Abstract The increased demand for molecular imaging tracers useful in assessing and monitoring diseases has stimulated research towards more efficient and flexible radiosynthetic routes, including ...newer technologies. The traditional vessel-based approach suffers from limitations concerning flexibility, reagent mass needed, hardware requirements, large number of connections and valves, repetitive cleaning procedures and overall big footprint to be shielded from radiation. For these reasons, several research groups have started to investigate the application of the fast growing field of microfluidic chemistry to radiosynthetic procedures. After the first report in 2004, many scientific papers have been published and demonstrated the potential for increased process yields, reduced reagent use, improved flexibility and general ease of setup. This review will address definitions occurring in microfluidics as well as analyze the different approaches under two macro-categories: microvessel and microchannel. In this perspective, several works will be collected, involving the use of positron emitting species (11 C,18 F,64 Cu) and the fewer examples of gamma emitting radionuclides (99m Tc,125/131 I). New directions in microfluidic research applied to PET radiochemistry, future developments and challenges are also discussed.
Complement factor H (FH) is a major regulator of the complement alternative pathway, its mutations predispose to an uncontrolled activation in the kidney and on blood cells and to secondary C3 ...deficiency. Plasma exchange has been used to correct for FH deficiency and although the therapeutic potential of purified FH has been suggested by in vivo experiments in animal models, a clinical approved FH concentrate is not yet available. We aimed to develop a purification process of FH from a waste fraction rather than whole plasma allowing a more efficient and ethical use of blood and plasma donations.IntroductionComplement factor H (FH) is a major regulator of the complement alternative pathway, its mutations predispose to an uncontrolled activation in the kidney and on blood cells and to secondary C3 deficiency. Plasma exchange has been used to correct for FH deficiency and although the therapeutic potential of purified FH has been suggested by in vivo experiments in animal models, a clinical approved FH concentrate is not yet available. We aimed to develop a purification process of FH from a waste fraction rather than whole plasma allowing a more efficient and ethical use of blood and plasma donations.Waste fractions from industrial plasma fractionation (pooled human plasma) were analyzed for FH content by ELISA. FH was purified from unused fraction III and its decay acceleration, cofactor, and C3 binding capacity were characterized in vitro. Biodistribution was assessed by high-resolution dynamic PET imaging. Finally, the efficacy of the purified FH preparation was tested in the mouse model of C3 glomerulopathy (Cfh-/- mice).MethodsWaste fractions from industrial plasma fractionation (pooled human plasma) were analyzed for FH content by ELISA. FH was purified from unused fraction III and its decay acceleration, cofactor, and C3 binding capacity were characterized in vitro. Biodistribution was assessed by high-resolution dynamic PET imaging. Finally, the efficacy of the purified FH preparation was tested in the mouse model of C3 glomerulopathy (Cfh-/- mice).Our purification method resulted in a high yield of highly purified (92,07%), pathogen-safe FH. FH concentrate is intact and fully functional as demonstrated by in vitro functional assays. The biodistribution revealed lower renal and liver clearance of human FH in Cfh-/- mice than in wt mice. Treatment of Cfh-/- mice documented its efficacy in limiting C3 activation and promoting the clearance of C3 glomerular deposits.ResultsOur purification method resulted in a high yield of highly purified (92,07%), pathogen-safe FH. FH concentrate is intact and fully functional as demonstrated by in vitro functional assays. The biodistribution revealed lower renal and liver clearance of human FH in Cfh-/- mice than in wt mice. Treatment of Cfh-/- mice documented its efficacy in limiting C3 activation and promoting the clearance of C3 glomerular deposits.We developed an efficient and economical system for purifying intact and functional FH, starting from waste material of industrial plasma fractionation. The FH concentrate could therefore constitute possible treatments options of patients with C3 glomerulopathy, particularly for those with FH deficiency, but also for patients with other diseases associated with alternative pathway activation.ConclusionWe developed an efficient and economical system for purifying intact and functional FH, starting from waste material of industrial plasma fractionation. The FH concentrate could therefore constitute possible treatments options of patients with C3 glomerulopathy, particularly for those with FH deficiency, but also for patients with other diseases associated with alternative pathway activation.
Abstract Objective An increasing number of epidemiological studies suggest that chronic low-dose irradiation increases the risk of atherosclerosis. We evaluated and compared the in vitro biological ...effects of both single and fractionated low-doses of X-ray irradiation on endothelial cells. Methods Human umbilical vein endothelial cells (HUVECs) were irradiated with X-rays, with single doses of 0.125, 0.25 and 0.5 Gy or fractionated doses of 2 × 0.125 Gy and 2 × 0.25 Gy, with 24 h interfraction interval. Survival, apoptosis, reactive oxygen species (ROS) production, nuclear factor-κB (NF-κB) activation, intercellular adhesion molecule-1 (ICAM-1) expression, HUVEC adhesiveness and DNA damage were investigated. Results We did not observe any effect on viability and apoptosis. Both single and fractionated doses induced ROS generation, NF-κB activation, ICAM-1 protein expression and HUVEC adhesiveness, but only fractionated doses increase significantly ICAM-1 mRNA. The effects measured after fractionated dose result always higher than those induced by the single dose. Moreover, we observed that DNA double strand break (DSB), visualized with γ-H2AX foci, is dose-dependent and that the kinetics of γ-H2AX foci is not affected by fractionated doses. Conclusions We showed that single and fractionated low-dose irradiations with low energy X-rays do not affect cell viability and DNA repair. Interestingly, the greater increase of ICAM-1 surface exposure and endothelial adhesiveness observed after fractionated irradiation, suggests that fractionated low-doses may accelerate chronic vascular inflammation, from which the atherosclerotic process can arise.
Objectives
The aim of the study is the assessment of Nadale 1, a Neanderthal deciduous tooth recently discovered in Northeastern Italy in the De Nadale cave (Middle Palaeolithic). Together with the ...clear archaeological context of the site, this study brings new insight on Neanderthal behavior and dental morphological variability.
Materials and methods
We used microCT data to provide a morphological description and morphometric analysis (diameter measurements and dental tissue volumes) of the Nadale 1 human tooth. Microwear analysis, taphonomical investigation and caries identification were performed using a stereomicroscope and Scanning Electron Microscope.
Results
In terms of morphology (i.e., incipient tuberculum molare, marked mesial marginal ridge and well‐developed mid‐trigonid crest connecting the protoconid and the metaconid, deep anterior fovea) and size, Nadale 1 presents features frequently observed in Neanderthal lower first deciduous molars. Microscope investigations reveal the presence of a small pit which could be correlated to an incipient caries.
Conclusion
Nadale 1 expands the Italian Middle Palaeolithic fossil record and provides further information on Neanderthal dm1s in terms of dimensional and morphological variability. Furthermore, the presence of an incipient caries brings further data on Neanderthal diet.
Obesity and diabetes associate with neurodegeneration. Brain glucose and BDNF are fundamental in perinatal development. BDNF is related to brain health, food intake and glucose metabolism. We ...characterized the relationship between glycemia and/or brain glucose utilization (by 18FDG-PET during fasting and glucose loading), obesity and BDNF in 4-weeks old (pre-obese) and 12-weeks old (obese) Zucker fa/fa rats, and their age-matched fa/+ controls. In 75 human infants, we assessed cord blood BDNF and glucose levels, appetite regulating hormones, body weight and maternal factors. Young and adult fa/fa rats showed glucose intolerance and brain hyper-utilization compared to controls. Glycemia and age were positively related to brain glucose utilization, and were negative predictors of BDNF levels. In humans, fetal glycemia was dependent on maternal glycemia at term, and negatively predicted BDNF levels. Leptin levels were associated with higher body weight and lower BDNF levels. Glucose intolerance and elevated brain glucose utilization already occur in young, pre-obese rats, suggesting that they precede obesity onset in Zucker fatty rats. Glycemic elevation and brain glucose overexposure predict circulating BDNF deficiency since perinatal and early life. Future studies should evaluate whether the control of maternal and fetal glycemia during late intrauterine development can prevent these unfavorable interactions.
Abstract Computed Tomography (CT) has long been used for investigating palaeontological specimens, as it is a nondestructive technique which avoids the need to dissolve or ionize the fossil sample. ...However, Magnetic Resonance Spectroscopy (MRS) and Magnetic Resonance Imaging (MRI) have recently gained ground as analytical tools for examination of palaeontological samples, by nondestructively providing information about the structure and composition of fossils. While MRI techniques are able to reveal the three-dimensional geometry of the trace fossil, MRS can provide information on the chemical composition of the samples. The multidimensional nature of MR (Magnetic Resonance) signals has potential to provide rich three-dimensional data on the palaeontological specimens and also to help in elucidating paleopathological and paleoecological questions. In this work the verified applications and the emerging uses of MRI and MRS in paleontology are reviewed, with particular attention to fossil spores, fossil plants, ambers, fossil invertebrates, and fossil vertebrates studies.
We have developed an integrated microfluidic platform for producing 2-(18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) in continuous flow from a single bolus of radioactive isotope solution, with constant ...product yields achieved throughout the operation that were comparable to those reported for commercially available vessel-based synthesisers (40-80%). The system would allow researchers to obtain radiopharmaceuticals in a dose-on-demand setting within a few minutes. The flexible architecture of the platform, based on a modular design, can potentially be applied to the synthesis of other radiotracers that require a two-step synthetic approach, and may be adaptable to more complex synthetic routes by implementing additional modules. It can therefore be employed for standard synthesis protocols as well as for research and development of new radiopharmaceuticals.
Aims/hypothesis
Maternal obesity negatively affects fetal development. Abnormalities in brain glucose metabolism are predictive of metabolic–cognitive disorders.
Methods
We studied the offspring ...(aged 0, 1, 6, 12 months) of minipigs fed a normal vs high-fat diet (HFD), by positron emission tomography (PET) to measure brain glucose metabolism, and ex vivo assessments of brain insulin receptors (IRβ) and GLUT4.
Results
At birth, brain glucose metabolism and IRβ were twice as high in the offspring of HFD-fed than control mothers. During infancy and youth, brain glucose uptake, GLUT4 and IRβ increased in the offspring of control mothers and decreased in those of HFD-fed mothers, leading to a 40–85% difference (
p
< 0.05), and severe glycogen depletion, lasting until adulthood.
Conclusions/interpretation
Maternal high-fat feeding leads to brain glucose overexposure during fetal development, followed by long-lasting depression in brain glucose metabolism in minipigs. These features may predispose the offspring to develop metabolic–neurodegenerative diseases.
Abstract Introduction The diffusion of PET as a pivotal molecular imaging modality has emphasized the need for new positron-emitting radiotracers to be used in diagnostic applications and research. ...Microfluidic represents an innovative approach, owing to its potential to increase radiochemical productivity in terms of yields, time reduction, precursor consumption and flexible experimental planning. Methods We focused on fluorine-18 labeling and used a microfluidic platform to perform sequential reactions, by using the same batch of18 F-labeling solution on one or more substrates, during the same experimental session. A solid-phase extraction (SPE) workup procedure was also implemented in the system to provide a repeatable purification step. Results We were able to quickly optimize the conditions for labeling of ethyl and propyl ditosylate and of a new cannabinoid type 2 (CB2) receptor agonist, CB41. In all substrates, we obtained good incorporation yields (60% to 85%) in short (<90 s) reaction times. Single dosages of the CB2 ligand were sequentially prepared, upon request, in satisfactory quantities and purity for small animal PET scanning. Conclusion This work demonstrates the usefulness of a microfluidic-based system for a rapid optimization of temperature, flow rate of reactants and their relative ratio in the labeling of different precursors by using the same18 F-fluoride batch. This approach was used to obtain in sequence several injectable doses of a novel CB2 ligand, thus providing the proof of principle that microfluidic systems permit a dose-on-demand production of new radiotracers.
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