystems. Heterotrophic and autotrophic picoplankton and phytoplankton are the most important entry points for Hg in aquatic ecosystems since they concentrate Hg2+ and MeHg from ambient water, making them available to planktonic consumers at higher trophic levels of lake food webs. In this investigation we studied the uptake of 197Hg2+ in natural plankton assemblages from four Andean lakes (Nahuel Huapi National Park, Patagonia, Argentina), comprised in the size fractions 0.2-2.7 µm (picoplankton), 0.2-20 µm (pico and nanoplankton) and 20-50 µm (microplankton) through experiments using Hg2+ labeled with 197Hg2+. The experimental results showed that the uptake of Hg2+ was highest in the smallest plankton fractions (0.2-2.7 µm and 0.2-20 µm) compared to the larger fraction comprising microplankton (20-50 um). This pattern was consistent in all lakes, reinforcing the idea that among pelagic organisms, heterotrophic and autotrophic bacteria with the contribution of nanoflagellates and dinoflagellates constitute the main entry point of Hg2+ to the pelagic food web. Moreover, a significant direct relationship was found between the Hg2+ uptake and surface index of the planktonic fractions (SIf). Thus, the smaller planktonic fractions which bore the higher SI were the major contributors to the Hg2+ passing from the abiotic to the biotic pelagic compartments of these Andean lakes.

Temporal Growth Inhibition of Rice Plant and Growth Recovery Observed under Application of Anaerobically-DigestedCattle Manure

A field experiment assessing the effect of the annual application of anaerobically-digested cattle manure (ADM), produced at a biogas plant, on paddy rice was conducted. In plots with ADM (MF), the early growth of rice plants, from transplanting to the active tillering stage, was inhibited compared to the plots with chemical fertilizers (CF). This phenomenon was observed over many growing seasons and was especially obvious in nitrogen uptake and leaf area index (LAI). However, after panicle initiation, the growth of MF-treated plants was equal to or superior to CF-treated plants. The grain yield in all the MF plots was 96 – 105% of that in the CF plots. The inorganic nitrogen content of the soil in the MF plots was higher than that in the CF plots, which was contradictory to the growth inhibition observed in the initial growth of plants in the MF plots. In contrast, the oxidation/reduction potential and pH of the surface soil in MF plots were within the normal range, indicating that these soil factors were not associated with growth inhibition observed in MF plots. Our results implied that rice cultivars with a long growing period that are able to recover from the initial growth inhibition, such as medium or late maturing cultivars, are suitable for paddy rice production fertilized with ADM.

Clinical Significance of 18F-fluorodeoxyglucose Positron Emission Tomography in Superficial Esophageal Squamous Cell Carcinoma

To assess the clinical usefulness and significance of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC). We examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically. The FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake-positive patients, depth of tumor invasion and histology were prognostic factors. FDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake-positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.

Exercise testing in late-onset glycogen storage disease type II patients undergoing enzyme replacement therapy

Enzyme replacement therapy (ERT) has recently became available for patients with glycogen storage disease type II. Previous studies have demonstrated clinical efficacy of enzyme replacement therapy, however, data on physiological variables related to exercise tolerance are scarce. Four glycogen storage disease type II late-onset patients (45 ± 6 years) performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before (BEFORE) and after 12 months of ERT (AFTER). Peak workload, oxygen uptake, heart rate, cardiac output (by impedance cardiography) and vastus lateralis oxygenation indices (by continuous-wave near-infrared spectroscopy, NIRS) were determined. Peak workload and oxygen uptake values significantly increased during ERT (54 ± 30 vs. 63 ± 31 watt, and 17.2 ± 4.4 vs. 19.7 ± 3.5 ml/kg/min, respectively, in BEFORE vs. AFTER). On the other hand, for both peak cardiac output (12.3 ± 5.3 vs. 14.8 ± 4.5 L/min) and the NIRS-determined peak skeletal muscle fractional O2 extraction, expressed as a percentage of the maximal values during a transient limb ischemia (30 ± 39% vs. 38 ± 28%), the observed increases were not statistically significant. Our findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. The findings need to be validated during a longer follow-up on a larger group of patients.

Involvement of a Novel Organic Cation Transporter in Verapamil Transport Across the Inner Blood-Retinal Barrier

To clarify the transport and inhibition characteristics involved in verapamil transport across the inner blood-retinal barrier (inner BRB). The transport of [(3)H]verapamil across the inner BRB was investigated using retinal uptake index and integration plot analyses in rats. The detailed transport characteristics were studied using TR-iBRB2 cells, a conditionally immortalized rat retinal capillary endothelial cell line that is an in vitro model of the inner BRB. The apparent influx permeability clearance of [(3)H]verapamil was 614μL/(min·g retina), which is 4.7-fold greater than that of brain. The retinal uptake of [(3)H]verapamil was slightly increased by 3mM verapamil and 10mM qunidine and inhibited by 40mM pyrilamine, supporting the carrier-mediated efflux and influx transport of verapamil across the inner BRB. TR-iBRB2 cells exhibited a concentration-dependent uptake of [(3)H]verapamil with a K (m) of 61.9μM, and the uptake was inhibited by several cations, such as pyrilamine, exhibiting a different profile from the identified transporters. These transport properties suggest that verapamil transport at the inner BRB takes place via a novel organic cation transporter. Our findings suggest that a novel organic cation transporter is involved in verapamil transport from the blood to the retina across the inner BRB.

425P - Clinical Impact of [11C]-Methionine Positron Emission Tomography on the Treatment of Primary and Recurrent Gliomas

ABSTRACT Purpose To assess whether 11C-methionine positron emission tomography (11C-MET PET) has a clinical significance in the management of glioma patients. Patients and methods Fifty-three patients with histologically proven primary gliomas (16 grade II, 15 grade III, and 22 grade IV) were investigated repeatedly with 11C-MET PET. A total of 249 PET scans were performed, with a median of 4 scans for each patient. Functional imaging with PET was compared with concurrent MRI or CT. Results We registered high sensibility and specificity in the management of glioma patients. The mean 11C-MET uptake index results significantly correlated with histological grade. The overall survival (OS) of GBM patients who underwent 11C-MET PET serial controls and parallel CT or MRI scans resulted to be 29.24 months, significantly higher compared to OS of GBM who underwent CT or MRI alone during follow up. Conclusion 11C-MET PET allowed the detection of malignant progression in low grade glioma patients and the assessment of post-surgery status in both low and anaplastic gliomas with high sensibility and specificity. Thus, 11C-MET PET expresses its maximum potential in earlier disclosing recurrence during the long-term follow-up of GBM patients, with a relevant impact on therapeutic course and survival of these patients. Disclosure All authors have declared no conflicts of interest.