Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution

Metaiodobenzylguanidine (MIBG) is an enzymatically stable synthetic analog of norepinephrine that when radiolabled with diagnostic ((123)I) or therapeutic ((131)I) isotopes has been shown to concentrate highly in sympathetically innervated tissues such as the heart and neuroendocrine tumors that possesses high levels of norepinephrine transporter (NET). As the transport of MIBG by NET is a saturable event, the specific activity of the preparation may have dramatic effects on both the efficacy and safety of the radiodiagnostic/radiotherapeutic. Using a solid labeling approach (Ultratrace), noncarrier-added radiolabeled MIBG can be efficiently produced. In this study, specific activities of >1200 mCi/micromol for (123)I and >1600 mCi/micromol for (131)I have been achieved. A series of studies were performed to assess the impact of cold carrier MIBG on the tissue distribution of (123/131)I-MIBG in the conscious rat and on cardiovascular parameters in the conscious instrumented dog. The present series of studies demonstrated that the carrier-free Ultratrace MIBG radiolabeled with either (123)I or (131)I exhibited similar tissue distribution to the carrier-added radiolabeled MIBG in all nontarget tissues. In tissues that express NETs, the higher the specific activity of the preparation the greater will be the radiopharmaceutical uptake. This was reflected by greater efficacy in the mouse neuroblastoma SK-N-BE(2c) xenograft model and less appreciable cardiovascular side-effects in dogs when the high-specific-activity radiopharmaceutical was used. The increased uptake and retention of Ultratrace (123/131)I-MIBG may translate into a superior diagnostic and therapeutic potential. Lastly, care must be taken when administering therapeutic doses of the current carrier-added (131)I-MIBG because of its potential to cause adverse cardiovascular side-effects, nausea, and vomiting

Spherical Categories

This paper is a study of monoidal categories with duals where the tensor product need not be commutative. The motivating examples are categories of representations of Hopf algebras and the motivating application is the definition of 6j-symbols as used in topological field theories. We introduce the new notion of a spherical category. In the first section we prove a coherence theorem for a monoidal category with duals following MacLane (1963). In the second section we give the definition of a spherical category, and construct a natural quotient which is also spherical. In the third section we define spherical Hopf algebras so that the category of representations is spherical. Examples of spherical Hopf algebras are involutory Hopf algebras and ribbon Hopf algebras. Finally we study the natural quotient in these cases and show it is semisimple.Comment: 16 pages. Minor correction

Phosphorylation of calmodulin by plasma-membrane-associated protein kinase(s)

Now known as FEBS Journal: Open Access content older than 1 year.Plasma-membrane-associated protein kinase(s) from normal rat liver phosphorylates exogenous bovine brain calmodulin in the absence of Ca2+ and in the presence of histone or poly(L-lysine). Maximum levels of calmodulin phosphorylation are obtained at a poly(L-lysine)/calmodulin molar ratio of 0.4. Phosphoamino acid analysis revealed that calmodulin is phosphorylated on serine, threonine and tyrosine residues. Endogenous plasma-membrane-associated calmodulin was also phosphorylated by plasma-membrane-associated protein kinase(s) in the absence of added cationic protein or polypeptide. The identity of endogenous phosphocalmodulin was confirmed by immunoprecipitation with a specific anti-calmodulin monoclonal antibody. Ehrlich ascites tumor cell plasma membranes do not contain endogenous calmodulin. However, membrane-associated protein kinase(s) from these tumor cells phosphorylates bovine brain calmodulin in the presence of poly(L-lysine). These data demonstrate that phosphocalmodulin is present in liver plasma membranes and suggest that this post-translational modification could have a physiological role in this location.This work was supported by Grants to A. V. from the Comisión lnterministerial de Ciencia y Tecnología (SAF392/93), from the Conejería de Educucición de la Comunidad de Madrid (AE16/94), and from the Direccición General de Investigaciones Científicas y Técnicas (PR94-343) (Spain), and Grant to D. B. S. from the National Institutes of Health (DK43682) (USA). A. B. is the recipient of a predoctoral fellowship from the Departamento de Educación, Universidades e Investigación del Gobierno Vasco (Spain). M. S. is the recipient of a postdoctoral fellowship from the Consejo Superior de Investigaciones Científicas (Spain). J. L. J. is the recipient of a postdoctoral fellowship (DK09062) from the National Institutes of Health (USA).Peer Reviewe

Data from: Population size is weakly related to quantitative genetic variation and trait differentiation in a stream fish

How population size influences quantitative genetic variation and differentiation among natural, fragmented populations remains unresolved. Small, isolated populations might occupy poor quality habitats and lose genetic variation more rapidly due to genetic drift than large populations. Genetic drift might furthermore overcome selection as population size decreases. Collectively, this might result in directional changes in additive genetic variation (VA) and trait differentiation (QST) from small to large population size. Alternatively, small populations might exhibit larger variation in VA and QST if habitat fragmentation increases variability in habitat types. We explored these alternatives by investigating VA and QST using nine fragmented populations of brook trout varying 50-fold in census size N (179-8416) and 10-fold in effective number of breeders, Nb (18-135). Across 15 traits, no evidence was found for consistent differences in VA and QST with population size and almost no evidence for increased variability of VA or QST estimates at small population size. This suggests that (i) small populations of some species may retain adaptive potential according to commonly adopted quantitative genetic measures and (ii) populations of varying sizes experience a variety of environmental conditions in nature, however extremely large studies are likely required before any firm conclusions can be made

R code for animal models and statistical analyses

Examples of R code specifying animal models to estimate quantitative genetic parameters and QST using the software package "MCMCglmm", as well as code for generating the posterior distribution of Pearson's correlation coefficient and for simple and partial Mantel tests (software package "vegan")

Trait measurements and pedigrees for Cape Race brook trout populations

Individual trait measurements and pedigrees used in animal models to estimate quantitative genetic parameters for fifteen traits for nine brook trout populations from Cape Race, Newfoundland, Canada