Genetic influences on vulnerability to, and protective factors for, adolescent drinking.

Using behavioral genetic analyses, we investigated and present a possible relationship between adolescent alcohol use and six domains of common problem behaviors in a community-based sample of 633 twin pairs who were under the legal drinking age of 21 (mean age = 15.0 years). The underlying etiology of the six problem behavioral domains, classified as conduct problems, hyperactivity, school problems, low self-esteem, neuroticism, and social withdrawal, was previously described (Siewert et al., 2003) as two heritable and genetically distinct dimensions of problem behavior. We took the two best-fitting models from that study (one that proposed a generalized behavior problem factor along with an internalizing behavior factor, and one that proposed an externalizing behavior factor along with an internalizing behavior factor) and extended the analyses in this study to include an index of alcohol use. Our results suggest that there is a strong genetic relationship between adolescent alcohol use and a broad spectrum of both externalizing and internalizing behavioral problems. The individual who seems to be at risk for either generalized or specifically externalizing behavioral problems is also at risk for adolescent alcohol use. However, the individual who exhibits internalizing problem behaviors appears to be protected from adolescent alcohol use. We propose that adolescent alcohol consumption needs to be understood in the context of these genetically influenced externalizing and internalizing propensities.     

Effect of neurotensin on pancreatic function in man

The effect of neurotensin on submaximally-stimulated hepatobiliary and pancreatic secretion was studied in 6 healthy subjects. An intravenous infusion of neurotensin 1.4 ± 0.3 pmol/kg/min, designed to reproduce plasma neurotensin immunoreactivity levels within the physiological range, produced a significant increase in pancreatic bicarbonate output. Plasma concentrations of pancreatic polypeptide rose by 83 ± 16 pmol/l and were associated with a small reduction in trypsin, but no significant change in bilirubin outputs.     

Investigation into the role of macrophages in the formation and degradation of beta2-microglobulin amyloid fibrils

Dialysis related amyloidosis is a serious complication of long-term hemodialysis in which beta(2)-microglobulin (beta(2)m) forms amyloid fibrils that deposit predominantly in cartilaginous tissues. How these fibrils form in vivo, however, is poorly understood. Here we perform a systematic investigation into the role of macrophages in the formation and degradation of beta(2)m amyloid fibrils, building on observations that macrophages are found in association with beta(2)m amyloid deposits in vivo and that these cells contain intra-lysosomal beta(2)m amyloid. In live cell imaging experiments we demonstrate that macrophages internalize monomeric beta(2)m, whereupon it is sorted to lysosomes. At lysosomal pH beta(2)m self-associates in vitro to form amyloid-like fibrils with an array of morphologies as visualized by atomic force microscopy. Cleavage of the monomeric protein by both macrophages and lysosomal proteases isolated from these cells results in the rapid degradation of the monomeric protein, preventing amyloid formation. Incubation of macrophages with preformed fibrils revealed that macrophages internalize amyloid-like fibrils formed extracellularly, but in marked contrast with the monomeric protein, the fibrils were not degraded within macrophage lysosomes. Correspondingly beta(2)m fibrils were highly resistant to degradation by high concentrations of lysosomal proteases isolated from macrophages. Despite their enormous degradative capacity, therefore, macrophage lysosomes cannot ameliorate dialysis-related amyloidosis by degrading pre-existing amyloid fibrils, but lysosomal proteases may play a protective role by eliminating amyloid precursors before beta(2)m fibrils can accumulate in what may represent an otherwise fibrillogenic environment.     

Ethnicity, body mass, and genome-wide data

This article combines social and genetic epidemiology to examine the influence of self-reported ethnicity on body mass index (BMI) among a sample of adolescents and young adults. We use genetic information from more than 5,000 single nucleotide polymorphisms in combination with principal components analysis to characterize population ancestry of individuals in this study. We show that non-Hispanic white and Mexican-American respondents differ significantly with respect to BMI and differ on the first principal component from the genetic data. This first component is positively associated with BMI and accounts for roughly 3% of the genetic variance in our sample. However, after controlling for this genetic measure, the observed ethnic differences in BMI remain large and statistically significant. This study demonstrates a parsimonious method to adjust for genetic differences among individual respondents that may contribute to observed differences in outcomes. In this case, adjusting for genetic background has no bearing on the influence of self-identified ethnicity.     

In vitro and in vivo evaluation of O-alkyl derivatives of tramadol

Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. O-Alkyl, N-desmethyl, and non-phenol containing derivatives of tramadol were synthesized to probe their effect on metabolic stability and both in vitro and in vivo potency.     

Desipramine Binding: Relationship to Central and Sympathetic Noradrenergic Activity

We examined the effects of treatments affecting norepinephrine release on the number of norepinephrine reuptake recognition sites as reflected by desipramine binding. To do this, we used manipulations having similar presynaptic but contrasting postsynaptic effects. Presynaptic inhibition by 6-hydroxydopamine lesion or by clonidine, and postsynaptic receptor stimulation by isoproterenol, reduced desipramine binding. Presynaptic stimulation by d-amphetamine and postsynaptic receptor blockade by prazosin increased desipramine binding. Similar effects and binding properties were seen in cerebral cortex, heart, and soleus muscle. After unilateral noradrenergic lesions, reduction in desipramine binding correlated with reduction in norepinephrine uptake. These results show that norepinephrine reuptake appears to be regulated by transmitter release regardless of effects on postsynaptic transmission, and that this regulation is analogous in the central and sympathetic nervous systems.