Nature versus nurture revisited: an old idea with a new twist

The nature versus nurture debate has recently resurfaced with the emergence of the field of developmental molecular neurobiology. The questions associated with "nature" have crystallized into testable hypotheses regarding patterns of gene expression during development, and those associated with "nurture" have given over to activity-dependent cellular mechanisms that give rise to variable phenotypes in developing nervous systems. This review focuses on some of the features associated with complex brains and discusses the evolutionary and activity-dependent mechanisms that generate these features. These include increases in the size of the cortical sheet, changes in cortical domain and cortical field specification, and the activity-dependent intracellular mechanisms that regulate the structure and function of neurons during development. We discuss which features are likely to be genetically mediated, which features are likely to be regulated by activity, and how these two mechanisms act in concert to produce the wide variety of phenotypes observed for the mammalian neocortex. For example, the size of the cortical sheet is likely to be under genetic control, and regulation of cell-cycle kinetics through upregulation of genes such as beta-catenin can account for increases in the size of the cortical sheet. Similarly, intrinsic signaling genes or gene products such as Wnt, Shh, Fgf2, Fgf8 and BMP may set up a combinatorial coordinate system that guides thalamic afferents. Changes in peripheral morphology that regulate patterned activity are also likely to be under genetic control. Finally, the intracellular machinery that allows for activity-dependent plasticity in the developing CNS may be genetically regulated, although the specific phenotype they generate are not. On the other hand, aspects of neocortical organization such as sensory domain assignment, the size and shape of cortical fields, some aspects of connectivity, and details of functional organization are likely to be activity-dependent. Furthermore, the role of genes versus activity, and their interactions, may be different for primary fields versus non-primary fields.     

Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men

AIMS: The influence of ageing on the pharmacokinetics of zolpidem, an extensively prescribed hypnotic medication, was evaluated in healthy human volunteers. METHODS: A series of 16 elderly (age: 61-85 years) and 24 young (age: 22-42 years) volunteers received single 5 mg oral doses of zolpidem tartrate. Serum zolpidem concentrations were determined by HPLC with fluorescence detection in samples drawn during 8 h after dosage. The effect of testosterone on zolpidem biotransformation was evaluated in vitro using human liver microsomes. Possible induction of CYP3A protein expression and function was studied in cultured human hepatocytes. RESULTS: Among men, apparent oral clearance of zolpidem was decreased in elderly compared to young subjects (3.8 vs 11.0 ml min-1 kg-1, P < 0.01), Cmax was increased (93 vs 40 ng ml-1, P < 0.01), and half-life increased (2.7 vs 1.5 h, P < 0.03). Among women, zolpidem oral clearance was decreased in the elderly (3.0 vs 5.8 ml min-1 kg-1, P < 0.02), Cmax increased (108 vs 60 ng ml-1, P < 0.001), with no difference in t1/2 (2.3 vs 2.4 h). Among male subjects, free serum testosterone concentrations were lower in the elderly (10.5 vs 19.0 pg ml-1, P < 0.01), and were significantly correlated with zolpidem clearance (r2 = 0.46, P < 0.001). Multiple regression analysis indicated a greater relative contribution of serum testosterone than age to the oral clearance of zolpidem among men. In human liver microsomes, co-incubation of zolpidem (10 micro m) with varying concentrations of testosterone produced activation of biotransformation of zolpidem to its principal hydroxylated metabolite. Maximum activation was achieved at equimolar concentrations of testosterone (10 micro m). However, testosterone did not induce immunoactive CYP3A4 expression or catalytic function in cultured human hepatocytes. CONCLUSIONS: The increased Cmax and lower oral clearance of zolpidem in the elderly are consistent with recommendations of lower clinical doses of zolpidem in the elderly. Our clinical and in vitro data both suggest that reduced free serum testosterone may have a modulatory role in age-dependent changes in zolpidem pharmacokinetics in men.     

Stimulation of defense factors for oysters deployed to contaminated sites in Pensacola Bay,Florida

A positive association between chemical contaminants and defense factors has been established for eastern oysters (Crassostrea virginica) from Florida, but it is unknown whether such factors can be stimulated through short-term exposure to contaminants in the field. Hatchery oysters were deployed at two contaminated sites and one reference site near Pensacola, Florida, during spring and summer in 1998. Putative defense measurements, notably hemocyte count and bactericidal activity, were significantly elevated after 12-week deployment during summer at the most contaminated site. This site exhibited a dramatic increase in chemical concentrations in oyster tissue relative to both the initial concentrations in hatchery oysters and to oysters deployed at the reference site. Hemocyte activity was not stimulated after 16-week deployment of hatchery oysters in spring, despite similar increases in tissue chemical concentrations, so defense activation by short-term exposure may covary with other unmeasured environmental or physiological parameters. Using the converse approach, Pensacola Bay oysters were collected from two contaminated sites and deployed at the reference site for 16 weeks during spring. Results from this converse deployment were ambiguous; serum lysozyme concentrations were reduced for oysters transplanted from both sites, but hemocyte activities were not significantly changed. The principal outcome from this study was the demonstration of enhanced defense activities for oysters upon short-term summer deployment at a contaminated site.     

Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma

There are two telomere maintenance mechanisms (TMMs) in human tumors, telomerase activation (TA) and, more rarely, the process termed alternative lengthening of telomeres (ALT). Unlike most carcinomas, sarcomas, including osteosarcomas (OS), have been reported to display TA and ALT in more balanced proportions and, thus, present an opportunity to examine the impact of different TMMs on clinical tumor behavior. We studied OS samples from 62 patients for molecular evidence of TA and ALT. Kaplan-Meier analysis demonstrated that the absence of both TA and ALT (in 18%) was more strongly associated with improved survival (P = 0.05) than were stage (P = 0.16) or chemotherapy response (P = 0.18) in this group of patients with OS. Subsets of OS cases with either TA or ALT did not differ significantly from each other in clinical outcome. There were no significant associations of presence, absence, or type of TMM with patient age, stage, or chemotherapy response. Thus, the absence of a detectable TMM may identify a favorable clinical subset of OS patients. Our study also suggests that the likelihood of detecting correlations between TMMs and clinical outcome in studies of certain other tumor types might be improved if, in addition to TA, ALT is included in future analyses. Finally, we note that OS cases with a TA-/ALT+ phenotype seem to be as clinically aggressive as TA+ cases in terms of stage and clinical outcome.     

A pharmacological examination of venom from the Papuan taipan (Oxyuranus scutellatus canni).

The Papuan taipan (Oxyuranus scutellatus canni) is the third most venomous terrestrial snake in the world, however, little is know about the pharmacology of the venom. In the chick biventer cervicis muscle, venom (10 μg/ml) abolished nerve-mediated twitches (time to 90% inhibition (t₉₀) 44±5 min, n=9). This inhibition was unaffected by prior incubation of the venom with the phospholipase A inhibitor 4-bromophenacyl bromide (4-BPB; 0.72 mM) (t₉₀ 48±7 min, n=8). The mouse phrenic nerve diaphragm preparation displayed greater sensitivity to venom (10 μg/ml) (t₉₀ 25±1 min, n=6). In the chick biventer muscle, venom (10 μg/ml) significantly inhibited responses to acetylcholine (1 mM) and carbachol (20 μM), but not KCl (40 mM), indicating activity at post-synaptic nicotinic receptors. Venom (10 μg/ml) did not affect direct muscle stimulation. Venom (3–30 μg/ml) produced dose-dependant contractions of the guinea-pig ileum. Contractile responses were significantly inhibited by indomethacin (1 μM) or prior incubation of the venom with 4-BPB (0.72 mM) indicating involvement of a PLA component. In rat phenylephrine (0.3 μM) precontracted aortae, venom (3–100 μg/ml) produced endothelium-independent relaxation which was unaffected by prior incubation of venom (30 μg/ml) with 4-BPB (0.72 mM). In anaesthetised rats, 10 μg/kg (i.v.) venom produced rapid respiratory and cardiovascular collapse while 5 μg/kg (i.v.) venom produced only a small transient decrease in mean arterial blood pressure. Prior administration of 5 μg/kg (i.v.) venom enabled subsequent administration of 10 and 100 μg/kg (i.v.) venom without respiratory or cardiovascular collapse. Further work is required to identify specific toxins with the above pharmacological activity.