Early deprivation and home basal cortisol levels: a study of internationally adopted children

Animal studies reveal that early deprivation impairs regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis, potentially increasing vulnerability to stressors throughout life. To examine early deprivation effects on basal HPA axis activity in humans, basal cortisol levels were examined in 164 internationally adopted children who had experienced varying degrees of preadoption deprivation. Duration of institutional care, age at adoption, and parent ratings of preadoption neglect indexed a latent factor of Deprived Care. Adoption measures of height and weight standardized to World Health Organisation norms indexed a latent factor of Growth Delay that was viewed as another reflection of deprivation. Cortisol samples were collected 3.3-11.6 years postadoption (Md = 7.3 years) at home on 3 days approximately 30 min after wakeup and before bedtime. Both early a.m. levels and the decrease in cortisol across the day were examined. A structural equation model revealed that preadoption Deprived Care predicted Growth Delay at adoption and Growth Delay predicted higher morning cortisol levels and a larger diurnal cortisol decrease.     

Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease

In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) after 5 and 12 weeks of treatment, has evolved as a strong prognostic factor in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. Individual treatment response may be influenced by copy number alterations (CNA) leading to altered gene expression. We aimed to evaluate CNA using high-resolution array-comparative genomic hybridization (array-CGH) in different treatment-response groups. Leukemic genomic profiles of 25 standard risk (MRD-SR) and 25 high risk (MRD-HR) patients were compared. CNAs were found in 46/50 patients (92%). The most significant difference was a gain of 1q23-qter because of an unbalanced t(1;19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (P < 0.001). The most frequent CNAs in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (Ig), e.g., 2p11.2 in 60% of MRD-HR compared to 28% of MRD-SR (P = 0.045). Combining all Ig loci, significantly more MRD-HR than MRD-SR patients displayed deletions (17:8 patients, P = 0.02). Frequency of other CNAs, such as loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and the first to suggest that such analyses may provide clinically important data. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.     

S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.     

Confronting the challenge: individualized immune monitoring after organ transplantation using the cellular immune function assay

The survival of a transplanted organ is dependent on avoidance of rejection, achieved through continuous immuno-suppression. Management of the transplant recipient confronts the clinician with a key challenge of post-transplant immune monitoring. Early detection of an activated allo-immune response is a harbinger of incipient rejection. Thus, timely intervention may prevent acute and chronic injury to the transplanted organ. Similarly, over immune-suppression can lead to infections or malignancies, hence the importance of early detection of the precarious suppression. The need for non-invasive systemic immune monitoring of the transplant recipient is therefore imperative. This review describes the cellular immune function assay--a non-invasive diagnostic method for evaluation of the net state of the recipient's cellular immune function. We describe the background that brought about the need for a reliable diagnostic tool for serial immune monitoring, and we overview the main mile-stones in the assimilation of the assay and its implementation in the clinic. The arising conclusion presents a novel non-invasive diagnostic bio-marker for post-transplant immune monitoring which enables the clinician to intervene prior to manifestation of clinical complications. The usefulness of the assay in detecting a state of over-suppression has been consensually described in multiple publications while its contribution in detection and management of under-suppression conditions remains to be determined by means of prospective interventional studies. The cellular immune function assay can be useful and beneficial for patient care only if used for longitudinal monitoring through serial testing.     

Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q(10), rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.     

Postadoption parenting and socioemotional development in postinstitutionalized children

Children adopted from institutions (e.g., orphanages) overseas are at increased risk of disturbances in social relationships and social understanding. Not all postinstitutionalized children exhibit these problems, although factors like the severity of deprivation and duration of deprivation increase their risk. To date, few studies have examined whether postadoption parenting might moderate the impact of early adverse care. Three groups were studied: postinstitutionalized and foster care children both adopted internationally and nonadopted children reared in their families of origin. The Emotional Availability (EA) Scales were assessed at 18 months in parent-child dyads. Parent emotional availability was found to predict two aspects of social functioning shown in previous studies to be impaired in postinstitutionalized children. Specifically, EA positively correlated with emotion understanding at 36 months; in interaction with initiation of joint attention at 18 months and group, it predicted indiscriminate friendliness as scored from a parent attachment interview at 30 months. Among the postinstitutionalized children but not among the children in other groups, higher EA scores reduced the negative association between initiation of joint attention and indiscriminate friendliness, thus suggesting that parenting quality may moderate the effects of early institutional deprivation.