Radiological studies of fetal alcohol spectrum disorders in humans and animal models: an updated comprehensive review

Fetal Alcohol Spectrum Disorders encompass a wide range of birth defects in children born to mothers who consumed alcohol during pregnancy. Typical mental impairments in FASD include difficulties in life adaptation and learning and memory, deficits in attention, visuospatial skills, language and speech disabilities, mood disorders and motor disabilities. Multimodal imaging methods have enabled in vivo studies of the teratogenic effects of alcohol on the central nervous system, giving more insight into the FASD phenotype. This paper offers an up-to-date comprehensive review of radiological findings in the central nervous system in studies of prenatal alcohol exposure in both humans and translational animal models, including Magnetic Resonance Imaging, Computed Tomography, Positron Emission Tomography, Single Photon Emission Tomography and Ultrasonography. (C) 2017 Elsevier Inc. All rights reserved

EphA2 as a Diagnostic Imaging Target in Glioblastoma: A Positron Emission Tomography/Magnetic Resonance Imaging Study

Noninvasive imaging is a critical technology for diagnosis, classification, and subsequent treatment planning for patients with glioblastoma. It has been shown that the EphA2 receptor tyrosine kinase (RTK) is overexpressed in a number of tumors, including glioblastoma. Expression levels of Eph RTKs have been linked to tumor progression, metastatic spread, and poor patient prognosis. As EphA2 is expressed at low levels in normal neural tissues, this protein represents an attractive imaging target for delineation of tumor infiltration, providing an improved platform for image-guided therapy. In this study, EphA2-4B3, a monoclonal antibody specific to human EphA2, was labeled with Cu-64 through conjugation to the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The resulting complex was used as a positron emission tomography (PET) tracer for the acquisition of high-resolution longitudinal PET/magnetic resonance images. EphA2-4B3-NOTA-Cu-64 images were qualitatively and quantitatively compared to the current clinical standards of [F-18] FDOPA and gadolinium (Gd) contrast-enhanced MRI. We show that EphA2-4B3-NOTA-Cu-64 effectively delineates tumor boundaries in three different mouse models of glioblastoma. Tumor to brain contrast is significantly higher in EphA2-4B3-NOTA-Cu-64 images than in [F-18] FDOPA images and Gd contrast-enhanced MRI. Furthermore, we show that nonspecific uptake in the liver and spleen can be effectively blocked by a dose of nonspecific (isotype control) IgG

The Evolution of Fangs, Venom, and Mimicry Systems in Blenny Fishes

Venom systems have evolved on multiple occasions across the animal kingdom, and they can act as key adaptations to protect animals from predators. Consequently, venomous animals serve as models for a rich source of mimicry types, as non-venomous species benefit from reductions in predation risk by mimicking the coloration, body shape, and/or movement of toxic counterparts. The frequent evolution of such deceitful imitations provides notable examples of phenotypic convergence and are often invoked as classic exemplars of evolution by natural selection. Here, we investigate the evolution of fangs, venom, and mimetic relationships in reef fishes from the tribe Nemophini (fangblennies). Comparative morphological analyses reveal that enlarged canine teeth (fangs) originated at the base of the Nemophini radiation and have enabled a micropredatory feeding strategy in non-venomous Plagiotremus spp. Subsequently, the evolution of deep anterior grooves and their coupling to venom secretory tissue provide Meiacanthus spp. with toxic venom that they effectively employ for defense. We find that fangblenny venom contains a number of toxic components that have been independently recruited into other animal venoms, some of which cause toxicity via interactions with opioid receptors, and result in a multifunctional biochemical phenotype that exerts potent hypotensive effects. The evolution of fangblenny venom has seemingly led to phenotypic convergence via the formation of a diverse array of mimetic relationships that provide protective (Batesian mimicry) and predatory (aggressive mimicry) benefits to other fishes. Our results further our understanding of how novel morphological and biochemical adaptations stimulate ecological interactions in the natural world

Effects of streptozotocin-induced diabetes on neural sigma receptors in the rat brain

To study the effect of diabetes mellitus on the density of sigma receptors, in vitro binding experiments were conducted in whole brain homogenate membranes of 5-week and 10-week control rats and streptozotocin (STZ)-induced diabetic rats. sigma-1 Receptors were labelled with [H-3](+)-pentazocine while sigma-2 receptors were labelled with [H-3] 1,3-di-o-tolylguanidine (DTG) in the presence of 0.5 mu M (+)-pentazocine to mask sigma-1 sites. Non-specific binding was determined in the presence of 20 mu M haloperidol. Scatchard analysis revealed a 27% (

Synthesis and preliminary evaluation of [123I]1-(4-cyanobenzyl)-4-[[(trans-iodopropen-2-yl)oxy]-methyl]piperidine: A novel high affinity sigma receptor radioligand for SPECT

1-(4-Cyanobenzyl)-4-[[(trans-iodopropen-2-yl)oxy]methyl]piperidine ((2) under bar) has been synthesized as a novel iodinated ligand for sigma receptors. This new compound exhibited high affinity (K-i = 0.38 nM) for the sigma-1 receptor and selectivity for sigma-1 vs, sigma-2 receptors (K-i sigma-1/sigma 0-2 = 0.02) using in vitro receptor binding assays, Moderate affinity for muscarinic M(1) (K-1 = 322 nM) and M(2) (K-1 = 1.78 nM) receptors and low affinity (K-i = 1,460 nM) for dopamine D-2, receptors was also noted. The lipophilicity of 2 (log P-7.5 = 3.24) is moderate, indicating that the ligand should readily cross the blood/brain barrier. The corresponding radioiodinated ligand,123I-(2) under bar, was synthesized from the appropriate trans vinyl tributylstan-nane precursor under acidic conditions using oxidative iododestannylation methods. HPLC purification provided the radioligand in yields ranging between 63 and 75% EOS (n = 5) and with > 99% radiochemical purity and a specific activity > 77,000 MBq/mu mol

Rare specimen identification in an un-integrated taxonomy: implications of DNA sequences from a Taiwanese Philine (Mollusca, Philinidae)

Many species of the gastropod genus Philine have been named from northeastern Asia but scanty descriptions based predominantly on shells make it difficult to determine which are valid. This, plus the sporadic anatomical and genetic information available for many of these species has led to what may be described as an un-integrated taxonomy. In this situation, it is generally preferable to postpone dissection of rare and unusual specimens until relevant diagnostic characters can be established in broader studies. Micro-CT scanning and DNA sequencing were used to examine such a specimen collected recently from deep waters off northeastern Taiwan. Micro-CT examination of the morphology of the internal shell and gizzard plates suggested that, among named species, the sequenced specimen is most similar to P. otukai. It cannot, however, be definitively referred to P. otukai as that species lacks adequate anatomical description or known DNA sequences. Phylogenetic analyses of newly collected DNA sequences show the specimen to be most closely related to, but distinct from the northern Atlantic Ocean and Mediterranean species, Philine quadripartita. The sequences also confirm genetically that five or more species of Philine occur in northeast Asia, including at least three subject to considerable taxonomic uncertainty

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats

Chronic hypoxia induces an overall sympathetic hyperactivation associated with a myocardial beta-receptor desensitization. The mechanisms involved in this desensitization were evaluated in 32 male Wistar rats kept in a hypobaric pressure chamber (Po-2 = 40 Torr, atmospheric pressure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditions, plasma norepinephrine (NE) levels were higher(2.1 +/- 0.7 vs. 0.6 +/- 0.2 ng/ml) with no difference in the plasma epinephrine levels (2.2 +/- 0.7 vs. 1.8 +/- 0.3 ng/ml). In hypoxia neuronal NE uptake measured by [H-3]NE was decreased by 32% in the right ventricle (RV) and by 35% in the left ventricle (LV), and [H-3]mazindol in vitro binding showed a decrease in uptake-1 carrier protein density by 38% in the RV and by 41% in the LV. In vitro binding assays with [H-3]CGP-12177 indicate beta-adrenoceptor density reduced by 40% in the RV and by 32% in the LV, and this was due to reduced beta(1)-subtype fraction (competition binding experiments with practolol). Hypoxia reduced the production of cAMP induced by isoproterenol (36% decrease in the RV and 41% decrease in the LV), 5'-guanylylimododiphosphate (40% decrease in the RV and 42% decrease in the LV), and forskolin (39% decrease in the RV and 41% decrease in the LV) but did not alter the effect of MnCl2 and NaF. Quantitation of inhibitory G-protein alpha-subunit by immunochemical analysis showed a 46% increase in the cardiac-specific isoform Gi(alpha 2) in hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia leads to changes in pre- and postsynaptic myocardial adrenergic function. The myocardial desensitization associated with both a reduction in externalized beta(1)-adrenoceptor and an increase in inhibitory G-protein subunit may be caused by increased synaptic NE levels due to impaired uptake-1 system

Kinetics of the norepinephrine analog [76Br]-metabromobenzylguanidine in isolated working rat heart

A related set of kinetic studies of the norepinephrine analog [Br-76]-meta-bromobenzylguanidine (MBBG) were performed with an isolated working rat heart preparation. A series of constant infusion studies over a wide range of MBBG concentrations allowed estimation of the Michaelis-Menten constants for transport by the neuronal norepinephrine transporter (uptake(1)) and the extraneuronal uptake system (uptake(2)). Pharmacological blocking studies with inhibitors of uptake(1), uptake(2) and vesicular uptake were performed to delineate the relative importance of these norepinephrine handling mechanisms on the kinetics of MBBG in the rat heart. Bolus injection studies were done to assess the ability of compartmental modeling techniques to characterize the kinetics of MBBG. These studies demonstrate that MBBG shares many of the same uptake mechanisms as norepinephrine in the rat heart. PET imaging studies with MBBG would be useful for assessing sympathetic nerve status in the living human heart. (C) 1998 Elsevier Science Inc

Pharmacological evaluation of (+)-2-[123I]A-69024 A radioligand for in vivo studies of dopamine D1 receptors

(+)-2-[ I-123]A-69024, [(+)-1-(2-[I-123]iodo-4,5-dimethoxy-benzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline]. is a specific acid enantioselective dopamine D1 receptor radioligand. The in vivo biodistribution of this radioligand in rats showed high brain uptake and a distribution consistent with the density of dopamine D1 receptors. Highest uptake was observed in the striatum (0.65 %ID/g) at 5 min followed by clearance, As a measure of specificity the striatum/cerebellar ratio reached a maximum of 3.9 at 30 min post-injection. Radioactivity in the striatum was reduced by 68% by pre-administration of the D1 antagonist SCH 23390. Pre-administration of other dopamine binding drugs, spiperone (D2), 7-OH-DPAT (D3), and clozapine (D4) displayed no inhibitory effect on (+)2-[I-123]A-69024 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C) and haloperidol (D2 receptor antagonist/sigma receptor ligand) also displayed no inhibitory effect in any brain region studied. With the pharmacologically inactive enantiomer, (-)-2-[I-123]A-69024. the brain uptake was determined to be non-specific since a striatum/cerebellar ratio of near 1 was observed throughout the time course of the experiment. (+)-2-[I-123]A-69024 displays enantioselectivity for dopamine D1 receptors and may deserve further investigation as a possible SPECT radioligand, (C) 2001 Elsevier Science Inc. All rights reserved

In vitro and in vivo characterisation of [3H]ANSTO-14 binding to the σ1 binding sites

ABSTRACT. N-(4-phenylbutyl)-3-hydroxy-4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane (ANSTO-14) showed the highest activity for the σ1 site ( Ki=9.4 nM) and 19-fold σ1/σ2 selectivity. The present study showed that [3H]ANSTO-14 binds to a single high-affinity site in guinea pig brain membranes with an equilibrium Kd of 8.0 ± 0.3 nM, in good agreement with the kinetic studies ( Kd=13.3±5.4 nM, n=4), and a Bmax of 3,199 ± 105 fmol/mg protein ( n=4). The in vivo biodistribution of [3H]ANSTO-14 showed a high uptake in the diencephalon. Pretreatment of rats with σ ligands including (+)-pentazocine (σ1), ANSTO-14 (σ1), and DTG (σ1 and σ2) did not significantly reduce radiotracer uptake in the brain, but did in the spleen. A labelled metabolite was found in the liver and brain. Due to its insensitivity to σ ligands, the accumulation of [3H]ANSTO-14 in the brain indicates high nonspecific binding. Therefore, [3H]ANSTO-14 is a suitable ligand for labelling σ1 sites in vitro but is not suitable for brain imaging of σ binding sites in vivo