No association between fluctuating asymmetry in highly stabilized traits and second to fourth digit ratio (2D:4D) in human fetuses

Recent studies have suggested that the ratio of the length of the second and fourth digit (2D:4D) may be associated with developmental instability (DI) as measured by the left-right asymmetry of the same digits. Because the 2D:4D ratio is amongst others, determined prenatally as a result of exposure to sex hormones, such an association could indicate that the same prenatal developmental processes determine levels of DI. In this study we criticize these earlier findings and show by simulations that they are confounded by the fact that (non-) linear combinations of the digit lengths are used as both dependent (average asymmetry in digits 2 and 4) and independent (ratio of the lengths of digits 2 and 4) variable. We therefore studied associations between 2D:4D ratios and asymmetry not only in digits but also in several other skeletal elements in deceased human fetuses. In contrast to the earlier studies, we did not find an association between 2D:4D ratios and asymmetry in digits 2 and 4. We argue that this may be due to the low levels of DI in this study, which limits the confounding effects of DI. Also, no associations were detected with the asymmetry of all other trait either. Thus, there appears to be very little evidence of any link between DI and 2D:4D in this population for limb measurements. We conclude that highly stabilized and functionally important traits such as human limbs may in general show limited increases in asymmetry with prenatal stress.     

Systemic hyperthermia induces ischemic brain injury in neonatal mice with ligated carotid artery and jugular vein

Postnatal d 7 (p7) or p12 mice had their right carotid artery (CA) and jugular vein (JV) ligated to mimic veno-arterial (VA) access for extracorporeal membrane oxygenation (ECMO). At p9-11 (early) or p19-21 (late) mice were exposed to hyperthermia or normothermia followed by assessment of neuropathological injury score. In separate cohorts of mice, cerebral and peripheral blood flow (CBF, PBF) and cerebral ATP content was measured. Hyperthermia resulted in ischemic brain injury in 57% and 77% of mice subjected to early or late hyperthermia, respectively. Isolated CA+JV ligation induced minimal injury (score 0.47 +/- 0.34) in 2/8 mice from the late normothermia group. No cerebral injury was detected in mice subjected to early normothermia. In 3/19 shams (2/10 early, 1/9 late) hyperthermia induced a subtle (score, 0.6 +/- 0.27) injury in the ipsilateral to the site of surgery cortex. CBF and PBF increased in response to hyperthermia in all mice. The rise in CBF was significantly attenuated in the "ligated" versus intact hemisphere, which was associated with a profound depletion of ATP content. Systemic hyperthermia induces ischemic brain injury in mice with ligated CA+JV. We speculate that hyperthermia/fever can be a potential risk factor for brain injury in infants treated with VA ECMO.     

Motor control in children with ADHD and non-affected siblings: deficits most pronounced using the left hand

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is strongly influenced by heritability. Identifying heritable vulnerability traits (endophenotypes) that mark a relatively high risk of developing the disorder can contribute to the identification of risk genes. A fruitful area for the search for such endophenotypes may be motor control in children with ADHD, since the disorder is frequently accompanied by motor problems. METHOD: The current study used a large sample of 350 children with ADHD, 195 non-affected siblings and 271 normal controls aged 5-19 years. Children were administered two computerised motor control tasks in which they had to trace a path between two circles (Tracking task) and follow a randomly moving target (Pursuit task). Both tasks were performed with both the right and the left hand. RESULTS: Children with ADHD were less precise and stable than controls. Non-affected siblings also deviated from controls, but only on the Tracking task. Group differences were modulated by the use of the right versus the left hand: no group differences emerged when the right hand was used, yet group differences did emerge when the left hand was used. Performance on both tasks was significantly familial. CONCLUSIONS: Imprecision and instability of movements in children with ADHD and in their non-affected siblings as measured by the Tracking task might be suitable endophenotypic candidates: these deficits are familially present in children having ADHD as well as in their non-affected siblings. Motor performance might be best assessed in children using their left hand, because motor control deficits are most pronounced using the left hand. This might relate to right hemispheric brain pathology in children with ADHD (and possibly in their non-affected siblings) that is related to the control of the left hand and/or relate to differential effects of daily life practice on both hands, which may be smaller on the left hand.     

Heart rate and reinforcement sensitivity in ADHD

BACKGROUND: Both theoretical and clinical accounts of attention-deficit/hyperactivity disorder (ADHD) implicate a dysfunctional reinforcement system. This study investigated heart rate parameters in response to feedback associated with reward and response cost in ADHD children and controls aged 8 to 12. METHODS: Heart rate responses (HRRs) following feedback and heart rate variability (HRV) in the low frequency band (.04-.08 Hz), a measure of mental effort, were calculated during a time production paradigm. Performance was coupled to monetary gain, loss or feedback-only in a cross-over design. RESULTS: Children with ADHD exhibited smaller HRRs to feedback compared to controls. HRV of children with ADHD decreased when performance was coupled to reward or response cost compared to feedback-only. HRV of controls was similar across conditions. CONCLUSIONS: Children with ADHD were characterised by (a) possible abnormalities in feedback monitoring and (b) motivational deficits, when no external reinforcement is present.     

Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel.

PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2). RESULTS: The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.