Uptake Index Research Articles

Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats

Cyclosporin A (CsA) is a well known inhibitor of the organic anion-transporting polypeptide (OATP/Oatp) family transporters, causing a large number of transporter-mediated drug-drug interactions in clinical situations. In the present study, we examined the inhibitory effect of CsA on the hepatic uptake of sulfobromophthalein (BSP) in rats, focusing on a long-lasting inhibition. Twenty-one hours after the subcutaneous administration of CsA, the hepatic clearance of BSP was decreased. The liver uptake index study revealed that hepatic uptake of BSP was reduced in CsA-treated rats for at least 3 days. Comparison of uptake studies using isolated hepatocytes prepared from control and CsA-treated rats showed that hepatic uptake in CsA-treated rats was decreased. In primary cultured hepatocytes, after preincubation with CsA, the uptake of [(3)H]BSP was reduced even after removal of CsA from the incubation buffer although a preincubation time dependence was not observed. However, the expression of Oatp1a1 and Oatp1b2, which are involved in the hepatic uptake of BSP, and the amount of intrahepatic glutathione, a driving force of Oatp1a1, did not change in CsA-treated rats. Thus, we can conclude that CsA modulates the transporter function sustainably. It can cause a potent in vivo drug-drug interaction. The modulation of transporters is not caused by reduced expression or driving force of transporters. It may be affected by CsA accumulated in the liver or its metabolites. The inhibitory effect of CsA on the transporter-mediated uptake of BSP cannot be explained by a simple competitive mechanism and a novel mechanism should be considered.

Salivary gland functional recovery after sialendoscopy

To date, there has been no report on the salivary gland functional outcomes after sialendoscopic surgery. The purpose of this study is to evaluate salivary gland functional recovery after sialendoscopic management of obstructive salivary gland disease. A prospective, self-control study. The present study was undertaken among patients scheduled for sialendoscopic surgery with unilateral salivary ductal obstructions. Glandular function was quantitatively assessed with the use of sialometry and scintigraphy preoperatively and at least 3 months postoperatively. A consecutive series of 17 patients were followed for 14 +/- 8 months. Sialendoscopic procedures included removal of calculi in 15 cases and dilatation of stenosis in two cases. All patients were free of symptoms during follow-up. Before surgery, there was a significant decline in the resting and stimulated saliva flow rate, uptake index, and excretion fraction of the obstructive glands compared with the contralateral normal glands. Postoperatively, although the degrees of functional recovery varied in individuals, statistical analysis revealed that the glandular function increased significantly in the affected glands and had no differences when compared to the contralateral glands. These data provide a unique functional assessment after sialendoscopic surgery. Our results demonstrate that sialendoscopy is an organ-preserving surgical approach which can achieve satisfactory functional recovery in the management of salivary ductal obstructions.

Preparation and evaluation of ethyl [18F]fluoroacetate as a proradiotracer of [18F]fluoroacetate for the measurement of glial metabolism by PET

Changes in glial metabolism in brain ischemia, Alzheimer's disease, depression, schizophrenia, epilepsy and manganese neurotoxicity have been reported in recent studies. Therefore, it is very important to measure glial metabolism in vivo for the elucidation and diagnosis of these diseases. Radiolabeled acetate is a good candidate for this purpose, but acetate has little uptake in the brain due to its low lipophilicity. We have designed a new proradiotracer, ethyl [(18)F]fluoroacetate ([(18)F]EFA), which is [(18)F]fluoroacetate ([(18)F]FA) esterified with ethanol, to increase the lipophilicity of fluoroacetate (FA), allowing the measurement of glial metabolism. The synthesis of [(18)F]EFA was achieved using ethyl O-mesyl-glycolate as precursor. The blood-brain barrier permeability of ethyl [1-(14)C]fluoroacetate ([(14)C]EFA) was estimated by a brain uptake index (BUI) method. Hydrolysis of [(14)C]EFA in the brain was calculated by the fraction of radioactivity in lipophilic and water fractions of homogenized brain. Using the plasma of five animal species, the stability of [(14)C]EFA was measured. Biodistribution studies of [(18)F]EFA in ddY mice were carried out and compared with [(18)F]FA. Positron emission tomography (PET) scanning using common marmosets was performed for 90 min postadministration. At 60 min postinjection of [(18)F]EFA, metabolite studies were performed. Organs were dissected from the marmosets, and extracted metabolites were analyzed with a thin-layer chromatography method. The synthesis of [(18)F]EFA was accomplished in a short time (29 min) and with a reproducible radiochemical yield of 28.6+/-3.6% (decay corrected) and a high radiochemical purity of more than 95%. In the brain permeability study, the BUI of [(14)C]EFA was 3.8 times higher than that of sodium [1-(14)C]fluoroacetate. [(14)C]EFA was hydrolyzed rapidly in rat brains. In stability studies using the plasma of five animal species, [(14)C]EFA was stable only in primate plasma. Biodistribution studies in mice showed that the uptake of [(18)F]EFA in selected organs was higher than that of [(18)F]FA. From nonprimate PET studies, [(18)F]EFA was initially taken into the brain after injection. Metabolites related to the tricarboxylic acid (TCA) cycle were detected in common marmoset brain. [(18)F]EFA rapidly enters the brain and is then converted into TCA cycle metabolites in the brains of common marmosets. [(18)F]EFA shows promise as a proradiotracer for the measurement of glial metabolism.

Intérêt de l’analyse factorielle discriminante pour classer les syndromes parkinsoniens à partir de la tomoscintigraphie d’émission monophotonique

Introduction The objective was to assess the value of single photon emission computerized tomography (SPECT) and factorial discriminant analysis (FDA) in the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Patients and methods Sixty-two patients with clinical diagnoses of either CBD, PSP or PD were studied using brain HmPaO-SPECT. Thirteen pairs of regions of interest (ROIs) were drawn on the slices located 50 mm and 90 mm above the canthomeatal plane. Twenty-six uptake indices and 13 asymmetry indices were determined. FDA was performed in order to determine whether or not the patients could be classified into the correct clinical group on the basis of SPECT data alone. The most discriminant parameters were used to generate two predictive scores, which were tested in a second group of 15 patients. Results FDA of all 39 variables correctly classified all the patients. A subset of 10 variables was used to build predictive scores, which correctly classified 90% of PD patients, 100% of PSP patients and 86% of CBD patients. When tested in the validation group of 15 patients, these predictive scores correctly classified 87% of the individuals. The frontal medial, temporoparietal and parietal regions were the most discriminant. Conclusion Using SPECT data alone, this study enabled us to distinguish between PD, PSP and CBD in patients with clear clinical presentations of the diseases in question. This novel, statistical approach provides reliable information. However, a prospective study dealing with de novo parkinsonian syndromes will be necessary.

Evaluation of hepatic perfusion and function with modified hepatobiliary scintigraphy

The quantitative relationship between changes in portal vein pressure and the perfusion index was studied, and hepatocellular function was evaluated. A modified protocol of hepatobiliary dynamic scintigraphy with Tc-99m-labeled ethylene hepatobiliary iminodiacetic acid (EHIDA) was performed in 37 patients with hepatic cirrhosis and 12 healthy controls. In 18 patients, the portal vein pressure (PVP) was measured intra-operatively during the portal vein bypass procedure. The portal vein perfusion index (PVI) was obtained by a two-compartment model of hepatic perfusion. A three-compartment model was applied in the hepatocellular extracted and excreted time-radioactivity curves, and the hepatic functional index was calculated including the hepatic uptake index (UI), the mean residual index (MRI), the uptake speed index (UsI), the descent speed index (DsI), the peak uptake (PU), and the peak time (PT) of hepatic uptake. These function indices in the cirrhotic patients were compared to the indices in the healthy controls with a two-sided t-test; specifically, the PU (18.94 ± 6.80 vs. 29.67 ± 18.98, P < 0.01), UI (0.84 ± 5.99 vs. 18.41 ± 13.87, P < 0.05), and UsI (0.58 ± 0.39 vs. 1.23 ± 0.81, P < 0.01) were slower in patients with hepatic cirrhosis compared with the healthy controls. The PT (16.83 ± 4.89 vs. 10.95 ± 2.79, P < 0.001) and MRI (5.93 ± 2.96 vs. 2.74 ± 0.97, P < 0.001) were more prolonged and the DsI (0.07 ± 0.09 vs. 0.18 ± 0.14, P < 0.01) was less compared to controls. The PVI were significantly higher in cirrhotic patients than in controls (46.17 ± 7.83 vs. 29.07 ± 5.71, P < 0.001), and the PVI correlated to the PVP ( r = 0.79, P < 0.01). In conclusion, modified quantitative hepatobiliary dynamic scintigraphy can evaluate the changes of portal vein blood flow and monitor hepatocellular function, in which the portal vein blood flow can estimate portal vein pressure.

Interaction between Glomus geosporum, Azotobacter chroococcum, and Bacillus coagulans and their Influence on Growth and Nutrition of Melia azedarach L.

A green house nursery study was conducted to assess the interaction between arbuscular mycorrhizal fungus, a nitrogen fixing bacterium, Glomus geosporum, Azotobacter chroococcum, and a mycorrhiza helper bacterium (MHB), Bacillus coagulans, in soil and their consequent effect on growth and nutrition of Melia azedarach L. seedlings. Triple inoculation of G. geosporum, A. chroococcum, and B. coagulans resulted in maximum plant biomass, N, P, Zn, and Cu uptake, and biovolume and quality index of M. azedarach seedlings. It also increased the mycorrhizal root colonization and spore numbers in the root zone soil of the inoculated plants over uninoculated control plants. The enzyme activity, namely acid phosphatase and dehydrogenase, in the root zone soil was found high in the 3-combination treatments and low in the uninoculated control. Triple inoculation with G. geosporum + A. chroococcum + B. coagulans proved to be the best microbial consortium for inoculating M. azedarach at nursery level in order to get healthy and vigorously growing seedlings.

Ionization-Specific Prediction of Blood–Brain Permeability

This study presents a mechanistic QSAR analysis of passive blood–brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo log PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log PS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSE < 0.5) and simple physicochemical interpretations (log P and pKa), thus providing a clear route towards property-based design of new CNS drugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:122–134, 2009

肝細胞造影相を利用した肝機能情報の取得法に関する検討

In a field of contrast-enhanced magnetic resonance imaging of the liver, attention has been focused on evaluation of liver function using gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid(EOB). In this study, we examined the possibility of obtaining liver function in only one hepatobiliary phase 60 minutes after injection. First, in regard to the difference between the signal intensity of two materials, we examined the effects of slice gap, surface coil intensity correction(SCIC), and others. Secondly, we compared the difference between liver and spleen signal intensity with biochemical laboratory tests, Child-Pugh class, liver damage class, and the two indices(HH(15) and LHL(15))calculated by 99mTc-DTPA-galactosyl-human serum albumin hepatic scintigraphy in patients with chronic liver diseases. Finally, we designated the "Liver EOB uptake index(L-EOB(60))" from those results, compared with HH(15) and LHL(15). The results demonstrated that the difference between the signal intensity of two materials increased in the lack of slice gap explained by cross talk, and decreased with SCIC. The difference between liver and spleen signal intensity decreased with worsened liver and kidney function. In the case of slice gap >20% and direct bilirubin <0.5 mg/dL without SCIC, the correlation coefficient between L-EOB(60) and LHL(15) was 0.97. L-EOB(60) was strongly proportional to LHL(15). We conclude that L-EOB(60) meeting the above conditions can be employed as a useful index to determine liver function.

Regional analysis of age‐related decline in dopamine transporters and dopamine D2‐like receptors in human striatum

The purpose of this study was to evaluate the mechanisms of age-related decline of dopamine transporter (DAT) and dopamine D(2)-like receptor (D2R) densities in the human striatum by focusing on regional difference. Positron emission tomography (PET) with [(11)C]CFT and [(11)C]raclopride for measuring DATs and D2Rs, respectively, was performed on 16 healthy volunteers ranging from 21 to 74 years in age. To evaluate in detail the regional difference within the striatum, in addition to the conventional region-of-interest-based analysis, we created a parametric image that enabled us to visualize the regional decline rate on a voxel-by-voxel basis, mapping the slope of the regression line between the age and uptake index of each tracer. The decreasing rates corresponded to 6.1, 5.5, and 5.6% per decade for DATs and 5.8, 4.9, and 4.8% per decade for D(2)Rs in the caudate nucleus, anterior putamen, and posterior putamen, respectively. The caudate nucleus for both DATs and D(2)Rs were the fastest among the striatum, and the regional difference of the decreasing rate for DATs was consistently associated with that for D2Rs. Meanwhile, previous histological studies have shown that age-related cell loss in the substantia nigra is likely to preferentially affect its dorsomedial part, which projects to the caudate nucleus. These results suggested that neuronal cell loss in the substantia nigra may be associated with the age-related DAT decline, and DAT decline may be associated functionally with age-related D2R decline.

13N-NH3: a selective contrast-enhancing tracer for brain tumor

The purpose of this study is to determine whether there is a qualitative and quantitative relationship between the breakdown of the blood-brain barrier, defined radiologically by the contrast enhancement of MRI, and the uptake of N-NH3 in brain tumors. The results of N-NH3 PET in 42 patients suspected of having brain tumors were compared with the findings of contrast-enhanced MRI. A histopathological diagnosis was carried out in 33 patients, and a clinical diagnosis was performed in the remaining patients. PET and MRI images were visually inspected, and the contrast index (CI) of MRI and the uptake index (UI) of N-NH3 were measured. Contrast enhancement of MRIs was seen in 20 of 29 brain tumors (69%). Increased uptake of N-NH3 was seen in 24 of 29 brain tumors (83%). Nineteen of 20 contrast-enhancing brain tumors exhibited the increased uptake of N-NH3 (95%). Areas of the increased N-NH3 uptake corresponded to areas enhanced on MR images in the majority of cases. Five out of nine nonenhancing tumors exhibited increased uptake of N-NH3 (56%). The contrast enhancement of MRIs was seen in nine of 13 nonneoplastic lesions (69%). None of the nonneoplastic lesions showed increased uptake of N-NH3, yielding a specificity of 100% for brain tumors (0 of 13). CI for tumor tissue was 1.46+/-0.64. UI of N-NH3 for tumor tissue was 1.64+/-0.71. CI and UI for tumor tissue were significantly correlated (r=0.86, P<0.01). A statistically significant difference in uptake levels of N-NH3 between contrast-enhancing tumors and nonenhancing tumors (1.88+/-0.66, n=20 vs. 1.11+/-0.52, n=9, P<0.01) was observed. UI was higher in brain tumors compared with the nonneoplastic lesions (1.64+/-0.71 vs. 0.71+/-0.19, P<0.01). N-NH3 is a potential selective contrast-enhanced tracer for brain tumor, and may prove especially useful for evaluating the contrast-enhancing lesions on MRI to distinguish brain tumors from nonneoplastic lesions.

Luminal flow patterns dictate arterial drug deposition in stent-based delivery

Endovascular stents reside in a dynamic flow environment and yet the impact of flow on arterial drug deposition after stent-based delivery is only now emerging. We employed computational fluid dynamic modeling tools to investigate the influence of luminal flow patterns on arterial drug deposition and distribution. Flow imposes recirculation zones distal and proximal to the stent strut that extend the coverage of tissue absorption of eluted drug and induce asymmetry in tissue drug distribution. Our analysis now explains how the disparity in sizes of the two recirculation zones and the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry. When temporal periodicity was introduced as a model of pulsatile flow, the net luminal flow served as an index of flow-mediated spatio-temporal tissue drug uptake. Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug-eluting stents should be appropriately considered where luminal flow, strut design and pulsatility have direct effects on tissue drug uptake after local delivery.

Leaf transmittance measurements can improve predictions of the nitrogen status for winter wheat crop

Dynamic crop models can be used to predict the occurrence of nitrogen deficiency during crop growth and optimize nitrogen fertilisation. However, prediction errors can be large and may lead to wrong recommendations. The objective of our work is to study the value of correcting the dynamic model Azodyn using transmittance measurements made with the N-Tester ® (Yara) to predict the nitrogen status of a winter wheat crop. Our approach is to use a Bayesian method called the “interacting particle filter” to fit the model's state variables to measurements obtained over the course of the season. This approach was assessed on 44 experimental plots. Predictions of crop biomass, nitrogen uptake and nitrogen nutrition index were first performed for each plot by using the model without any correction. A second series of predictions was then performed for the same variables by correcting the model with N-Tester measurements at GS 7 on Feekes’ scale. The results showed that the second series of predictions were more accurate. Depending on the prediction dates, model corrections reduced the root mean squared error by 18.1–53.2% for nitrogen nutrition index, by 9.1–10.1% for biomass, and by 17.1–45.0% for nitrogen uptake. The predictions were improved up to 52 days after the measurement but the degree of improvement was higher when the prediction date was close to the measurement date. The results also showed that, when corrected, model predictions were very sensitive to values of N-Tester measurements. It is therefore necessary to use N-Tester measurements which are as precise as possible.

Early uptake of 99mTc-C2A in the acute phase of myocardial infarction as a prognostic indicator for follow-up cardiac dysfunction

The C2A domain of Synaptotagmin I is a molecular probe for the specific imaging of cell death. Here we test the hypothesis that the uptake of 99mTc-C2A in the acute phase of an infarction is associated with cardiac dysfunction in follow-ups. The left coronary artery was occluded in Sprague-Dawley rats for 0, 10, 20, and 30 min. 99mTc-C2A was injected intravenously at 2 h of reperfusion. Anterior planar images were acquired with one million counts on a gamma camera 3 h after injection. 99mTc-C2A uptake was calculated as the total counts in the left ventricle region minus blood pool signal. The in-vivo signal detected was correlated with wall motion score index at 1 and 3 weeks follow-ups measured by echocardiography. 99mTc-C2A uptake was higher with increased ischemic time (2244+/-852, 4054+/-1223, and 6178+/-1451 for 10, 20, and 30 min ischemia, analysis of variance P<0.001). A significant correlation was found between 99mTc-C2A uptake and wall motion score index at 1 week (R=0.800, P=0.0006) and 3 weeks (R=0.810, P=0.0008). In this ischemia/reperfusion model, 99mTc-C2A uptake in the acute phase was associated with functional abnormality at 1 and 3 weeks. This demonstrates the potential diagnostic and prognostic value of 99mTc-C2A as a novel imaging agent.

Supervised and home-based exercise training for patients with intermittent claudication

Home-based exercise training, applied as the primary treatment in patients with intermittent claudication, has produced inconsistent effects on walking capacity in previous published studies. The aim of the present study was to evaluate whether a home-based exercise training program could maintain improved walking capacity and other functional variables achieved through a supervised exercise training program. The present design was a 48-week self-controlled study. The first 12-week period was a control stage in which no prescribed exercise program was provided, the second 12-week period was a supervised treadmill-walking training program and the following 24-week period was a home-based exercise program. Twenty-two subjects with intermittent claudication were recruited initially; 15 of them (14 men and one woman) completed the whole program. Walking capacity, peak oxygen uptake, walking economy and ankle-brachial index were measured at baseline and at 12, 24 and 48 weeks. There was no significant change in the measured variables after the control stage. The 12-week supervised treadmill-walking training program significantly increased pain-free walking time, maximal walking time and peak oxygen uptake. Walking economy was also significantly improved. These improvements were successfully maintained after 24 weeks of home-based training. The results indicated that 12 weeks of supervised treadmill-walking training followed by a home-based training program is an effective model of exercise rehabilitation for patients with intermittent claudication.

Decreased dopamine D2receptor binding in essential blepharospasm

The purpose of this study was to investigate whether dopamine D(2) receptor binding was altered in the striatum of essential blepharospasm patients. Striatal dopamine D(2) receptor binding was measured with positron emission tomography and [(11)C]raclopride. We studied eight drug-naive patients with bilateral blepharospasm and eight age-matched normal controls. The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. This study indicates decreased dopamine D(2) receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D(2) receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.

Suitability of contact angle measurement as an index of overall oil degradation and oil uptake during frying

The aim of the work was to investigate the suitability of contact angle measurement as an index of overall oil degradation phenomena and oil uptake of French fries during frying. In order to measure the contact angle, an image analysis method was developed and applied to four vegetable oils (palm oil, palm super olein, sunflower oil and a blend of hazelnut and high-oleic sunflower oil) in actual frying experiments. With liquid oils, contact angle modification proved to be a sound index of overall oil degradation, being inversely correlated with oil acidity, peroxide value, total carbonyl compounds, K 232, and viscosity. A significant correlation between contact angle and potato oil uptake was found for sunflower oil. For the other oils, factors such as the structure of food subjected to frying or the oil melting point and viscosity seem to be important in influencing oil uptake.

Comparaison de six méthodes de segmentation du volume tumoral sur la 18F-FDG TEP-TDM avec le volume de référence anatomopathologique dans les cancers bronchopulmonaires non à petites cellules

The 18F-FDG TEP has demonstrated its importance in oncology, for initial extension and efficacy of antitumoral therapeutics. Several studies have attempted to prove its utility to define tumoral volumes for conformational radiotherapy in nonsmall cell lung cancers. Some authors have suggested the use of threshold of tumor intensity uptake with 40 or 50% of maximal intensity. Black et al. have determined contouring with linear regression formula of mean semi-quantitative index of tumor uptake (standard uptake value): SUV threshold = 0.307 SUV average + 0.588. Nestlé et al. have taken into account the background noise intensity and mean intensity of the tumor: I threshold = β I average + I noise with β = 0.15. Our study was done in collaboration with Inserm U618 team and has compared volumes defined on PETscan defined according to different methods based on intensity or SUV to the tumour volume determined on CT scan by radiophysicist. We have compared those volumes with histological volume that we considered for reference. Four patients have been included. They had 18F-FDG PETscan followed by complete tumoral removal surgery. Specific histological procedure allowed to define complete size of the tumor in reexpanded lung. Comparatively to pathology, the volumes obtained using I max 40 and I max 50 are all underestimated. The volumes defined by Black's et al. method are underevaluated for the two largest tumours (15.8% to 22%) and overestimated for the two smallest ones (17.9 to 82.9%). Nestlé's et al. method, using β = 0.15, correctly estimates two tumor volumes over 2 cm, but overestimates the two small tumors (79.6 to 124%). Finally, the corrected Nestlé's et al. formula (using β = 0.264) overestimates three tumours. Volumes defined on CT scan by radiophysicist are correct for one lesion, underestimated for one and overestimated for two other ones (44 and 179.5%). Nestlé's et al. method seems to be the most accurate for tumours over 2 cm of diameter. Today no method can correctly estimate the volume of smaller tumours. To improve those segmentation approaches, partial volume effect correction needs to be implemented for small tumours or tumours close to mediastinal local extension. The main indication of segmentation based on FDG PET is tumour greater than 2 cm for which treatment will be radiotherapy alone or radiotherapy associated with chemotherapy. Our study is important because it compares the different methods described in the literature with the reference histological volume of the tumor, which is the only way to validate tumor segmentation method.

Translational research impacting on crop productivity in drought-prone environments

Conventional breeding for drought-prone environments (DPE) has been complemented by using exotic germplasm to extend crop gene pools and physiological approaches that consider water uptake (WU), water-use efficiency (WUE), and harvest index (HI) as drivers of yield. Drivers are associated with proxy genetic markers, such as carbon-isotope discrimination for WUE, canopy temperature for WU, and anthesis-silking interval for HI in maize. Molecular markers associated with relevant quantitative trait loci are being developed. WUE has also been increased through combining understanding of root-to-shoot signaling with deficit irrigation. Impacts in DPE will be accelerated by combining proven technologies with promising new strategies such as marker-assisted selection, and genetic transformation, as well as conservation agriculture that can increase WU while averting soil degradation.

RETRACTED: Cardiac overexpression of alcohol dehydrogenase exacerbates chronic ethanol ingestion-induced myocardial dysfunction and hypertrophy: Role of insulin signaling and ER stress

Chronic alcohol intake leads to alcoholic cardiomyopathy characterized by cardiac hypertrophy and contractile dysfunction possibly related to the toxicity of the ethanol metabolite acetaldehyde. This study examined the impact of augmented acetaldehyde exposure on myocardial function, geometry, and insulin signaling via cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH transgenic and wild-type FVB mice were placed on a 4% alcohol diet for 12 weeks. Echocardiographic, glucose tolerance, glucose uptake, insulin signaling, and ER stress indices were evaluated. Mice consuming alcohol exhibited glucose intolerance, dampened cardiac glucose uptake, cardiac hypertrophy and contractile dysfunction, all of which with the exception of whole body glucose tolerance were exaggerated by the ADH transgene. Cardiomyocytes from ethanol-fed mice exhibited depressed insulin-stimulated phosphorylation insulin receptor (tyr1146) and IRS-1 (tyrosine) as well as enhanced serine phosphorylation of IRS-1. ADH-augmented alcohol-induced effect of IRS-1 phosphorylation (tyrosine/serine). Neither alcohol nor adh affected expression of insulin receptor and IRS-1. Alcohol reduced phosphorylation of Akt and GSK-3beta as well as GSK-3beta expression and the effect was exaggerated by ADH. The transcriptional factors GATA4, c-jun and c-jun phosphorylation were upregulated by alcohol, which was amplified by ADH. The ratios of phospho-c-Jun/c-Jun and phospho-GATA4/GATA4 remained unchanged. Chronic alcohol intake upregulated expression of the endoplasmic reticulum stress markers eIF2alpha, IRE-1alpha, GRP78 and gadd153, the effect of which was exaggerated by ADH. These data suggest that elevated cardiac acetaldehyde exposure via ADH may exacerbate alcohol-induced myocardial dysfunction, hypertrophy, insulin insensitivity and ER stress, indicating a key role of ADH gene in alcohol-induced cardiac dysfunction and insulin resistance.

3‐Iodothyronamine is a novel suppressor of fetal sheep cardiomyocyte proliferation in vitro

OBJECTIVES:Fetal cardiomyocyte (CMC) maturation results in cells losing ability to divide. In late‐gestation sheep CMCs thyroid hormone (T3) decreased proliferation and changed signaling protein levels in favor of cell cycle arrest (Chattergoon et al, 2007). 3‐Iodothyronamine (T1AM) is a naturally occurring relative of T3 that does not bind classical thyroid receptors (TRs). We hypothesized that T1AM may depress CMC proliferation similar to T3.METHODS:Isolated right and left ventricular fetal sheep CMCs were cultured with T1AM (1nM, 10nM) and Bromodeoxyuridine (BrdU; 10μM) for 48 hours. Two ages were studied—100 days gestational age (dGA) and 135dGA—to determine developmental variations. BrdU uptake (index of proliferation) in fixed cells was analyzed.RESULTS:Basal BrdU uptake in serum free medium (SFM) was 10–12% in 100dGA CMCs versus 1–2% in 135dGA CMCs (p&lt;0.01). BrdU uptake in response to 10% serum medium (SM) increased to 20% in 100dGA cells versus 8–10% in 135dGA CMCs (p&lt;0.01). Similar to T3, T1AM does not affect cells exposed to SFM but decreases BrdU uptake by CMCs exposed to SM by 50% (p&lt;0.05).CONCLUSIONS:These data suggest T1AM is as potent an inhibitor of fetal CMC proliferation as T3. Because T1AM does not activate TRs, non‐classical signaling of T1AM and T3 may be important in CMC growth and maturation.Grant support: NICHD (P01HD34430) and Minority Supplement (3PO1 HD034430‐09S1).