Childhood socio‐economic disadvantage predicts reduced myelin growth across adolescence and young adulthood

Socio‐economic disadvantage increases exposure to life stressors. Animal research suggests early life stressors impact later neurodevelopment, including myelin developmental growth. To determine how early life disadvantage may affect myelin growth in adolescence and young adulthood, we analysed data from an accelerated longitudinal neuroimaging study measuring magnetisation transfer (MT), a myelin‐sensitive marker, in 288 participants (149 female) between 14 and 25 years of age at baseline. We found that early life economic disadvantage before age 12, measured by a neighbourhood poverty index, was associated with slower myelin growth. This association was observed for magnetization transfer in cortical, subcortical and core white matter regions, and also in key subcortical nuclei. Participant IQ at baseline, alcohol use, body mass index, parental occupation and self‐reported parenting quality did not account for these effects, but parental education did so partially. Specifically, positive parenting moderated the effect of socio‐economic disadvantage in a protective manner. Thus, early socioeconomic disadvantage appears to alter myelin growth across adolescence. This finding has potential translational implications, including clarifying whether reducing socio‐economic disadvantage during childhood, and increasing parental education and positive parenting, promote normal trajectories of brain development in economically disadvantaged contexts.     

A study of adaptive responses in cell signaling in migraine and cluster headache: correlations between headache type and changes in gene expression

The project was an investigation into whether changes in the expression of G-proteins underlie altered cell signaling in migraine and cluster headache. The basis for this assumption is that altered physiological responses are seen in migraineurs and that differences in cell signaling are detected biochemically in various cell types isolated from peripheral blood. Levels of three G-protein mRNAs—Gsα, Giα, and Gqα were quantified in lymphocytes from clinically well-defined migraine and cluster headache patients and correlated with headache type and influence of drug treatment. Giα mRNA was reduced by 50% in all migraine patients compared with control subjects; similarly in patients with or without aura, in patients with a migraine headache at the time of sampling, and patients in a quiescent state. No reduction in the levels of Gsα or Gqα mRNA were seen in migraine patients. A smaller reduction was seen in cluster headache patients, most marked in those without medication. Levels of Gsα. mRNA were significantly reduced in cluster headache patients compared with migraine patients. The marked down-regulation of Giα mRNA in migraine, whether quiescent or acute, indicates either an adaptive response to headache in this group of patients or that low levels of Giα mRNA make individuals more susceptible to migraine.     

Biogenesis of corticosteroids in monolayer cultures of human foetal adrenal cells.

Human foetal adrenal cells were grown in monolayer culture and their steroidogenic capacity observed for up to a month. The cells produced a complex array of steroids and some of their ester sulphates from endogenous as well as from [14C] and [3H] precursors. ACTH stimulated corticoidogenesis, particularly cortisol secretion, and markedly enhanced the incorporation of progesterone and pregnenolone into cortisol. Following incubation with the same precursors, large amounts of radioactivity remained water soluble. From the butanol extractable material of this fraction, dehydroepiandrosterone sulphate was characterized as the main metabolite of pregnenolone and corticosterone and 11-deoxycorticosterone sulphates as the main metabolites of progesterone. With time in culture there was a decrease in steroidogenesis as well as a steady decline in responsiveness to ACTH, mainly manifested by cortisol secretion. The medium from homologous foetal pituitary cultures stimulated cortisol production by the human adrenal cell monolayer.     

N-dimethylisopropyl propranolol. Effects on myocardial oxygen demands.

N-Dimethylisopropyl propranolol (DMP) is a quaternary derivative which lacks significant beta-adrenergic blocking and local anesthetic effects. It has been reported, nonetheless, to be effective in treating experimental arrhythmias and in limiting the extent of ST-segment elevations following experimental coronary occlusion. The present study examined the effects of DMP on the hemodynamics and myocardial oxygen demands of anesthetized dogs. After a single dose of 3 mg/kg, heart rate fell from 146 +/- 8 to 124 +/- 6 beats/min (P less than 0.0025), and aortic systolic pressure fell from 151 +/- 11 to 141 +/- 9 mm Hg (0.05 less than P less than 0.10), resulting in a 16.8% reduction in the tension-time index. Stroke volume was reduced by 10% despite a 54% increase in left ventricular end-diastolic pressure, suggesting a negative inotropic effect. This was supported by a decrease in maximum extrapolated contractile element velocity from 9.10 +/- 1.05 to 6.61 +/- 65 units/sec (P less than 0.0025). Myocardial oxygen consumption was reduced from 12.0 +/- 1.4 to 9.9 +/- 1.5 ml/min/100 g tissue (P less than 0.05). Myocardial oxygen extraction was unchanged, indicating that the decrease in oxygen consumption resulted from a reduction in myocardial oxygen demand. When heart rate and systolic pressure were artificially restored to control levels, after the administration of DMP, myocardial oxygen consumption remained significantly below the control level. DMP, therefore, appeared to reduce myocardial oxygen demands primarily by its negative inotropic effect. This drug may have application in the treatment of ischemic heart disease.     

Effect of insulin-like growth factors on human foetal, adult normal and tumour pituitary function in tissue culture

To determine the direct effects of insulin-like growth factors (IGFs) on hormone release by the human pituitary gland, human foetal, adult normal and tumour pituitary tissues were maintained in culture for 2 to 4 weeks and tested with acute (3 h) exposures to different preparations of IGF peptides. Adult normal pituitaries and adenomas were tested with a semipurified preparation of IGFs, free of immunoreactive insulin, containing IGF-I and IGF-II in a ratio of approximately 1:4. Human foetal pituitaries were tested with the semipurified IGFs as well as more purified preparations of IGF-I and IGF-II. Culture media were assayed for hGH, hPrl, hACTH and hLH using specific radioimmunoassays. Both foetal (n = 16 (No. of pituitaries), 33 (No. of observations] and normal adult (n = 3, 16) human pituitaries cultures responded to the semipurified IGFs (2-25 ngEq/ml for foetal and 2-4 ngEq/ml for adult pituitaries) with a significant decrease in hGH release compared to basal (P less than 0.01) whereas the GH-secreting pituitary tumours showed no effect when tested with from 2 to 25 ngEq/ml (n = 8, 129, NS). The effect of IGFs on human foetal somatotrope activity was dose-related for both the semipurified IGFs (2-25 ngEq/ml, n = 16, 33) and IGF-I or IGF-II (10-100 ng/ml; n = 3, 18).(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory chain defects in the mitochondria of cultured skin fibroblasts from three patients with lacticacidemia.

The cultured skin fibroblasts from three patients with lacticacidemia were found to have low rates of 1-[14C]pyruvate oxidation in the face of normal pyruvate dehydrogenase activity. After incubation with 1 mM glucose, these three cell strains also exhibited lactate/pyruvate ratios which were three times greater than those of controls. In two of the patients, both ATP and oxygen consumption in fibroblast mitochondrial preparations was deficient with NAD-linked substrates but normal with succinate and ascorbate/N'N'N'N' tetramethyl phenylene diamine. In the third patient, ATP synthesis in mitochondrial preparations was deficient with all substrates tested. Measurement of Rotenone-sensitive NADH-cytochrome c reductase in mitochondrial preparations from skin fibroblasts showed that two of the patients had 14 and 18%, respectively, of control activity. In the third patient, cytochrome oxidase activity was 15% of that in controls. We conclude that respiratory chain defects can be demonstrated in cultured skin fibroblasts with consistency using a number of different techniques.     

Rapid loss of renal parenchyma after acute obstruction

Urinary tract obstruction (UTO) is a frequent cause of renal failure in the pediatric population. We report a patient with type I/I cystinuria, followed prospectively from birth with yearly ultrasonography, who developed acute UTO due to a cystine stone at 10 years of age. In animal models of UTO, acute obstruction produces rapid loss of renal parenchyma secondary to apoptosis of tubular cells. Since we had prospectively obtained serial ultrasonographic measurements of renal growth, we were able to document sudden decrease in kidney size and function following UTO, suggesting that programmed cell death may similarly have caused the rapid irreversible loss of renal parenchyma in our patient. Despite surgical relief of the obstruction, kidney size decreased for at least 3–4 months. We speculate that anti-apoptotic drugs might be considered as a therapeutic strategy to protect ongoing renal parenchyma loss in UTO. Received: 26 April 2001 / Revised: 28 June 2001 / Accepted: 29 June 2001