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SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone β-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.

Background: Tc-99m pertechnetate is a well-known anion, used for clinical imaging of thyroid function. This gamma emitter is transported by the sodium iodide symporter but is not incorporated into thyroglobulin. Scintigraphy using Tc-99m pertechnetate or 123 iodide represents a powerful tool for the study of sodium iodide symporter activity in different organs of living animal models. However, in many studies that have been performed in mice, the thyroid could not be distinguished from the salivary glands. In this work, we have evaluated the use of a clinically dedicated single-photon emission computed tomography (SPECT) camera for thyroid imaging and assessed what improvements are necessary for the development of this technique. Methods: SPECT of the mouse neck region, with pinhole collimation and geometric calibration, was used for the individual measurement of Tc-99m pertechnetate uptake in the thyroid and the salivary glands. Uptake in the stomach was studied by planar whole-body imaging. Uptake kinetics and biodistribution studies were performed by sequential imaging. Results: This work has shown that thyroid imaging in living mice can be performed with a SPECT camera originally built for clinical use. Our experiments indicate that Tc-99m pertechnetate uptake is faster in the thyroid than in the salivary glands and the stomach. The decrease in Tc-99m pertechnetate uptake after injection of iodide or perchlorate as competitive inhibitors was also studied. The resulting rate decreases were faster in the thyroid than in the salivary glands or the stomach. Conclusions: We have shown that a clinically dedicated SPECT camera can be used for thyroid imaging. In our experiments, SPECT imaging allowed the analysis of Tc-99m pertechnetate accumulation in individual organs and revealed differences in uptake kinetics.

International audience; In the present study, we evaluated, in mice, the efficacy of the tetrafunctional block copolymer 704 as a nonviral gene delivery vector to the lungs. SPECT/CT molecular imaging of gene expression, biochemical assays, and immunohistochemistry were used. Our dataset shows that the formulation 704 resulted in higher levels of reporter gene expression than the GL67A formulation currently being used in a clinical trial in cystic fibrosis patients. The inflammatory response associated with this gene transfer was lower than that induced by the GL67A formulation, and the 704 formulation was amenable to repeated administrations. The cell types transfected by the 704 formulation were type I and type II pneumocytes, and transgene expression could not be detected in macrophages. These results emphasize the relevance of the 704 formulation as a nonviral gene delivery vector for lung gene therapy. Further studies will be required to validate this vector in larger animals, in which the lungs are more similar to human lungs.

Assessment of myocardial viability is an important clinical issue for patient management during the acute and chronic stages of myocardial infarction. BMIPP (15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid) is a free fatty acid analogue which is trapped in the myocardium, thus permitting for metabolic imaging with single photon emission computerized tomography (SPECT). Less BMIPP than flow tracers that may be observed in the areas of infarction, may reflect the metabolic shift from fatty acid to glucose utilization in ischaemic myocardium. In this sense, the combined imaging of BMIPP and a flow tracer with SPECT may provide similar and important information as fluoro-18 deoxyglucose (FDG) and positron emission tomography (PET) regarding the assessment of myocardial viability. The purpose of this article is to review the clinical impact of BMIPP in patients with acute and with chronic left ventricular dysfunction for the identification of jeopardized but viable myocardium and the prediction of the functional outcome.

International audience; Respiratory motion may blur the tomographic reconstruction of PET or SPECT images, which subsequently impairs quantitative measurements, e.g. in the upper abdomen area. Respiratory phase-based gated reconstruction addresses this problem for CT images, but deteriorates the signal-to-noise ratio and other intensity-based quality measures for ET images. This article describes an image-based motion detection method for dynamic images, which works for both 4D-CT and 4D-SPECT images. This method allowed us to identify the motionless phases from the image-based motion signal. Interestingly, we found that the peak of motion according to the pressure signal, recorded during the acquisition and considered as a reference, is temporally shifted compared to the motion-phases identified by the proposed method. Moreover, these observations permit to reconstruct a breath hold like 3D SPECT image improving the quality of the 3D reconstruction compared to both 4D reconstruction and standard 3D reconstruction.

Respiratory motion can blur the tomographic reconstruction of positron emission tomography or single-photon emission computed tomography (SPECT) images, which subsequently impair quantitative measurements, e.g. in the upper abdomen area. Respiratory signal phase-based gated reconstruction addresses this problem, but deteriorates the signal-to-noise ratio (SNR) and other intensity-based quality measures. This paper proposes a 3D reconstruction method dedicated to micro-SPECT imaging of mice. From a 4D acquisition, the phase images exhibiting motion are identified and the associated list-mode data are discarded, which enables the reconstruction of a 3D image without respiratory artefacts. The proposed method allows a motion-free reconstruction exhibiting both satisfactory count statistics and accuracy of measures. With respect to standard 3D reconstruction (non-gated 3D reconstruction) without breathing motion correction, an increase of 14.6% of the mean standardized uptake value has been observed, while, with respect to a gated 4D reconstruction, up to 60% less noise and an increase of up to 124% of the SNR have been demonstrated.

The utilisation of the Na/I symporter (NIS) and associated radiotracers as a reporter system for imaging gene expression is now reaching the clinical setting in cancer gene therapy applications. However, a formal assessment of the methodology in terms of normalisation of the data still remains to be performed, particularly in the context of the assessment of activities in individual subjects in longitudinal studies. In this context, we administered to mice a recombinant, replication-incompetent adenovirus encoding rat NIS, or a human colorectal carcinoma cell line (HT29) encoding mouse NIS. We used (99m)Tc pertechnetate as a radiotracer for SPECT/CT imaging to determine the pattern of ectopic NIS expression in longitudinal kinetic studies. Some animals of the cohort were culled and NIS expression was measured by quantitative RT-PCR and immunohistochemistry. The radioactive content of some liver biopsies was also measured ex vivo. Our results show that in longitudinal studies involving datasets taken from individual mice, the presentation of non-normalised data (activity expressed as %ID/g or %ID/cc) leads to 'noisy', and sometimes incoherent, results. This variability is due to the fact that the blood pertechnetate concentration can vary up to three-fold from day to day. Normalisation of these data with blood activities corrects for these inconsistencies. We advocate that, blood pertechnetate activity should be determined and used to normalise the activity measured in the organ/region of interest that expresses NIS ectopically. Considering that NIS imaging has already reached the clinical setting in the context of cancer gene therapy, this normalisation may be essential in order to obtain accurate and predictive information in future longitudinal clinical studies in biotherapy.

Introduction: Progress with gene-based therapies has been hampered by difficulties in monitoring the biodistribution and kinetics of vector-mediated gene expression. Recent developments in non-invasive imaging have allowed researchers and clinicians to assess the location, magnitude and persistence of gene expression in animals and humans. Such advances should eventually lead to improvement in the efficacy and safety of current clinical protocols for future treatments. Areas covered: The molecular imaging techniques for monitoring gene therapy in the living subject, with a specific highlight on the key reporter gene approaches that have been developed and validated in preclinical models using the latest imaging modalities. The applications of molecular imaging to biotherapy, with a particular emphasis on monitoring of gene and vector biodistribution and on image-guided radiotherapy. Expert opinion: Among the reporter gene/probe combinations that have been described so far, one stands out, in our view, as the most versatile and easy to implement: the Na/I symporter. This strategy, exploiting more than 50 years of experience in the treatment of differentiated thyroid carcinomas, has been validated in different types of experimental cancers and with different types of oncolytic viruses and is likely to become a key tool in the implementation of human gene therapy.

Serotonergic drugs may lead to valvular heart disease in humans and more recently also in rats. Although clinical data suggest that dose dependency and reversibility after drug cessation might occur, proof of this is lacking. For that purpose, a total of 106 rats were prospectively enrolled: 22 control animals and 7 groups of 12 rats that received daily subcutaneous serotonin injections (5, 10, 20, 30, 40, 50 and 60 mg/kg respectively) for 12 weeks. At 12 weeks, half of the animals of each group were killed for histological analysis, whereas the remaining rats were further followed (without serotonin injections) for an additional 8 weeks. After 12 weeks of serotonin treatment, aortic and mitral regurgitation (AR, MR) were more frequently observed in the high dose groups (> 30 mg/kg) compared to controls. Moreover, aortic and mitral valves were also thicker in the high dose groups compared to controls. After 8 weeks free of serotonin injections, AR and MR were no longer significantly higher than controls. Moreover, aortic and mitral valve thickness had normalized, returning to control levels. In conclusion, this study provides evidence for a dose-dependent valvular toxicity of serotonergic drugs, which appears to be reversible after drug withdrawal.

The aim of this study was the comparison of the tumour uptake and the long-term retention of [I-123]-2-I-L-phenylalanine and [I-123]-2-I-D-phenylalanine with those of [I-123]-2-I-L-tyrosine and [I-123]-2-I-D-tyrosine in RIM rhabdomyosarcoma tumour-bearing rats. The biodistribution of the radioactivity as a function of time in RIM tumour-bearing rats was measured by planar gamma camera imaging (dynamic and static). If dissection was applied, the activity in the tumours and tissues of interest was measured by gamma counting.[I-123]-2-iodo-L-phenylalanine, [I-123]-2-iodo-D-phenylalaine, [I-123] -2-I-L-tyrosine showed a considerable turnout uptake reaching a maximum between 10 and 30 min. At 30 min p.i. the differential uptake ratio values of this uptake were, respectively, 2.1, 2.3, 2.5 and 1.7. The activity in the tumour was shown to be related to a tumour cell uptake and not to an increased blood pool activity. All the tracers showed a clearance from the blood to the bladder without renal retention. At longer times both L- and D-[I-123]-2-I-tyrosine were cleared for a large part from the tumours and the body. [I-123]-2-I-L-Phe and [I-123]-2-I-D-Phe showed a considerable and equal retention in the tumours: as compared with 0.5 h, 91% at 24 h and 80% at 48 h. This was related to the longer retention of activity in the blood pool noticed for these compounds (81% at 24 h and 65% at 48 h). The tumour-to-background ratio increased with 25% at those longer times. At short times all the tracers were taken up to a considerable extent in the tumours. In the RIM-bearing Wag/Rij rat model only [I-123]-2-1-L-phenylalanine and [I-123]-2-I-D-phenylalanine showed an especially high retention at long times without any significant difference between the enantiomers.

PURPOSE: 123I-2-iodo-tyrosine (123I-2IT) has been identified as a promising new amino acid tracer in animals. Uptake is mediated by LAT1 transport, which is increased in tumour cells. In this study we present the human biodistribution and first clinical results in glioma patients. METHODS: For the biodistribution study, six male volunteers received 60-95 MBq 123I-2IT. Whole-body scans and blood and urine samples were obtained up to 24 h after injection; dosimetry was calculated using OLINDA 1.0 software. Initial clinical evaluation of 123I-2IT SPECT was performed in 35 patients with suspected or known glioma, either as primary diagnosis or for detection of recurrence. Tumour-to-background (T/B) ratios were calculated for semi-quantitative analysis. The results were correlated with clinical and MRI follow-up data or histology. RESULTS: 123I-2IT showed both renal and intestinal clearance. Bladder (0.12 mGy/MBq) and small intestine (0.03 mGy/MBq) received the highest absorbed doses. The effective dose equivalent and effective dose were estimated at 0.020 and 0.016 mSv/MBq, respectively. In patients, 123I-2IT SPECT did not differentiate between neoplastic and non-neoplastic lesions after an indeterminate MRI. In follow-up of known glioma, 13/15 patients with disease recurrence had increased T/B values (range 1.39-3.91). Out of seven recurrence-negative patients, two showed an important increase in T/B, in one case due to radionecrosis (T/B 1.59) and in the other probably due to residual but stable disease (T/B 2.07). CONCLUSION: 123I-2IT has a favourable biodistribution for a tumour imaging agent. It shows increased uptake in central nervous system glioma and is potentially useful in the follow-up of glioma patients.

Positron emission tomography (PET) using fluorodeoxyglucose (FDG) plays an important role in the management of oncologic diseases. Interpretation of the FDG-PET data requires a profound knowledge of the normal variety of FDG biodistribution and of the different pitfalls that may mimic addit

Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, 99mTc, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4−) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4− required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4−–mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by 99mTc can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.

To characterize the myocardium after thrombolytic therapy for infarction single photon emission computed tomographic (SPECT) studies with 123I-(ortho-iodophenyl)-pentadecanoic acid (oPPA) and 99Tcm-methoxyisobutyl isonitrile (MIBI) were obtained at rest in nine patients within a fortnight after the acute event. A decreased oPPA activity compared to MIBI was observed in 15/45 segments (7/9 patients). The segments with discordant oPPA/MIBI activities showed less severe wall motion abnormalities than the segments with concordant decreased oPPA and MIBI activities (P = 0.004). A significant association was found between discordant oPPA/MIBI activities and the early evolution of wall motion following thrombolysis: discordant oPPA/MIBI activities were present in nine of the 11 segments (82%) with improved wall motion, while the wall motion of the seven segments with similar decreased oPPA and MIBI activities was unchanged or had deteriorated (P = 0.018). It is concluded that metabolic abnormalities often persist longer than perfusion and wall motion abnormalities soon after thrombolysis, and that 123I-oPPA in combination with 99Tcm-MIBI is useful to demonstrate myocardial areas which have been salvaged by thrombolysis.

info:eu-repo/semantics/published

A patient with diffuse hepatic arteriovenous microfistulae suffered from secondary high-output right ventricular failure, pulmonary hypertension, and ascites, all of which could be managed by selective embolization of the hepatic artery. The vascular lesion of the liver seems to be essential, although hemorrhagic hereditary telangiectasia ,perhaps aggravated by administration of oral contraceptives, may be considered contributory factors in this case., info:eu-repo/semantics/published

Sodium acetoacetate (AcAc) was infused at a constant rate for 60 min in 2 groups of normal dogs. In the first group, the resulting hyperketonemia provoked a decrease of 19 mg/100 ml in blood glucose and an overall 40% drop in plasma free fatty acids (FFA) and blood glycerol; a sharp, but transient rise in peripheral and portal venous immunoreactive insulin (IRI) levels was observed. In the second group, a 5% glucose solution was given with the AcAc; normoglycemia was thus maintained and IRI levels remained high throughout the experiment. This indicates that glucose exerts a permissive effect on the insulinotropic action of ketone bodies in vivo.

Background. The 13C urea breath test (13C-UBT) is the most convenient method for diagnosing Helicobacter pylori infection noninvasively. Nondispersive isotope-selective infrared spectrometry (NDIRS) is an inexpensive and easy alternative to mass spectrometry. The objective of this study was to evaluate: (1) the reproducibility of the 13C-UBT as performed by using the NDIRS method; (2) the repeatability of bags analysis and the impact of delayed analysis; and (3) the need for fasting status for the 13C-UBT. Methods. The 13C-UBT was performed with 75 mg urea labeled with 13C, with breath samples collected at times 0 and 30 minutes. Results are expressed as delta over baseline (0/00). Fifty-three patients underwent two successive 13C-UBTs with an interval of 48 to 72 hours. The 106 collected bags were randomly reanalyzed immediately or 72 hours later. In 26 volunteer subjects, the 13C-UBT was performed both in a fasting condition and after a nonstandardized meal. The reproducibility was assessed by the method of Bland and Altman. Results. The mean of difference between two successive tests was 0.14 0/00 (standard deviation, 0.90), and the coefficient of repeatability was 1.80 (confidence interval, 95%). The difference between two successive analyses was always less than 2.2% of the initial value. The coefficient of variation between two successive tests for the influence of a meal was 11.24. Conclusion. The 13C-UBT as performed by using NDIRS is reproducible, analyses can be delayed up to 72 hours, and the test must be performed in fasting conditions.

Aging is associated with morphologic and functional alterations of the rat's left ventricle. However, the time-course of valvular function and morphology in normal aging rats has not yet been studied. For this purpose, 30 male Wistar rats (318 ± 5 g , 10 weeks old) underwent serial echocardiograms for 58 weeks under sodium pentobarbital 50 mg/kg IP anesthetization followed by necropsy. Histopathology was also performed in two additional groups of 10 rats at 10 and 30 weeks of age. Regurgitations were considered as any retrograde flow on 2-D or M-mode color Doppler echocardiography. Tricuspid regurgitation was already found at 10 weeks of age and became more frequent with age. Pulmonary, mitral and aortic regurgitation was seldom observed at 10 weeks but became more frequent after 30 weeks. For the mitral and aortic valve, this was also associated with an increase in valvular thickness because of nodular or segmental myxoid leaflet changes. The severity of valvular regurgitations did not increase with age. In conclusion, aging leads to morphologic and functional valvular changes in normal rats. This is important when investigating models of valvular heart disease in small animals. (E-mail: steven_droogmans@yahoo.com )