Adolescent behavioral and neural reward sensitivity: a test of the differential susceptibility theory.

Little is known about the causes of individual differences in reward sensitivity. We investigated gene-environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes.

Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists.

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.

Evidence that Tmevd2 and eae3 may represent either a common locus or members of a gene complex controlling susceptibility to immunologically mediated demyelination in mice.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination and experimental allergic encephalomyelitis are the principal immunologically mediated, genetically controlled models of multiple sclerosis. Previous studies using different mapping techniques identified susceptibility loci for both diseases on chromosomes 3, 6, and 17. To more precisely map these TMEV and experimental allergic encephalomyelitis loci relative to each other, linkage analysis using microsatellite markers and a (BALB/cByJ x DBA/2J) x BALB/cByJ backcross population segregating for TMEV-induced disease was conducted. Comparisonwise and chromosomewise critical values based on permutation theory were estimated for each chromosome. Evidence for linkage to markers on chromosome 17 was not seen. Chromosomewise linkage (p = 0.13) was detected with D6 Mit36 and D6 Mit149 (marker-specific chromosomewise p values = 0.02) at 40.4 cM on chromosome 6. Chromosomewise linkage (p < 0.01) (marker-specific chromosomewise p value = 0.0) and comparisonwise linkage (p < < 0.0001) to D3 Mit156 at 33.9 cM on chromosome 3 were observed along with chromosomewise linkage (p < 0.05) and comparisonwise linkage (p < < 0.0001) to D3 Mit29, D3 Mit311, D3 Mit28, and D3 Mit11 from 33.9 to 37.2 cM, respectively. Significant linkage to D3 Mit156 places Tmevd2 1.1 cM proximal of D3 Mit101 (35 cM), the maximally linked marker to the eae3 susceptibility gene. Maximum likelihood estimates conducted by multilocus linkage analysis localized Tmevd2 within a 95% confidence interval bordered by D3 Mit29 and D3 Mit10, at 33.9 and 37.2 cM, respectively. Taken together these results suggest that Tmevd2 and eae3 may represent either a single, common susceptibility gene or members of a gene complex involved in central nervous system immunopathology.

[Value of anorectal manometry in assessment of constipation in childhood]. / Stellenwert der anorektalen Manometrie bei der Abklärung der Obstipation im Kindesalter.

We studied retrospectively 210 anorectal manometries of constipated children. Of the 87 patients with an anal fissure or a functional constipation, 83 had normal sphincter relaxation. All of the 23 patients with Hirschsprung's disease lacked the sphincter relaxation, as well as 22 of the patients with a dysganglionosis. Eleven patients with innervation defects showed pathologic sphincter contractions. Anorectal manometry is a valuable tool to differentiate between innervation defects and constipation of other etiologies.

Properties of ABT-299, a prodrug of A-85783, a highly potent platelet activating factor receptor antagonist.

ABT-299 is an aqueous soluble prodrug that is converted rapidly in vivo to A-85783, a novel, highly potent, specific platelet activating factor (PAF) antagonist. The K, for inhibiting PAF binding to rabbit platelet membranes is 3.9 and 0.3 nM for human platelets. Inhibition is selective and reversible and is correlated with functional antagonism of PAF-mediated cellular responses (calcium mobilization, priming of superoxide generation, aggregation and degranulation). The in vivo generation of A-85783 from ABT-299 leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension and edema) and PAF-induced lethality. When administered i.v., the potency (ED50) of ABT-299 for inhibiting PAF responses was between 6 to 10 micrograms/kg in the rat and mouse and 100 micrograms/kg in the guinea pig. A dose of 100 micrograms/kg in the rat provided greater than 60% protection for 8 to 16 hr against cutaneous and systemic PAF challenge. This duration was also evidenced by ex vivo inhibition of platelet aggregation in guinea pig and sheep. In addition to being active parenterally, ABT-299 exhibited p.o. activity in the rat and mouse (ED50 = 100 micrograms/kg in both species). Pharmacokinetic studies in the rat revealed that ABT-299 was converted rapidly to A-85783 and, in turn, metabolized to the corresponding pyridine-N-oxide and sulfoxide metabolites. These metabolites exhibited significant potency in vitro and in vivo and thus may contribute to the activity observed after administration of ABT-299.

N-(acyloxyalkyl)pyridinium salts as soluble prodrugs of a potent platelet activating factor antagonist.

Pyrrolothiazole 4 is a potent antagonist of platelet activating factor-mediated effects in a variety of in vitro and in vivo assays. Despite its positive activity in models of inflammation and septic shock, 4 lacks the aqueous solubility necessary for intravenous administration. This deficit was overcome by conversion of 4 to water-soluble pyridinium prodrugs. A two-step procedure was used to prepare a series of N-(acyloxyalkyl)pyridinium salts, all of which exhibited aqueous solubility of greater than 20 mg/mL. The rate of conversion of these prodrugs to 4 was faster in human plasma than in pH 7 aqueous buffer. This rate difference was shown to be due to serum enzymes since the conversion in plasma was significantly slower in the presence of a serine esterase inhibitor. A strong correlation between prodrug structure and buffer/plasma half-life was established. The N-(acetyloxymethyl)pyridinium prodrug 11 (ABT-299) is currently undergoing clinical evaluation for the treatment of sepsis.

Synthesis and structure-activity relationships of a series of novel benzopyran-containing platelet activating factor antagonists.

A class of N-substituted tetrahydrobenzopyrano[3,4-c]pyridines, I, have been identified as antagonists of platelet activating factor (PAF). The structural features essential for PAF binding were determined by systematic modification of three sites in the molecule. While O-alkyl analogues had little effect on binding potency, N-alkyl analogues exhibited a wide range of activity. Structural changes in the core ring system generally resulted in a loss of binding activity. Optimization of the N- and O-substituents resulted in the analogues 25-27 which exhibited Ki values ranging between 131 and 167 nM in a [3H]PAF binding assay. Compound 23 was also active in a model of PAF-induced shock in the mouse following intravenous administration.

Monophosphoryl lipid A inhibits neutrophil priming by lipopolysaccharide.

It is known that lipopolysaccharides (endotoxin) prime neutrophils for oxygen radical production. Monophosphoryl lipid A is a nontoxic derivative of lipid A that protects against lethal endotoxemia. We examined the effects of Salmonella minnesota monophosphoryl lipid A on S. minnesota lipopolysaccharide-induced priming of neutrophil superoxide anion generation. Human neutrophils were preincubated with and without either lipopolysaccharide or monophosphoryl lipid A before stimulation with 10(-5) formyl-norleucyl-leucyl-phenylalanine. Neutrophil priming reached a plateau at a concentration of 100 ng/ml of lipopolysaccharide, where superoxide anion generation increased from 10.1 +/- 0.8 to 25.2 +/- 1.7 nmol superoxide anions/10(6) neutrophils/10 min (p less than 0.01). In contrast, monophosphoryl lipid A did not exhibit any priming activity. Monophosphoryl lipid A also exhibited a time-dependent inhibitory effect on lipopolysaccharide-induced priming of neutrophils, which was maximal when monophosphoryl lipid A was added 15 minutes before lipopolysaccharide. Preincubation with monophosphoryl lipid A induced a dose-dependent inhibition of neutrophil priming by 1000 ng/ml lipopolysaccharide. Neutrophil superoxide anion generation decreased by 47% from 19.0 +/- 0.6 to 10.0 +/- 0.7 nmol superoxide anions/10(6) neutrophils/10 min by 2000 ng/ml monophosphoryl lipid A (p less than 0.01). These data indicate that monophosphoryl lipid A does not enhance neutrophil superoxide generation in response to formyl-norleucyl-leucyl-phenylalanine. Monophosphoryl lipid A also inhibits lipopolysaccharide-induced priming in a dose-dependent manner that may reflect blocking of lipopolysaccharide by monophosphoryl lipid A at cellular binding sites.