Robert H. Harrison

Maternal Depressive Symptoms Affect Infant Cognitive Development in Barbados

This longitudinal study is part of a series examining the relationships between maternal mood, feeding practices, and infant growth and development during the first 6 months of life in 226 well-nourished mother-infant dyads in Barbados. In this report, we assessed maternal moods (General Adjustment and Morale Scale and Zung Depression and Anxiety Scales), feeding practices (scales describing breast-feeding and other practices associated with infant feeding in this setting), and infant cognitive development (Griffiths Mental Development Scales). Multivariate analyses, with and without controlling for background variables, established significant relationships between maternal moods and infant cognitive development. Infants of mothers with mild moderate depression had lower Griffiths scores than infants of mothers without depression. Maternal depressive symptoms and lack of trust at 7 weeks predicted lower infant social and performance scores at 3 months. Maternal moods at 6 months were associated with lower scores in motor development at the same age. Although no independent relationships emerged between feeding practices and infant cognitive development, the combination of diminished infant feeding intensity and maternal depression predicted delays in infant social development. These findings demonstrate the need to carefully monitor maternal moods during the postpartum period, in order to maximize the benefits of breast-feeding and related health programs to infant cognitive development.

Maternal moods predict breastfeeding in Barbados.

This study was designed to identify psychosocial variables affecting early infant feeding practices in Barbados. The sample included 93 healthy women and infants born at the Queen Elizabeth Hospital who were extensively evaluated 7 weeks, 3 months, and 6 months after birth. Maternal moods were assessed with the Zung Depression and Anxiety Scales and the General Adjustment and Morale Scale. Feeding practices were evaluated using a questionnaire developed for this population. The prevalence of mild depression in this population was 16% at 7 weeks and increased to 19% at 6 months, whereas there were very few cases of moderate-to-severe depression. Disadvantaged environmental conditions, including less information-seeking by the mother, lower family income, and poor maternal health, were closely associated with increased symptoms of depression and anxiety in all women. However, significant predictive relationships between mood and feeding practices remained even when the effects of the home environment were controlled. Specifically, depressive symptoms at 7 weeks postpartum predicted a reduced preference for breastfeeding at current and later infant ages. Conversely, feeding practices did not predict maternal moods at later ages. These findings have important implications for public policy dealing with programs promoting breastfeeding. Early interventions designed to treat mild postnatal depression should be instituted early in the postpartum period to improve the chances for successful breastfeeding.

Early Childhood Malnutrition Predicts Depressive Symptoms at Ages 11–17

BACKGROUND We examined the prevalence of depressive symptoms in Barbadian youth with histories of infantile malnutrition and in a healthy comparison group and the extent to which the effect of malnutrition was mediated/moderated by maternal depression. METHODS Depressive symptoms were assessed using a 20-item scale administered to youths (11-17 years of age) who had experienced an episode of protein-energy malnutrition (marasmus or kwashiorkor) during the first year of life and in a comparison group of healthy youths without a history of malnutrition. Their mothers completed the same questionnaire on the same test on three occasions when their children were 5-17 years of age at 2-5-year intervals. RESULTS The prevalence of depressive symptoms was elevated among previously malnourished youth relative to healthy comparison children (p < .001). When youth depression scores were subjected to a longitudinal multiple regression analysis, adjusting for the effect of maternal depressive symptoms, significant effects due to the history of early childhood malnutrition remained and were not discernibly attenuated from an unadjusted analysis. We also found significant independent effects of maternal depressive symptoms on youth depressive symptoms. CONCLUSION Early childhood malnutrition contributed independently to depressive symptoms in youths who experienced a significant episode of malnutrition in the first year of life. This relationship was not mediated or moderated by the effects of maternal depression. Whether the later vulnerability to depression is a direct effect of the episode of malnutrition and related conditions early in life or whether it is mediated by the more proximal neurobehavioral effects of the malnutrition remains to be determined.

A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol

A 10-aa motif in transmembrane helix 1 of diphtheria toxin that is conserved in anthrax edema factor, anthrax lethal factor, and botulinum neurotoxin serotypes A, C, and D was identified by blast, clustal w, and meme computational analysis. Using the diphtheria toxin-related fusion protein toxin DAB389IL-2, we demonstrate that introduction of the L221E mutation into a highly conserved residue within this motif results in a nontoxic catalytic domain translocation deficient phenotype. To further probe the function of this motif in the process by which the catalytic domain is delivered from the lumen of early endosomes to the cytosol, we constructed a gene encoding a portion of diphtheria toxin transmembrane helix 1, T1, which carries the motif and is expressed from a CMV promoter. We then isolated stable transfectants of Hut102/6TG cells that express the T1 peptide, Hut102/6TG-T1. In contrast to the parental cell line, Hut102/6TG-T1 cells are ca. 104-fold more resistant to the fusion protein toxin. This resistance is completely reversed by coexpression of small interfering RNA directed against the gene encoding the T1 peptide in Hut102/6TG-T1 cells. We further demonstrate by GST-DT140-271 pull-down experiments in the presence and absence of synthetic T1 peptides the specific binding of coatomer protein complex subunit β to this region of the diphtheria toxin transmembrane domain.

The influence of early malnutrition on subsequent behavioral development. IV. Soft neurologic signs.

Summary: Soft neurologic signs were evaluated in 101 Barbadian school children, ages 4-11 years, who were malnourished in the first year of life, and 101 comparison children matched for age, sex, and handedness, but who had no history of malnutrition. Previously malnourished children performed significantly slower than comparison children on several timed motor tasks when using the nondominant hand only. Boys were found to perform significantly slower than girls, and younger (4-7 years of age) children performed slower than older (8-11 years of age) children. A model is presented that displays interrelationships among previous malnutrition, soft neurologic signs, classroom behavior, intelligence, and physical growth. In summary, slow motor performance was associated with lower verbal and performance IQ and the presence of attention deficit disorder, as assessed by the childs teacher. The time to perform the motor tests was unrelated to measures of physical growth.

Characterization of the Role of the Divalent Metal Ion-Dependent Transcriptional Repressor MntR in the Virulence of Staphylococcus aureus

ABSTRACT DtxR-type metal ion-dependent repressors, present in many bacterial pathogens, may regulate expression of virulence genes such as that encoding diphtheria toxin. SirR, a DtxR homologue initially identified in Staphylococcus epidermidis, governs the expression of the adjacent sitABC operon encoding a putative metal ion ABC transporter system. We identified a sirR homologue, mntR, in Staphylococcus aureus and demonstrated by gel shift assay that the corynebacterial repressor DtxR binds to the S. aureus mntABC operator in the presence of Fe2+ or Mn2+. Since a mutant DtxR, DtxR(E175K), functions as an iron-independent hyperrepressor in certain settings, we constructed a heterodiploid S. aureus strain expressing dtxR(E175K) from the native mntR promoter. Transcription of the S. aureus mntABC operon was repressed in the presence of Fe2+ or Mn2+ in wild-type and heterodiploid S. aureus strains. Under metal ion-limiting conditions, mntABC transcription was reduced but not abolished in S. aureus isolates expressing dtxR(E175K) compared with an isogenic control, suggesting that DtxR(E175K) binds the S. aureus MntR box in vivo. Under all conditions tested, mntABC transcription in the dtxR(E175K)-expressing strain was reduced relative to the isogenic control, indicating that DtxR(E175K) function was constitutively active. In the mouse skin abscess model, dtxR(E175K)-expressing S. aureus recombinants showed significantly reduced CFU levels compared with the isogenic wild-type control. We conclude that the S. aureus MntR box is recognized by corynebacterial DtxR proteins and thus belongs to the DtxR family of metal-dependent operator sites. Moreover, constitutive repression by DtxR(E175K) reduces the virulence of S. aureus in the mouse skin abscess model.

Developmental changes in children's abilities to match and label emotionally laden situations

In two studies, male and female preschoolers and third- and fourth-graders were tested on their abilities to match and generate affective labels for 19 types of emotionally laden situations. Age changes were found in the accuracy with which situations were both labeled and matched; the ability to match similar situations was more strongly related to age than was the ability to label emotions. Matching and labeling abilities were positively related to each other. Both age groups were best at labeling situations depicting happiness, anger, and sadness, and at matching situations depicting sadness, anger, and disgust, but both age groups were capable of matching a wide variety of emotions depicted in situations at a better than chance rate. Only situations depicting fear, nervousness, and embarrassment were not matched better than chance by either preschoolers or third- and fourth-graders.

COPI coatomer complex proteins facilitate the translocation of anthrax lethal factor across vesicular membranes in vitro

The delivery of the diphtheria toxin catalytic domain (DTA) from acidified endosomes into the cytoplasm of eukaryotic cells requires protein–protein interactions between the toxin and a cytosolic translocation factor (CTF) complex. A conserved peptide motif, T1, within the DT transmembrane helix 1 mediates these interactions. Because the T1 motif is also present in the N-terminal segments of lethal factor (LF) and edema factor (EF) in anthrax toxin, we asked whether LF entry into the cell might also be facilitated by target cell cytosolic proteins. In this study, we have used LFnDTA and its associated ADP-ribosyltransferase activity (DTA) to determine the requirements for LF translocation from the lumen of endosomal vesicles to the external medium in vitro. Although low-level release of LFnDTA from enriched endosomal vesicles occurs in the absence of added factors, translocation was enhanced by the addition of cytosolic proteins and ATP to the reaction mixture. We show by GST-LFn pull-down assays that LFn specifically interacts with at least ζ-COP and β-COP of the COPI coatomer complex. Immunodepletion of COPI coatomer complex and associated proteins from cytosolic extracts blocks in vitro LFnDTA translocation. Translocation may be reconstituted by the addition of partially purified bovine COPI to the translocation assay mixture. Taken together, these data suggest that the delivery of LF to the cytosol requires either COPI coatomer complex or a COPI subcomplex for translocation from the endosomal lumen. This facilitated delivery appears to use a mechanism that is analogous to that of DT entry.

Cognitive Impairment as a Mediator in the Developmental Pathway From Infant Malnutrition to Adolescent Depressive Symptoms in Barbadian Youth

Objective: Depressive symptoms are elevated in adolescents who experienced significant malnutrition early in life. Early malnutrition can also have a significant impact on cognitive functioning, presumably because of the adverse impact of the malnutrition on the very young brain. In the context of a developmental cascade model, we tested the hypothesis that the association between early malnutrition and adolescent depressive symptoms is mediated by the cognitive impairment that ensues from the malnutrition. Methods: We evaluated Barbadian youth (N = 57) hospitalized for moderate to severe protein-energy malnutrition in the first year of life and healthy controls (N = 60) longitudinally. The primary hypothesis was tested by multiple regression models. Results: After adjusting for covariates, early malnutrition predicted both cognitive functioning in childhood (IQ, p < .001; attention problems, p < .01; Common Entrance Examination, p < .01; and adolescent depressive symptoms, p < .05). Childhood cognitive functioning mediated the association between early malnutrition and depressive symptoms in adolescence (p < .001). Maternal depressive symptoms were a significant but independent predictor of adolescent depressive symptoms (p < .05). Conclusions: Cognitive compromise in childhood accounts indirectly for elevated depressive symptoms in previously malnourished adolescents, consistent with a developmental cascade model. The direct link between malnutrition and depressive symptoms in adolescence is small.

Differential effects of prenatal protein malnutrition and prenatal cocaine on a test of homing behavior in rat pups

The effects of prenatal cocaine exposure and protein malnutrition on orientation to home nest material was assessed in rat pups. Sprague-Dawley dams were fed a diet of low protein content (6% casein), and isocaloric diet of adequate protein content (25% casein, control), or a laboratory chow diet prior to mating and throughout pregnancy. Within each diet group, rats received either cocaine injections (30 mg/kg IP 2 times per week prior to mating and the 30 mg/kg SC daily from day 3 to 18 of pregnancy) or saline injections. All litters were fostered on the day of birth to control mothers fed an adequate diet. On postnatal days 7, 9, and 11, a single pup from each litter (n = 11-15 per treatment) was tested repeatedly in a clean test cage for the rapidity of approach, and level of attraction to their own home (nest) bedding compared with fresh bedding. Prenatal malnutrition and prenatal cocaine exposure each gave rise to independent effects on performance, based upon factor analysis. Prenatal malnutrition, but not prenatal cocaine increased the time taken for rat pups to approach their nest bedding, reduced the time spent on this bedding, decreased the number of entries into the sector containing the home bedding and reduced pup weight. Prenatal cocaine, but not prenatal malnutrition, produced a reduction in activity, but had no effect on pup weight. The lower activity level was most pronounced on postnatal day 7. Surprisingly, interactive effects of prenatal cocaine and prenatal malnutrition were not observed on any behavior examined. Nevertheless, the co-existence of drug addiction and malnutrition in human populations raises the possibility that some of the effects generally attributed to drug exposure may, in fact, be due to malnutrition.