Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of cold stimulus.

PURPOSE: Brown adipose tissue (BAT) is considered a potential target for combatting obesity, as it produces heat instead of ATP in cellular respiration due to uncoupling protein-1 (UCP-1) in mitochondria. However, BAT-specific thermogenic capacity, in comparison to whole-body thermogenesis during cold stimulus, is still controversial. In our present study, we aimed to determine human BAT oxygen consumption with [(15)O]O2 positron emission tomography (PET) imaging. Further, we explored whether BAT-specific energy expenditure (EE) is associated with BAT blood flow, non-esterified fatty acid (NEFA) uptake, and whole-body EE. METHODS: Seven healthy study subjects were studied at two different scanning sessions, 1) at room temperature (RT) and 2) with acute cold exposure. Radiotracers [(15)O]O2, [(15)O]H2O, and [(18)F]FTHA were given for the measurements of BAT oxygen consumption, blood flow, and NEFA uptake, respectively, with PET-CT. Indirect calorimetry was performed to assess differences in whole-body EE between RT and cold. RESULTS: BAT-specific EE and oxygen consumption was higher during cold stimulus (approx. 50 %); similarly, whole-body EE was higher during cold stimulus (range 2-47 %). However, there was no association in BAT-specific EE and whole-body EE. BAT-specific EE was found to be a minor contributor in cold induced whole-body thermogenesis (almost 1 % of total whole-body elevation in EE). Certain deep muscles in the cervico-thoracic region made a major contribution to this cold-induced thermogenesis (CIT) without any visual signs or individual perception of shivering. Moreover, BAT-specific EE associated with BAT blood flow and NEFA uptake both at RT and during cold stimulus. CONCLUSION: Our study suggests that BAT is a minor and deep muscles are a major contributor to CIT. In BAT, both in RT and during cold, cellular respiration is linked with circulatory NEFA uptake.

Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart.

Highly endurance-trained athlete's heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [(15)O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70 ± 21 vs. 63 ± 11 % at rest and 86 ± 13 vs. 73 ± 10 % during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (p = 0.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.

Prognostic value of tumour blood flow, [¹8F]EF5 and [¹8F]FDG PET/CT imaging in patients with head and neck cancer treated with radiochemotherapy.

PURPOSE: In order to improve the treatment of squamous cell carcinoma of the head and neck, precise information on the treated tumour's biology is required and the prognostic importance of different biological parameters needs to be determined. The aim of our study was to determine the predictive value of pretreatment PET/CT imaging using [(18)F]FDG, a new hypoxia tracer [(18)F]EF5 and the perfusion tracer [(15)O]H2O in patients with squamous cell cancer of the head and neck treated with radiochemotherapy. METHODS: The study group comprised 22 patients with confirmed squamous cell carcinoma of the head and neck who underwent a PET/CT scan using the above tracers before any treatment. Patients were later treated with a combination of radiochemotherapy and surgery. Parametric blood flow was calculated from dynamic [(15)O]H2O PET images using a one-tissue compartment model. [(18)F]FDG images were analysed by calculating standardized uptake values (SUV) and metabolically active tumour volumes (MATV). [(18)F]EF5 images were analysed by calculating tumour-to-muscle uptake ratios (T/M ratio). A T/M ratio of 1.5 was considered a significant threshold and used to determine tumour hypoxic subvolumes (HS) and hypoxic fraction area. The findings were finally correlated with the pretreatment clinical findings (overall stage and TNM stage) as well as the outcome following radiochemotherapy in terms of local control and overall patient survival. RESULTS: Tumour stage and T-classification did not show any significant differences in comparison to the patients' metabolic and functional characteristics measured on PET. Using the Cox proportional hazards model, a shorter overall survival was associated with MATV (p = 0.008, HR = 1.108), maximum [(18)F]EF5 T/M ratio (p = 0.0145, HR = 4.084) and tumour HS (p = 0.0047, HR = 1.112). None of the PET parameters showed a significant effect on patient survival in the log-rank test, although [(18)F]EF5 maximum T/M ratio was the closest (p = 0.109). By contrast, tumour blood flow was not correlated with any of the clinical endpoints. There were no statistically significant correlations among [(18)F]FDG SUVmax, [(18)F]EF5 T/M ratio and blood flow. CONCLUSION: Our study in a limited number of patients confirmed the importance of MATV in the prognosis of locally advanced squamous cell carcinoma of the head and neck. It is of interest that high uptake of the hypoxia tracer [(18)F]EF5 showed a stronger correlation with a poor clinical outcome than [(18)F]FDG uptake. This confirms the importance of hypoxia in treatment outcome and suggests that [(18)F]EF5 may act as a surrogate marker of radioresistance.

Effects of adenosine, exercise, and moderate acute hypoxia on energy substrate utilization of human skeletal muscle.

Glucose metabolism increases in hypoxia and can be influenced by endogenous adenosine, but the role of adenosine for regulating glucose metabolism at rest or during exercise in hypoxia has not been elucidated in humans. We studied the effects of exogenous adenosine on human skeletal muscle glucose uptake and other blood energy substrates [free fatty acid (FFA) and lactate] by infusing adenosine into the femoral artery in nine healthy young men. The role of endogenous adenosine was studied by intra-arterial adenosine receptor inhibition (aminophylline) during dynamic one-leg knee extension exercise in normoxia and acute hypoxia corresponding to ∼3,400 m of altitude. Extraction and release of energy substrates were studied by arterial-to-venous (A-V) blood samples, and total uptake or release was determined by the product of A-V differences and muscle nutritive perfusion measured by positron emission tomography. The results showed that glucose uptake increased from a baseline value of 0.2 ± 0.2 to 2.0 ± 2.2 µmol·100 g(-1)·min(-1) during adenosine infusion (P < 0.05) at rest. Although acute hypoxia enhanced arterial FFA levels, it did not affect muscle substrate utilization at rest. During exercise, glucose uptake was higher (195%) during acute hypoxia compared with normoxia (P = 0.058), and aminophylline had no effect on energy substrate utilization during exercise, despite that arterial FFA levels were increased. In conclusion, exogenous adenosine at rest and acute moderate hypoxia during low-intensity knee-extension exercise increases skeletal muscle glucose uptake, but the increase in hypoxia appears not to be mediated by adenosine.

Intrapericardial, but not extrapericardial, fat is an independent predictor of impaired hyperemic coronary perfusion in coronary artery disease.

OBJECTIVE: To measure intrapericardial fat (IPF), extrapericardial fat (EPF), and myocardial perfusion (MBF) in patients with and without coronary artery disease (CAD), hypothesizing that perfusion is more strongly associated with IPF because it is in direct anatomic contiguity with the myocardium or coronary arteries. METHODS AND RESULTS: Fat surrounding the heart may increase the risk of CAD and calcification, but little is known about the role of MBF in this relationship. The study included 107 patients with an intermediate likelihood of CAD. Positron emission tomography/computed tomography was used to measure IPF and EPF volumes and coronary artery calcium level, together with MBF at rest and during adenosine-induced hyperemia. Subsequently, all subjects underwent coronary angiography and were grouped for presence/absence of CAD and severity of myocardial hypoperfusion. IPF and EPF levels were higher in men and in patients with CAD (n=85) than in those without CAD (n=22) (P<0.001). EPF was increased regardless of the degree of stenoses (n=45), whereas IPF was selectively increased in subjects with obstructive stenoses (n=40). IPF and EPF levels were both associated with coronary artery calcium scores (R=0.25 and R=0.26, respectively; P<0.02), coronary flow reserve (R=-0.37 and R=-0.38, respectively; P<0.001), and hyperemic MBF (R=-0.36 and R=-0.44, respectively; P<0.0005). Male sex was a strong negative predictor of MBF. After discounting for confounders, myocardial hyperemic perfusion was predicted independently by sex, coronary artery calcium score, and IPF, but not EPF. CONCLUSIONS: CAD is accompanied by augmented fat depots surrounding the heart, which are negatively related to coronary flow hyperemia. Among fat depots, IPF was the only independent predictor of hyperemic MBF, supporting the hypothesis of a direct paracrine/vasocrine effect.

Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition.

The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H(2)O(15) and (15)O(2) during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of L-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced (P < 0.05) muscle blood flow. NOS inhibition increased (P < 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ∼20% increase (P < 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased (P < 0.05). NOS and COX inhibition reduced (P < 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake.

Dual-gated cardiac PET-clinical feasibility study.

PURPOSE: Both respiratory and cardiac motions reduce image quality in myocardial imaging. For accurate imaging of small structures such as vulnerable coronary plaques, simultaneous cardiac and respiratory gating is warranted. This study tests the feasibility of a recently developed robust method for cardiac-respiratory gating. List-mode data with triggers from respiratory and cardiac cycles are rearranged into dual-gated segments and reconstructed with standard algorithms of a commercial PET/CT scanner. Cardiac gates were defined as three fixed phases and one variable diastolic phase. Chest motion was measured with a respiratory gating device and post-processed to determine gates. Preservation of quantification in dual-gated images was tested with an IEC whole-body phantom. METHODS: Minipig and human studies were performed to evaluate the feasibility of the method. In minipig studies, a coronary catheter with radioactive tip was guided in coronary artery for in vivo and ex vivo acquisitions. Dual gating in humans with suspected cardiac disorders was performed using 18-F-FDG as a tracer. RESULTS: The method was found feasible for in vivo imaging and the radioactive catheter tip was better resolved in gated images. In human studies, the dual gating was found feasible and easy for clinical routine. Maximal movement of myocardial surface in cranio-caudal direction was over 20 mm. The shape of myocardium was clearly different between the gates and papillary muscles become more visible in diastolic images. CONCLUSION: The first clinical experiences using robust cardiac-respiratory dual gating are encouraging. Further testing in larger clinical populations using tracers designed especially for plaque imaging is warranted.

Dual gated PET/CT imaging of small targets of the heart: method description and testing with a dynamic heart phantom.

BACKGROUND: In PET imaging respiratory and cardiac contraction motions interfere the imaging of heart. The aim was to develop and evaluate dual gating method for improving the detection of small targets of the heart. METHODS: The method utilizes two independent triggers which are sent periodically into list mode data based on respiratory and ECG cycles. An algorithm for generating dual gated segments from list mode data was developed. RESULTS: The test measurements showed that rotational and axial movements of point source can be separated spatially to different segments with well-defined borders. The effect of dual gating on detection of small moving targets was tested with a moving heart phantom. Dual gated images showed 51% elimination (3.6 mm out of 7.0 mm) of contraction motion of hot spot (diameter 3 mm) and 70% elimination (14 mm out of 20 mm) of respiratory motion. Averaged activity value of hot spot increases by 89% when comparing to non-gated images. Patient study of suspected cardiac sarcoidosis shows sharper spatial myocardial uptake profile and improved detection of small myocardial structures such as papillary muscles. CONCLUSIONS: The dual gating method improves detection of small moving targets in a phantom and it is feasible in clinical situations.

Myocardial Blood Flow and Metabolic Rate of Oxygen Measurement in the Right and Left Ventricles at Rest and During Exercise Using 15O-Labeled Compounds and PET.

Aims: Simultaneous measurement of right (RV) and left ventricle (LV) myocardial blood flow (MBF), oxygen extraction fraction (OEF), and oxygen consumption (MVO2) non-invasively in humans would provide new possibilities to understand cardiac physiology and different patho-physiological states. Methods: We developed and tested an optimized novel method to measure MBF, OEF, and MVO2 simultaneously both in the RV and LV free wall (FW) using positron emission tomography in healthy young men at rest and during supine bicycle exercise. Results: Resting MBF was not significantly different between the three myocardial regions. Exercise increased MBF in the LVFW and septum, but MBF was lower in the RV compared to septum and LVFW during exercise. Resting OEF was similar between the three different myocardial regions (~70%) and increased in response to exercise similarly in all regions. MVO2 increased approximately two to three times from rest to exercise in all myocardial regions, but was significantly lower in the RV during exercise as compared to septum LVFW. Conclusion: MBF, OEF, and MVO2 can be assessed simultaneously in the RV and LV myocardia at rest and during exercise. Although there are no major differences in the MBF and OEF between LV and RV myocardial regions in the resting myocardium, MVO2 per gram of myocardium appears to be lower the RV in the exercising healthy human heart due to lower mean blood flow. The presented method may provide valuable insights for the assessment of MBF, OEF and MVO2 in hearts in different pathophysiological states.

18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer.

UNLABELLED: The aim of this study was to evaluate 2-(2-nitro-(1)H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) labeled with (18)F-fluorine to image hypoxia in patients with squamous cell carcinoma of the head and neck (HNSCC). METHODS: Fifteen patients with HNSCC were studied. Measurement of tumor blood flow was followed by an (18)F-EF5 PET/CT scan. On a separate day, (18)F-FDG PET/CT was performed to determine the metabolically active tumor volume. In 6 patients, dynamic (18)F-EF5 images of the head and neck area were acquired, followed by static images acquired at 1, 2, and 3 h after injection. In the remaining 9 patients, only static images were obtained. (18)F-EF5 uptake in tumors was compared with that in neck muscle, and the (18)F-EF5 findings were correlated with the (18)F-FDG PET/CT studies. RESULTS: A total of 13 primary tumors and 5 lymph node metastases were evaluated for their uptake of (18)F-EF5. The median tumor-to-muscle (18)F-EF5 uptake ratio (T/M) increased over time and was 1.38 (range, 1.1-3.2) 3 h after tracer injection. The median blood flow in tumors was 36.7 mL/100 g/min (range, 23.3-78.6 mL/100 g/min). Voxel-by-voxel analysis of coregistered blood flow and (18)F-EF5 images revealed a distinct pattern, resulting in a T/M of 1.5 at 3 h to be chosen as a cutoff for clinically significant hypoxia. Fourteen of 18 tumors (78%) had subvolumes within the metabolically active tumor volumes with T/M greater than or equal to 1.5. CONCLUSION: On the basis of these data, the potential of (18)F-EF5 to detect hypoxia in HNSCC is encouraging. Further development of (18)F-EF5 for eventual targeting of antihypoxia therapies is warranted.

Brain function during multi-trial learning in mild cognitive impairment: a PET activation study.

We explored functional brain changes with positron emission tomography (PET) in mild cognitive impairment (MCI) patients and elderly normal controls by employing an episodic memory task that included two successive encoding trials of semantically related word-pairs and final retrieval. Both groups demonstrated significant learning across the two trials. The control group showed predominantly left frontal activity during encoding, and right frontal plus left temporal activity during retrieval. However, the MCI patients recruited partly different brain regions. They failed to activate right frontal and left temporal areas during retrieval, and failed to show any different activation for encoding on the first and second trials, whereas the controls activated a region of posterior cingulate. There was indication of compensatory increases in rCBF of the occipital cortex during incremental learning and the left frontal lobe during retrieval in the patients. These results suggest different episodic memory processing in the MCI group, and a possible over-reliance on semantic processing. Subtle functional changes occur in the pre-Alzheimer brain before there are marked structural or behavioural abnormalities.

Mobile phone affects cerebral blood flow in humans.

Mobile phones create a radio-frequency electromagnetic field (EMF) around them when in use, the effects of which on brain physiology in humans are not well known. We studied the effects of a commercial mobile phone on regional cerebral blood flow (rCBF) in healthy humans using positron emission tomography (PET) imaging. Positron emission tomography data was acquired using a double-blind, counterbalanced study design with 12 male subjects performing a computer-controlled verbal working memory task (letter 1-back). Explorative and objective voxel-based statistical analysis revealed that a mobile phone in operation induces a local decrease in rCBF beneath the antenna in the inferior temporal cortex and an increase more distantly in the prefrontal cortex. Our results provide the first evidence, suggesting that the EMF emitted by a commercial mobile phone affects rCBF in humans. These results are consistent with the postulation that EMF induces changes in neuronal activity.

Evaluation of motion-correction methods for dual-gated cardiac positron emission tomography/computed tomography imaging.

BACKGROUND: Dual gating is a method of dividing the data of a cardiac PET scan into smaller bins according to the respiratory motion and the ECG of the patient. It reduces the undesirable motion artefacts in images, but produces several images for interpretation and decreases the quality of single images. By using motion-correction techniques, the motion artefacts in the dual-gated images can be corrected and the images can be combined into a single motion-free image with good statistics. AIM: The aim of the present study is to develop and evaluate motion-correction methods for cardiac PET studies. We have developed and compared two different methods: computed tomography (CT)/PET-based and CT-only methods. METHODS: The methods were implemented and tested with a cardiac phantom and three patient datasets. In both methods, anatomical information of CT images is used to create models for the cardiac motion. RESULTS: In the patient study, the CT-only method reduced motion (measured as the centre of mass of the myocardium) on average 43%, increased the contrast-to-noise ratio on average 6.0% and reduced the target size on average 10%. Slightly better figures (51, 6.9 and 28%) were obtained with the CT/PET-based method. Even better results were obtained in the phantom study for both the CT-only method (57, 68 and 43%) and the CT/PET-based method (61, 74 and 52%). CONCLUSION: We conclude that using anatomical information of CT for motion correction of cardiac PET images, both respiratory and pulsatile motions can be corrected with good accuracy.

Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes.

Rosiglitazone, a thiazolidinedione, enhances peripheral insulin sensitivity in patients with type 2 diabetes. Because the synergic action of insulin and exercise has been shown to be decreased in insulin resistance, the aim of this study was to compare the effects of rosiglitazone and metformin on muscle insulin responsiveness at rest and during exercise in patients with type 2 diabetes. Therefore, 45 patients with newly diagnosed or diet-treated type 2 diabetes were randomized for treatment with rosiglitazone (4 mg b.i.d.), metformin (1 g b.i.d.), or placebo in a 26-week double-blind trial. Skeletal muscle glucose uptake was measured using fluorine-18-labeled fluoro-deoxy-glucose and positron emission tomography (PET) during euglycemic-hyperinsulinemic clamp and one-legged exercise before and after the treatment period. Rosiglitazone (P < 0.05) and metformin (P < 0.0001) treatment lowered the mean glycosylated hemoglobin. The skeletal muscle glucose uptake was increased by 38% (P < 0.01) and whole-body glucose uptake by 44% in the rosiglitazone group. Furthermore, the exercise-induced increment during insulin stimulation was enhanced by 99% (P < 0.0001). No changes were observed in skeletal muscle or whole-body insulin sensitivity in the metformin group. In conclusion, rosiglitazone but not metformin 1) improves insulin responsiveness in resting skeletal muscle and 2) doubles the insulin-stimulated glucose uptake rate during physical exercise in patients with type 2 diabetes. Our results suggest that rosiglitazone improves synergic action of insulin and exercise.

Regression analysis utilizing subjective evaluation of emotional experience in PET studies on emotions.

A methodological study on subject-specific regression analysis (SSRA) exploring the correlation between the neural response and the subjective evaluation of emotional experience in eleven healthy females is presented. The target emotions, i.e., amusement and sadness, were induced using validated film clips, regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET), and the subjective intensity of the emotional experience during the PET scanning was measured using a category ratio (CR-10) scale. Reliability analysis of the rating data indicated that the subjects rated the intensity of their emotional experience fairly consistently on the CR-10 scale (Cronbach alphas 0.70-0.97). A two-phase random-effects analysis was performed to ensure the generalizability and inter-study comparability of the SSRA results. Random-effects SSRAs using Statistical non-Parametric Mapping 99 (SnPM99) showed that rCBF correlated with the self-rated intensity of the emotional experience mainly in the brain regions that were identified in the random-effects subtraction analyses using the same imaging data. Our results give preliminary evidence of a linear association between the neural responses related to amusement and sadness and the self-evaluated intensity of the emotional experience in several regions involved in the emotional response. SSRA utilizing subjective evaluation of emotional experience turned out a feasible and promising method of analysis. It allows versatile exploration of the neurobiology of emotions and the neural correlates of actual and individual emotional experience. Thus, SSRA might be able to catch the idiosyncratic aspects of the emotional response better than traditional subtraction analysis.

Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients.

BACKGROUND AND PURPOSE: CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood. METHODS: CBF and rCMR(gluc) were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced > or =1 strokes. RESULTS: The mean CBF in the CADASIL patients was significantly lower in both frontal (P=0.019) and occipital (P=0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR(gluc) values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR(gluc). CONCLUSIONS: In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR(gluc) in the WM.

68Ga-labeled oligonucleotides for in vivo imaging with PET.

UNLABELLED: The biologic evaluation in living rats of (68)Ga-labeled oligonucleotides as imaging agents for PET is reported. METHODS: (68)Ga, a positron-emitting radionuclide (half-life, 68 min), along with a macrocyclic chelating agent, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), was used for labeling of antisense oligonucleotides targeting activated human K-ras oncogene. The biologic properties of 3 different forms of the oligonucleotides-that is, 2'-deoxyphosphodiester (PO), 2'-deoxyphosphorothioate (PS), and 2'-O-methyl phosphodiester (OMe)-were studied first. The biodistribution and biokinetics were evaluated in vivo in athymic rats, each bearing a tumor of A549 cells, containing K-ras point mutation in codon 12, and a tumor of BxPC-3 cells, containing wild-type K-ras. Dynamic PET imaging lasting up to 2 h was performed immediately after intravenous injection of (68)Ga-oligonucleotide. Blank studies were performed using (68)GaCl(3) or (68)Ga-DOTA alone without oligonucleotide. The (68)Ga-antisense oligonucleotide uptake in tumors was also compared with the (18)F-FDG and (68)Ga-sense oligonucleotide uptakes. In addition, oligonucleotide binding to human plasma proteins and to human albumin was examined by means of ultrafiltration. RESULTS: The oligonucleotides can be stably labeled with (68)Ga and DOTA chelate. Intravenously injected (68)Ga-oligonucleotides of 17-mer length revealed high-quality PET images, allowing quantification of the biokinetics in major organs and in tumors. The biodistribution and biokinetics of intravenously administered (68)Ga-oligonucleotide varied considerably with the nature of the oligonucleotide backbone. CONCLUSION: We conclude that (68)Ga labeling of oligonucleotides is a convenient approach for in vivo imaging and quantification of oligonucleotide biokinetics in living animals with PET.

Different brain activation patterns during production of animals versus artefacts: a PET activation study on category-specific processing.

To study neural correlates of category-specific processing, we measured relative cerebral blood flow changes by PET (oxygen-15) in young healthy subjects while they produced exemplars of animals or artefacts to written subcategory prompts. In comparison to a baseline (word reading), production of animal names elicited increased rCBF in the right inferior temporal region. This fits to recent lesion data on semantic impairment with animals, as well as imaging data on object recognition and semantic retrieval. In our study, it may represent an involvement of visual imagery in generation of animal names. In contrast, production of artefact names elicited increased rCBF in frontoparietal regions previously related to attention and mental effort.

Harmonization of antimicrobial susceptibility testing among veterinary diagnostic laboratories in the five Nordic countries.

A total of 100 bacterial strains (25 Escherichia coli, 25 Salmonella enterica, 25 Staphylococcus aureus, and 25 Enterococcus strains) and four reference strains were tested for susceptibility toward 8-12 antimicrobial agents in 12 veterinary diagnostic laboratories in the five Nordic countries using routine methodology. In addition, the 25 Enterococcus strains were identified to species level. A total of 22,598 (97.2%) out of 23,259 test results were in accordance when the data were categorized as susceptible or resistant. When the reported results were categorized according to the National Committee of Clinical Laboratory Standards breakpoints, the percentage of concordant results increased to 98.4% and the performance between laboratories varied between 94.2 and 99.4% concordant results. For E. coli, S. aureus, and Salmonella, all laboratories except one had more than 97% concordant results, whereas for Enterococcus spp., two laboratories had less than 90% concordant results. Susceptibility testing of Salmonella to fluoroquinolones gave rise to almost 0.5% nonconcordant results and susceptibility testing of S. aureus to vancomycin resulted in that 1.8% of the strains were incorrectly reported as vancomycin resistant. Ten laboratories identified the Enterococcus spp. to species level. All five Enterococcus faecium and 10 Enterococcus faecalis selected from the strain collection at the Danish Veterinary Institute were correctly identified by all laboratories, whereas some problems were observed identifying other enterococcal species. This study showed a good performance and agreement in antimicrobial susceptibility testing at the 12 participating laboratories and that surveillance data covering susceptibility test results of E. coli, S. aureus, and Salmonella from animals in the Nordic countries are comparable. But it also showed that some aspects can be improved. In addition, the study showed that the different laboratories are capable of identifying E. faecalis and E. faecium.

Ventilator add-on for delivering PET tracer gases.

OBJECTIVES: The increasing use of PET for assessing cerebral blood flow, oxygen metabolism, and blood volume in critically ill patients has created a need for reliable technical solutions for delivering (15)O-tracer gases to mechanically ventilated subjects. Our objective was to create such a solution. METHODS: We designed a ventilator add-on unit that enables complex functional brain studies using labeled oxygen and carbon monoxide gases as tracers. The unit manages both steady-state and bolus inhalations, and the latter can be manually initiated using a remote trigger. All parts conducting breathing gases can be sterilized. The unit can be operated during both spontaneous pressure support breathing and volume-controlled ventilation. It supports the standard safety features and alarms of the ventilator and includes an overflow valve in the bolus reservoir. RESULTS: The count rate curves obtained using the new unit were similar to those from the standard bag-inhalation method. CONCLUSION: The unit we describe offers an economical and easily operated solution for providing uninterrupted ventilator treatment while performing PET brain studies, and the provided treatment meets intensive care criteria.