Variation in the mu-opioid receptor gene (OPRM1) moderates the influence of maternal sensitivity on child attachment.

The endogenous opioid system is thought to play an important role in mother-infant attachment. In infant rhesus macaques, variation in the µ-opioid receptor gene (OPRM1) is related to differences in attachment behavior that emerges following repeated separation from the mother; specifically, infants carrying at least one copy of the minor G allele of the OPRM1 C77G polymorphism show heightened and more persistent separation distress, as well as a pattern of increased contact-seeking behavior directed towards the mother during reunions (at the expense of affiliation with other group members). Research in adult humans has also linked the minor G allele of the analogous OPRM1 A118G polymorphism with greater interpersonal sensitivity. Adopting an interactionist approach, we examined whether OPRM1 A118G genotype and maternal (in)sensitivity are associated with child attachment style, predicting that children carrying the G allele may be more likely to develop an ambivalent attachment pattern in response to less sensitive maternal care. The sample consisted of 191 mothers participating with their children (n = 223) in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project, a community-based, birth cohort study of Canadian mothers and their children assessed longitudinally across the child's development. Maternal sensitivity was coded from at-home mother-child interactions videotaped when the child was 18 months of age. Child attachment was assessed at 36 months using the Strange Situation paradigm. As predicted, G allele carriers, but not AA homozygotes, showed increasing odds of being classified as ambivalently attached with decreasing levels of maternal sensitivity. Paralleling earlier non-human animal research, this work provides support for the theory that endogenous opioids contribute to the expression of attachment behaviors in humans.

Specific and cumulative lifetime stressors in the aetiology of major depression: A longitudinal community-based population study.

AIMS: Early-life stressful circumstances (i.e. childhood maltreatment) coupled with stressful events later in life increase the likelihood of subsequent depression. However, very few studies have been conducted to examine the specific and cumulative effects of these stressors in the development of depression. There is also a paucity of research that simultaneously considers the role of biological factors combined with psychosocial stressors in the aetiology of depression. Guided by the biopsychosocial model proposed by Engel, the present study aims to examine to what extent the experience of stressors across the lifespan is associated with depression while taking into account the role of genetic predispositions. METHODS: Data analysed were from the Social and Psychiatric Epidemiology Catchment Area of the Southwest of Montreal (ZEPSOM), a large-scale, longitudinal community-based cohort study. A total of 1351 participants with complete information on the lifetime diagnoses of depression over a 10-year follow-up period were included in the study. Stressful events across the lifespan were operationalised as specific, cumulative and latent profiles of stressful experiences. Latent profile analysis (LPA) was used to explore the clustering of studied stressors including childhood maltreatment, poor parent-child relationship, and stressful life events. A polygenetic risk score was calculated for each participant to provide information on genetic liability. Multivariate logistic regression was used to examine the association between specific, cumulative and latent profiles of stressors and subsequent depression. RESULTS: We found that different subtypes of childhood maltreatment, child-parent bonding and stressful life events predicted subsequent depression. Furthermore, a significant association between combined effects of cumulative stressful experiences and depression was found [odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.12-1.28]. Three latent profiles of lifetime stressors were identified in the present study and named as 'low-level of stress' (75.1%), 'moderate-level of stress' (6.8%) and 'high-level of stress' (18.1%). Individuals with a 'high-level of stress' had a substantially higher risk of depression (OR = 1.80, 95% CI: 1.08-3.00) than the other two profiles after adjusting for genetic predispositions, socio-demographic characteristics, and health-related factors. CONCLUSIONS: While controlling for genetic predispositions, the present study provides robust evidence to support the independent and cumulative as well as compositional effects of early- and later-on lifetime psychosocial stressors in the subsequent development of depression. Consequently, mental illness prevention and mental health promotion should target the occurrence of stressful events as well as build resilience in people so they can better cope with stress when it inevitably occurs.

Associations between epigenetic aging and childhood peer victimization, depression, and suicidal ideation in adolescence and adulthood: A study of two population-based samples.

Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation. Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6-8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15-17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7-11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath's pan-tissue (Horvath1), Horvath's Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress). Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation. Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings.

Maternal antenatal mood and child development: an exploratory study of treatment effects on child outcomes up to 5 years.

Effective treatment of maternal antenatal depression may ameliorate adverse neurodevelopmental outcomes in offspring. We performed two follow-up rounds of children at age 2 and age 5 whose mothers had received either specialized cognitive-behavioural therapy or routine care for depression while pregnant. Of the original cohort of 54 women, renewed consent was given by 28 women for 2-year follow-up and by 24 women for 5-year follow-up. Child assessments at the 2-year follow-up included the Parenting Stress Index (PSI), Bayley Scales of Infant Development (BSID-III) and the Child Behaviour Checklist (CBCL). The 5-year follow-up included the Wechsler Preschool and Primary Scales of Intelligence (WPPSI-III) and again the CBCL. Treatment during pregnancy showed significant benefits for children's development at age 2, but not at age 5. At 2 years, intervention effects were found with lower scores on the PSI Total score, Parent Domain and Child domain (d=1.44, 1.47, 0.96 respectively). A non-significant trend favoured the intervention group on most subscales of the CBCL and the BSID-III (most notably motor development: d =0.52). In contrast, at 5-year follow-up, no intervention effects were found. Also, irrespective of treatment allocation, higher depression or anxiety during pregnancy was associated with higher CBCL and lower WPPSI-III scores at 5 years. This is one of the first controlled studies to evaluate the long-term effect of antenatal depression treatment on infant neurodevelopmental outcomes, showing some benefit. Nevertheless, caution should be taken interpreting the results because of a small sample size, and larger studies are warranted.

A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team.

OBJECTIVE: The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 300 assessed the clinical efficacy and safety of combination zidovudine/lamivudine (ZDV/3TC) compared with either didanosine (ddI) alone or combination ZDV/ddI. STUDY DESIGN: Children with symptomatic human immunodeficiency virus (HIV) infection, 6 weeks through 15 years of age, were stratified according to age and randomly assigned to receive ddI, ZDV/3TC, or ZDV/ddI. The primary endpoint was time to first progression of HIV disease or death. Enrollment in the ZDV/ddI arm stopped after 11 months on the basis of results of PACTG Protocol 152, but blinded follow-up continued. RESULTS: For the 471 children who could be evaluated, the median age was 2.7 years, median CD4 cell count was 699 cells/mm3, and median log10 HIV RNA was 5.1/mL. Median follow-up was 9.4 months. Patients receiving ZDV/3TC had a lower risk of HIV disease progression or death than those receiving ddI alone (15 vs 38 failures, P = .0006) and a lower risk of death (3 vs 15 deaths, P = .0039). Weight and height growth rates, CD4+ cell counts, and RNA concentrations showed results favoring ZDV/3TC. For patients concurrently randomized to all 3 treatment arms, both ZDV/3TC and ZDV/ddI recipients had lower risk of HIV disease progression than those who received ddI alone (P = .0026 and P = .0045). CONCLUSIONS: Combination therapy with either ZDV/3TC or ZDV/ddI was superior, as determined by clinical and laboratory measures, to monotherapy with ddI.

State control in the substance-exposed fetus. I. The fetal neurobehavioral profile: an assessment of fetal state, arousal, and regulation competency.

Behavioral states are stable structures of behaviors that become more definable and coordinated with increasing age. With ultrasound we can see the fetus move, breathe, and react to changes in its environment. Ultrasound used in conjunction with Doppler fetal heart rate recording provides behavioral and neurophysiologic data useful in state determination. The Fetal Neurobehavioral Profile (FNP) was developed by our group as an assessment of fetal behaviors reflecting CNS integrity in the drug-exposed fetus. The FNP was designed to parallel methods of examining the newborn infant, especially in state-related behaviors. The FNP measures: fetal responsiveness and arousal after environmental perturbation with vibroacoustic stimulation (VAS); habituation to VAS; state recovery; and self-regulation post-VAS. From the behavioral and physiologic recordings, the constructs of state differentiation, organization, and regulation as well as fetal arousal and regulation competency can be measured. Previous work using the FNP showed that those fetuses with abnormal or suspect fetal state regulation demonstrated impaired performance on the NBAS (Am. J. Obstet. Gynecol. 161: 685, 1989). To expand these observations, three populations are currently being studied: prenatal nicotine-exposed, prenatal cocaine-exposed, and controls. Data are from 97 women/fetus dyads and a total of 236 FNP at ages 28-30 weeks gestational age, 31-34 weeks gestational age, and > 36 weeks gestational age. Although there are no group differences in the ability to achieve state by 36 weeks, interesting trends emerge: fetuses prenatally cocaine-exposed spend less time in 1F, more time in 4F and have fewer transitions. At FNP, fewer cocaine-exposed fetuses had an initial reaction to VAS, whereas fewer nicotine-exposed fetuses habituated. Although the ability to habituate to VAS did not discriminate the cocaine group from the control or nicotine groups, the number of stimuli required for habituation differed between groups: 7 for the cocaine-exposed, 3 for the nicotine, and 5 for the control groups. Thus latency, a measure of arousal, differs among the groups Preliminary data also suggest a correlation of prenatal data with postnatal outcome.

Molecular diagnostics resources on the internet.

The global network of computers known as the Internet has become one of the most talked-about phenomena of the 1990s. Media attention has tended to focus on some of the more sensational aspects of the resources available. This is unfortunate, because the Internet contains many resources of use to workers in the field of molecular diagnostics, ranging from tools for the analysis of nucleic acid and protein sequences to discussion forums on diagnostics and related subjects.

Prenatal cocaine exposure alters postnatal hypoxic arousal responses and hypercarbic ventilatory responses but not pneumocardiograms in prenatally cocaine-exposed term infants.

To test the hypothesis that respiratory control is altered in cocaine-exposed infants, we evaluated the hypoxic arousal response and the ventilatory response to carbon dioxide (CO2) in 18 term newborn infants prenatally exposed to cocaine and in 10 healthy, term newborn infants within the first week of life. Three infants could not be tested for the hypoxic arousal response because of low baseline oxygen saturation, and data from these infants were excluded from analysis. Twelve hour overnight pneumocardiograms were performed on all infants. Results show that 60% (9/15) of the prenatally cocaine-exposed infants had an abnormal hypoxic arousal response and 87% (13/15) had abnormal hypercarbic ventilatory response. Only 6% (1/15) of the prenatally cocaine-exposed infants demonstrated any abnormality on pneumocardiogram. In contrast, all control infants (10/10) were aroused by the hypoxic challenge and 80% (8/10) had normal ventilatory response to CO2. No abnormalities were found in the assessment of the overnight pneumocardiogram in the control infants. For the cocaine-exposed infants, test abnormalities were not correlated with a concurrent positive urine toxicology for cocaine, suggesting that the injury occurs early in development. These findings support the hypothesis that infants prenatally exposed to cocaine demonstrate abnormalities of respiratory control.

Cocaine and development: mechanisms of fetal toxicity and neonatal consequences of prenatal cocaine exposure.

As cocaine use during pregnancy has become increasingly recognized, there also has been increased concern about the toxic and teratogenic properties of cocaine on the fetus. A significant literature exists describing the adverse fetal and neonatal outcomes associated with in utero cocaine exposure. However, specific causality by cocaine on outcome in the human is difficult to ascertain because of multiple confounding variables associated with substance abuse including social factors and polydrug use as well as difficulty in confirming timing, dose and frequency of cocaine exposure. Most literature suggests that prenatal cocaine exposure is associated with developmental risk to the fetus. What is currently unknown is the extent of risk, the additive and/or synergistic factors contributing to cocaine's toxicity and the reversibility of the injury. In this paper we review the pharmacologic properties of cocaine as related to a model of mechanisms for developmental injury secondary to cocaine exposure and the published literature on the adverse fetal and neonatal outcomes associated with cocaine use during pregnancy. Specific attention has been focused on the structural, neurobehavioral and respiratory control teratogenesis.

Duplication of both xyl catabolic operons on TOL plasmid pWW15.

Pseudomonas fluorescens MT15 is the host of the large (250 kbp) TOL plasmid pWW15. We have shown by a combination of hybridization, molecular cloning and enzyme assay that pWW15 carries two distinct regions which share homology with the upper pathway operons (xylCMABN) of other TOL plasmids and two distinct regions which are homologous to the meta pathway operons (xylXYZLTEGFJQKIH) of other TOL plasmids. Both the areas of homology to the upper pathway operons appear to carry all of the structural genes for the three catabolic enzymes of the operon. One of the regions of meta pathway operon homology encodes a complete functional pathway, but the second is incomplete and appears to carry only the genes from xylF downstream.

Maternal cocaine addiction and fetal behavioral state. I: A human model for the study of sudden infant death syndrome.

Abnormalities of respiratory regulation, such as apnea and abnormal hypoxic arousal during sleep, are mechanistic in the pathophysiology of SIDS. In utero cocaine exposure is associated with poor head growth, abnormal neurodevelopment, and an increased incidence of sudden, unexplained death, suggesting that in utero cocaine exposure disrupts the central regulation of breathing. It is likely that this disruption is due to altered CNS maturation. Indeed, cocaine alters norepinephrine metabolism within the locus coeruleus, important in arousal from sleep, suggesting that the increased incidence of SIDS in cocaine exposed infants may be secondary to sleep-related deficits in arousal. Since components of fetal behavioural state organization reflect the successful integration of the Central Nervous System, have a specific developmental timetable, and can be studied by fetal ultrasound techniques, we developed a strategy for assessing the state organization of the fetus by ultrasound techniques. We hypothesize that fetal evaluation of state will be a marker of abnormal CNS maturation and a predictor of risk, i.e. abnormal neurodevelopment and/or state related arousal deficits predisposing the cocaine exposed neonate to SIDS. We propose that the study of in utero cocaine exposed fetuses will provide a human model for examining the pathophysiology of SIDS.

In utero cocaine exposure: observations of fetal behavioral state may predict neonatal outcome.

Components of fetal behavioral state organization reflect the successful integration of the central nervous system, have a specific developmental timetable, and can be studied with fetal ultrasonographic techniques. To test the hypothesis that evaluation of state organization is a marker of abnormal central nervous system maturation and a predictor of risk, we studied 20 fetuses and newborns exposed to cocaine in utero. Fetal assessments were accomplished by serial ultrasonographic examination, videotaped, and scored by a scheme developed by the authors to assess organization and regulation of behavioral states. Newborn neurobehavioral assessments also emphasized organization and regulation of behavioral state. Abnormal or delayed state behavior was identified in 13 of 20 fetuses. State organization was evaluated as suspect or abnormal for 16 of the 20 exposed newborns. Disorganized behavioral state in the fetus successfully predicted abnormal newborn behavior. These findings support the concepts that cocaine exposure disrupts central nervous system development and that fetal assessment of state is predictive of neonatal outcome.

Electronic health claims--1988 and beyond.

The board members of NEIC: Aetna Life and Casualty, CIGNA, EQUICOR-Equitable HCA Corp., John Hancock Mutual Life, Metropolitan Life, McDonnell Douglas Corp., and The Travelers, as well as the other owners and carrier members, are committed to electronic media claims. It is not a question of if, but when, all claims and attendant transactions will be submitted electronically. It will happen because it makes sound economic sense for the provider and for the carrier, and it will make life easier for the insured. It is no wonder EMC has become one of the hottest topics and growth areas in the healthcare information systems industry today.

Prolonged mechanical ventilation and intracranial hemorrhage: impact on developmental progress through 18 months in infants weighing 1,200 grams or less at birth.

In this prospective, longitudinal study, the relative impact of intracranial hemorrhage and prolonged mechanical ventilation on developmental progress during the first 18 months of life of infants weighing 1,200 g or less at birth was examined. A total of 159 surviving infants were divided into two groups: infants with and those without intracranial hemorrhage. These groups were then subdivided into groups of infants receiving prolonged mechanical ventilation (greater than 21 days) and those mechanically ventilated for 21 days or less, thus creating four subgroups. Group 1 (intracranial hemorrhage and prolonged mechanical ventilation) and group 3 (intracranial hemorrhage and no prolonged mechanical ventilation) showed no statistically significant differences for severity of intracranial hemorrhage, persistence of ventriculomegaly, or presence of periventricular leukomalacia. A repeated-measures analysis of variance demonstrated a main effect for prolonged mechanical ventilation on outcome as measured by the Bayley Mental Development Index and Bayley Psychomotor Development Index at 4, 8, 12, and 18 months of age (corrected for prematurity). Forward stepwise regression revealed prolonged mechanical ventilation to the best predictor of Bayley indexes at all ages except 4 months of age, for which the Psychomotor Development Index was best predicted by length of hospitalization. No main effect for intracranial hemorrhage was demonstrated, but the motor performance of infants with intracranial hemorrhage declined significantly with age. By contrast prolonged mechanical ventilation was associated with uniformly poor performance at every age and serves as a powerful marker for poor developmental progress during the first 18 months of life in infants weighing 1,200 g or less at birth.

Intracranial hemorrhage and neurodevelopmental outcome at one year in infants weighing 1200 grams or less. Prognostic significance of ventriculomegaly at term gestational age.

Seventy-five surviving infants weighting 1200 g or less at birth were followed up longitudinally, employing real-time ultrasonographic examination of the brain from birth to term corrected gestational age. Evaluations using the Milani-Comparetti Motor Developmental Screening Test and developmental testing using the Bayley Scales of Infant Development were performed at 4, 8, and 12 months corrected age. Thirty-five (46.7%) of the infants were diagnosed to have intracranial hemorrhage (ICH). These infants were significantly smaller and lighter and were mechanically ventilated close to five times longer than infants without ICH. ICH was predictive of poorer developmental outcome through the first postnatal year. ICH infants had significantly lower Bayley motor scores at both 4 and 12 months. Sixteen of the 20 who scored less than 84 on one or both of the Bayley Scales at one year had a history of ICH. When infants with hemorrhage and normal ventricles at term (ICH-no VM) were compared to infants with hemorrhage and ventriculomegaly at term (ICH-VM), the poorest motor outcome was seen in the ICH-VM group. Only the ICH-VM group showed motor performance significantly poorer than the non-ICH group at 12 months of age. Regardless of severity of hemorrhage, the data suggested an added risk for poorer developmental outcome in ICH survivors who had ventriculomegaly or abnormal periventricular morphology at term. Thus, intracranial hemorrhage per se indicates significantly greater risk of short-term motor sequelae continuing through the first four postnatal months, but persistently abnormal ventricles serve as a more significant "marker" of risk for longer term neuromotor delays at one year corrected age.(ABSTRACT TRUNCATED AT 250 WORDS)