Transplantation of Human Neural Progenitor Cells (NPC) into Putamina of Parkinsonian Patients: A Case Series Study, Safety and Efficacy Four Years after Surgery.

Individuals with Parkinson's disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients' dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients' neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson's disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513.

Biodistribution and radiation dosimetry of [64Cu]copper dichloride: first-in-human study in healthy volunteers.

BACKGROUND: In recent years, Copper-64 (T1/2 = 12.7 h) in the chemical form of copper dichloride ([64Cu]CuCl2) has been identified as a potential agent for PET imaging and radionuclide therapy targeting the human copper transporter 1, which is overexpressed in a variety of cancer cells. Limited human biodistribution and radiation dosimetry data is available for this tracer. The aim of this research was to determine the biodistribution and estimate the radiation dosimetry of [64Cu]CuCl2, using whole-body (WB) PET scans in healthy volunteers. Six healthy volunteers were included in this study (3 women and 3 men, mean age ± SD, 54.3 ± 8.6 years; mean weight ± SD, 77.2 ± 12.4 kg). After intravenous injection of the tracer (4.0 MBq/kg), three consecutive WB emission scans were acquired at 5, 30, and 60 min after injection. Additional scans were acquired at 5, 9, and 24 h post-injection. Low-dose CT scan without contrast was used for anatomic localization and attenuation correction. OLINDA/EXM software was used to calculate human radiation doses using the reference adult model. RESULTS: The highest uptake was in the liver, followed by lower and upper large intestine walls, and pancreas, in descending order. Urinary excretion was negligible. The critical organ was liver with a mean absorbed dose of 310 ± 67 µGy/MBq for men and 421 ± 56 µGy/MBq for women, while the mean WB effective doses were 51.2 ± 3.0 and 61.8 ± 5.2 µSv/MBq for men and women, respectively. CONCLUSIONS: To the best of our knowledge, this is the first report on biodistribution and radiation dosimetry of [64Cu]CuCl2 in healthy volunteers. Measured absorbed doses and effective doses are higher than previously reported doses estimated with biodistribution data from patients with prostate cancer, a difference that could be explained not just due to altered biodistribution in cancer patients compared to healthy volunteers but most likely due to the differences in the analysis technique and assumptions in the dose calculation.

Positron range in tissue-equivalent materials: experimental microPET studies.

In this work an experimental investigation was carried out to study the effect that positron range has over positron emission tomography (PET) scans through measurements of the line spread function (LSF) in tissue-equivalent materials. Line-sources consisted of thin capillary tubes filled with (18)F, (13)N or (68)Ga water-solution inserted along the axis of symmetry of cylindrical phantoms constructed with the tissue-equivalent materials: lung (inhale and exhale), adipose tissue, solid water, trabecular and cortical bone. PET scans were performed with a commercial small-animal PET scanner and image reconstruction was carried out with filtered-backprojection. Line-source distributions were analyzed using radial profiles taken on axial slices from which the spatial resolution was determined through the full-width at half-maximum, tenth-maximum, twentieth-maximum and fiftieth-maximum. A double-Gaussian model of the LSFs was used to fit experimental data which can be incorporated into iterative reconstruction methods. In addition, the maximum activity concentration in the line-sources was determined from reconstructed images and compared to the known values for each case. The experimental data indicates that positron range in different materials has a strong effect on both spatial resolution and activity concentration quantification in PET scans. Consequently, extra care should be taken when computing standard-uptake values in PET scans, in particular when the radiopharmaceutical is taken up by different tissues in the body, and more even so with high-energy positron emitters.

Preparation and preclinical evaluation of (66)Ga-DOTA-E(c(RGDfK))2 as a potential theranostic radiopharmaceutical.

INTRODUCTION: Integrin αvß3 plays an important role in angiogenesis and is over-expressed in tumoral endothelial cells and some other tumor cells. RGD (Arg-Gly-Asn) peptides labeled with (68)Ga (t1/2=68min) have showed good characteristics for imaging of αvß3 expression using positron emission tomography (PET). Gallium-66 has been proposed as a PET imaging alternative to (68)Ga and given the unique high energy of its emitted positrons (Emax 4.15MeV) it may also be useful for therapy. The aim of this research is to prepare [(66)Ga]DOTA-E-[c(RGDfK)]2 and evaluate in mice its potential as a new theranostic radiopharmaceutical. METHODS: High specific activity (66)Ga was produced via the (66)Zn(p,n) reaction, and the labelling method of DOTA-E-[c(RGDfK)]2 with (66)Ga was optimized. Radiochemical purity was determined by TLC, and in vitro stability and protein binding were determined. Serial microPET imaging and biodistribution studies were carried out in nude mice bearing C6 xenografts. Radiation absorbed dose estimates were based on the biodistribution studies, where tumor and organs of interest were collected at 0.5, 1, 3, 5 and 24h post-injection of [(66)Ga]DOTA-E-[c(RGDfK)]2. RESULTS: Our results have shown that [(66)Ga]DOTA-E-[c(RGDfK)]2 can be prepared with high radiochemical purity (>97%), specific activity (36-67GBq/µmol), in vitro stability, and moderate protein binding. MicroPET imaging up to 24 post-injection showed contrasting tumors reflecting αvß3-targeted tracer accumulation. Biodistribution studies and dosimetry estimations showed a stable tumor uptake, rapid blood clearance, and favorable tumor-to-tissue ratios. CONCLUSIONS: The peptide conjugated DOTA-E-[c(RGDfK)]2 labeled with (66)Ga may be attractive as a theranostic agent for tumors over-expressing αvß3 integrins.

[Microbial interactions with heavy metals]. / Interacciones microbianas con metales pesados.

Living organisms are exposed in nature to heavy metals, commonly present in their ionized species. These ions exert diverse toxic effects on microorganisms. Metal exposure both selects and maintains microbial variants able to tolerate their harmful effects. Varied and efficient metal resistance mechanisms have been identified in diverse species of bacteria, fungi and protists. The study of the interactions between microorganisms and metals may be helpful to understand the relations of toxic metals with higher organisms such as mammals and plants. Some microbial systems of metal tolerance have the potential to be used in biotechnological processes, such as the bioremediation of environmental metal pollution or the recovery of valuable metals. In this work we analyze several examples of the interactions of different types of microbes with heavy metals; these cases are related either with basic research or with possible practical applications.

Sulphuric acid influence on liquid-liquid extraction of Co(II) and Zn(II) by MIBK from NH(4)SCN medium.

Liquid-liquid extraction of Co(II) and Zn(II) by methylisobutylcetone (MIBK) has been studied systematically from NH(4)SCN/H(2)SO(4) media. The influence of sulphuric acid concentration on the percentage of extraction of Co(II) and Zn(II) has been discussed. It is shown that sulphuric acid concentration has not the same effect on distribution curves of Co(II) and Zn(II). Thus, it is possible to have a separation of Zn(II) of Co(II) when [NH(4)SCN] is 0.5 mol l(-1) and [H(2)SO(4)] is about 2 mol l(-1). Under these conditions the separation factor (S(Zn/Co)) is around 580. The results are treated in terms of thermodynamic activities in aqueous phase, to determine the composition of the extracted complexes (M:SCN(-)) and to discuss the extraction mechanism.