Dataset Information

Localized fetomaternal hyperglycemia: spatial and kinetic definition by positron emission tomography.

ABSTRACT:

Background

Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat.

Methodology and principal findings

We hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [18F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.9+/-0.1 and 2.8+/-0.3 fold under fasted and hyperinsulinemic conditions (p<10(-11) n=32-35 and p<10(-12) n=27-45) respectively. By contrast, centrally administered [3H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (10(3) mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained.

Conclusions and significance

This approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health.

SUBMITTER: Yao J

PROVIDER: S-EPMC2917372 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

Localized fetomaternal hyperglycemia: spatial and kinetic definition by positron emission tomography.

Yao Jianrong J Wang Chunlin C Walsh Susan A SA Hu Shanming S Sawatzke Alexander B AB Dang Diana D Segar Jeffrey L JL Ponto Laura L B LL Sunderland John J JJ Norris Andrew W AW

PloS one 20100806 8

<h4>Background</h4>Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat.<h4>Methodology and principal findings</h4>We hypothesized that glucos ...[more]

PMID: 20700464

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:BackgroundSpatial normalization is a prerequisite step for analyzing positron emission tomography (PET) images both by using volume-of-interest (VOI) template and voxel-based analysis. Magnetic resonance (MR) or ligand-specific PET templates are currently used for spatial normalization of PET images. We used computed tomography (CT) images acquired with PET/CT scanner for the spatial normalization for [18F]-N-3-fluoropropyl-2-betacarboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) PET images and compared target-to-cerebellar standardized uptake value ratio (SUVR) values with those obtained from MR- or PET-guided spatial normalization method in healthy controls and patients with Parkinson's disease (PD).MethodsWe included 71 healthy controls and 56 patients with PD who underwent [18F]-FP-CIT PET scans with a PET/CT scanner and T1-weighted MR scans. Spatial normalization of MR images was done with a conventional spatial normalization tool (cvMR) and with DARTEL toolbox (dtMR) in statistical parametric mapping software. The CT images were modified in two ways, skull-stripping (ssCT) and intensity transformation (itCT). We normalized PET images with cvMR-, dtMR-, ssCT-, itCT-, and PET-guided methods by using specific templates for each modality and measured striatal SUVR with a VOI template. The SUVR values measured with FreeSurfer-generated VOIs (FSVOI) overlaid on original PET images were also used as a gold standard for comparison.ResultsThe SUVR values derived from all four structure-guided spatial normalization methods were highly correlated with those measured with FSVOI (P < 0.0001). Putaminal SUVR values were highly effective for discriminating PD patients from controls. However, the PET-guided method excessively overestimated striatal SUVR values in the PD patients by more than 30% in caudate and putamen, and thereby spoiled the linearity between the striatal SUVR values in all subjects and showed lower disease discrimination ability. Two CT-guided methods showed comparable capability with the MR-guided methods in separating PD patients from controls and showed better correlation between putaminal SUVR values and the parkinsonian motor severity than the PET-guided method.ConclusionCT-guided spatial normalization methods provided reliable striatal SUVR values comparable to those obtained with MR-guided methods. CT-guided methods can be useful for analyzing dopamine transporter PET images when MR images are unavailable.

Dataset Information

Localized fetomaternal hyperglycemia: spatial and kinetic definition by positron emission tomography.

Background

Methodology and principal findings

Conclusions and significance

Publications

Localized fetomaternal hyperglycemia: spatial and kinetic definition by positron emission tomography.

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