Dosimetry of copper-64-labeled monoclonal antibody 1A3 as determined by PET imaging of the torso

We present biodistribution and dosimetry results for 64Cu-benzyl-TETA-MAb 1A3 from 15 human subjects injected with this tracer as determined by serial PET imaging of the torso. METHODS: PET imaging was used to quantify in vivo tracer biodistribution at two time points after injection. Absorbed dosimetry calculated using MIRD-11 and the updated MIRDOSE3 was compared with estimates obtained using rat biodistribution data. RESULTS: By measuring activity concentrations in the torso, and extrapolating for the whole body using standard organ and tissue volumes, we were able to account for 93% of the injected radiopharmaceutical over a range of imaging times from 0 to 36 hr postinjection. Based on PET imaging and the MIRD-11 schema, the liver and spleen are the critical organs with average absorbed doses of 0.12 and 0.10 mGy/MBq (0.44 and 0.39 rad/mCi). The revised MIRDOSE3 scheme yields similar values for these and other organs but also results in a dose of 0.14 mGy/MBq (0.53 rad/mCi) to the heart wall. In the rat, the large intestine is the critical organ at 0.14 mGy/MBq (0.52 rad/mCi), while liver and kidneys each receive 0.11 mGy/MBq (0.41 rad/mCi). Some disparities in absorbed doses determined by these methods are evident but are a result of dissimilar biodistributions in rats and humans. For most organs, rat extrapolated values are higher than the human measurements with PET. CONCLUSION: This study shows that torso PET imaging can quantitatively measure the whole-body biodistribution of a radiopharmaceutical as long as it has relatively slow pharmacokinetics.     

Superiority of hyperpolarizing to depolarizing cardioplegia in protection of coronary endothelial function

A sensitive, selective, and specific assay was needed to study the degradation kinetics of taurolidine and its stabilization by polyvinylpyrrolidone (PVP). The purpose of the present study was to evaluate the usefulness of the chromotropic acid method and other formaldehyde or amine derivatization methods. The methods evaluated included formaldehyde derivatization with chromotropic acid, acetylacetone, 4-amino-5-hydrazino-3-mercapto-1,2,4-triazole, semicarbazide hydrochloride, or 2,4-dinitrophenylhydrazine and taurolidine decomposition product derivatization with dansylchloride or 7-chloro-4-nitrobenz-2-oxa-1,3-diazole chloride. Results indicated that the chromotropic acid method provided sufficient selectivity, reproducibility and sensitivity. It was able to quench taurultam decomposition and avoided PVP interference. The method was optimized by performance based selection of reagent lots, appropriate reagent storage and preparation, and controlled derivatization conditions. In conclusion, the optimized chromotropic method was the most appropriate method for quantitating taurolidine decomposition.     

Prion diseases: transmission from mad cows?

Prion diseases in humans show considerable clinical and pathological heterogeneity. The identification of a new variant of Creutzfeldt-Jakob disease, and its interpretation as evidence of transmission of mad cow disease to man, rely critically on our understanding of the epidemiology of prion diseases.     

Distinctive forms of partial retrograde amnesia after asymmetric temporal lobe lesions: possible role of the occipitotemporal gyri in memory

We tested the hypothesis that partial forms of retrograde amnesia were associated with highly asymmetric lesions to the inferior and anterior-medial temporal lobe. Postencephalitic subjects EK and DR were both impaired on standardized retrograde memory tests, but showed strikingly different profiles in cognitive tasks of name stem completion, name:face matching, temporal ordering, forced choice recognition, and occupational judgments of famous names and faces from the past 3 decades. EK sustained left inferior and anterior-medial temporal lobe lesion with a small right temporal polar lesion, and showed near-complete loss of retrieval, knowledge, and familiarity associated with famous names but minimal deficiencies with famous faces. DR sustained right inferior and anterior-medial temporal lobe lesion and showed a milder retrograde loss limited to utilizing famous face prompts in name stem completion, name:face matching, occupational judgments, and forced choice recognition. These impairments were also different from the memory retrieval deficit, but intact recognition shown by a case of ruptured anterior communicating artery aneurysm with presumed basal forebrain damage. We hypothesize that EK's extensive loss of famous name knowledge was related to left inferior temporal lobe damage, particularly in the lateral and medial occipitotemporal gyri. This region in the left temporal lobe may serve as a critical processing area for retrograde memory that permits activation of established semantic, temporal, and visual (i.e., facial) associations biographically dependent on the category of proper names. On the basis of connectional anatomy patterns in the nonhuman primate, this region receives extensive hippocampal output and is interconnected with the temporal polar region and cortical association areas, which have been implicated in retrieval and storage aspects of retrograde memory. In the right hemisphere, the occipitotemporal gyri may serve an important role in famous face processing as part of a bilateral neural network.     

Development of recombinant adenoviruses that drive high level expression of the human metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 genes: characterization of their infection into rabbit smooth muscle cells and human MCF-7 adenocarcinoma cells

Remodelling of the extracellular matrix resulting from increased secretion of metalloproteinase enzymes (MMPs) is implicated in many pathological conditions, including rheumatoid arthritis, restenosis following balloon angioplasty, atherosclerosis and cancer cell invasion and metastasis. Clear definition of the normal and pathological function of individual MMPs will benefit from approaches that use gene transfer to produce increases in MMP levels that mimic those observed in pathological conditions. Similarly, gene transfer methods leading to controlled increases in levels of the tissue inhibitor of metalloproteinases (TIMPs) will help to define the function of MMPs both in vitro and in vivo. Gene transfer of TIMPs may also have therapeutic potential in pathological conditions where inhibition of MMP activity may be beneficial. We have used the adenovirus serotype 5 vector system to generate replication-deficient recombinant adenoviruses capable of expressing the MMP-9, TIMP-1 or -2 genes. High level expression is driven by the cytomegalovirus major immediate early promoter (CMV IEP). Efficient and selective over-production of each recombinant protein was shown by immunofluorescence in either rabbit smooth muscle cells (SMC) or human MCF-7 adenocarcinoma cells. High level secretion directly dependent on the multiplicity of infection (MOI) was observed for each functional transgene by gelatin zymography. Using a quantitative ELISA assay, levels of recombinant TIMP-1 were detected when SMC were infected with as low as three plaque forming units (pfu) of virus per cell in vitro. A linear increase in TIMP-1 secretion was observed up to 1000 pfu/cell of virus (0.75 ng/10(4) cells/24 h at 3 pfu/cell to 1243 ng/10(4) cells/24h at 1000 pfu/cell). Similar levels of secretion of MMP-9 and TIMP-2 were observed by Western blot analysis using the same MOI of adenovirus. Thus, recombinant adenoviruses are an efficient and flexible system for high level expression of MMPs and TIMPs and will be useful tools in the study of matrix remodelling in vivo and in vitro.     

Differentiation of Mycoplasma hyopneumoniae, M flocculare, and M hyorhinis on the basis of amplification of a 16S rRNA gene sequence

Cell damage is caused by energy depletion or by direct membrane damage, or a combination when a direct membrane damage affects energy depleted cells. In this report it was investigated whether the extent of direct membrane damage induced by lysophosphatidyl choline (LPC) or phospholipase C (PhC) on quiescent fibroblasts depended on the metabolic state of the cells. When glycolysis was inhibited cell damage was always extensively increased, whereas cell damage was also increased to a minor degree when exposed to PhC during sole inhibition of oxidative phosphorylation. Acceleration of glycolysis in cells with a low rate of glycolysis resulted in a dramatic improvement of the membrane susceptibility within a few minutes. Thus, susceptibility of the cell membrane to direct membrane damage depends on the metabolic state. The results also emphasize previous findings that glycolysis has a special role in maintaining membrane function and integrity.     

Selective inhibition of [D-Ala2, Glu4]deltorphin antinociception by supraspinal, but not spinal, administration of an antisense oligodeoxynucleotide to an opioid delta receptor

Evidence in vivo has suggested the existence of subtypes of the delta opioid receptor (DOR), which have been termed delta 1 and delta 2. These proposed DOR subtypes are thought to be activated by [D-Pen2, D-Pen5]enkephalin (DPDPE, delta 1) and [D-Ala2, Glu4]deltorphin (delta 2). Recent work in which an antisense oligodeoxynucleotide (oligo) to a cloned DOR was administered by the intrathecal (i.th.) route has demonstrated a reduction in the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin, but not of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO, mu agonist) in mice. The present investigation has extended these observations by administering the same DOR antisense oligo sequence by the intracerebroventricular (i.c.v.) route and evaluating the antinociceptive actions of i.c.v. agonists selective for delta, mu and kappa receptors. I.th. treatment with DOR antisense oligo, but not mismatch oligo, significantly inhibited the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin but not of i.th. DAMGO or U69,593 (kappa agonist), confirming previous data. In contrast, i.c.v. DOR antisense oligo, but not mismatch oligo, selectively inhibited the antinociceptive response to i.c.v. [D-Ala2, Glu4]deltorphin without altering the antinociceptive actions of i.c.v. DPDPE, DAMGO or U69,593. The data suggest that the cloned DOR corresponds to that pharmacologically classified as delta 2 and further, suggest that this delta receptor subtype may play a major role in eliciting spinal delta-mediated antinociception.