Parental care and control during childhood: associations with maternal perinatal mood disturbance and parenting stress

This study examined the associations between perceived parental care and control in childhood and maternal anxiety, depression and parenting stress during the transition to parenthood. Eighty-eight women completed the Parental Bonding Instrument, self-report measures of anxiety and depression and a structured diagnostic interview (Mini-plus International Neuropsychiatric Interview) during the third trimester of pregnancy. The MINI-Plus and anxiety and depression measures were re-administered at 7 months postpartum. The Parenting Stress Index was also administered at this time. Significant associations were found between maternal 'affectionless control' and prenatal and postnatal symptom measures of anxiety and depression, p values <0.005. Compared to women who reported optimal parenting, women who recalled maternal 'affectionless control' were also six times more likely to be diagnosed with an anxiety disorder during pregnancy (OR = 6.1, 95% CI = 2.17-30.11) and seven times more likely to be diagnosed with postnatal major depression (OR = 6.8, 95% CI = 1.80-25.37). Paternal 'affectionless control' was associated with significantly higher scores on symptom measures of prenatal and postnatal anxiety, p values <0.005. This study suggests that assessing a woman's own parenting history is important in identifying and managing the risk of prenatal and postnatal affective disorders and parenting stress.     

Intracoronary delivery of DNAzymes targeting human EGR-1 reduces infarct size following myocardial ischaemia reperfusion

Despite improvements in treatment, myocardial infarction (MI) remains an important cause of morbidity and mortality. Inflammation arising from ischaemic and reperfusion injury is a key mechanism which underpins myocardial damage and impairment of cardiac function. Early growth response-1 (Egr-1) is an early immediate gene and a master regulator that has been implicated in the pathogenesis of ischaemia-reperfusion (IR) injury. This study sought to examine the effect of selective inhibition of Egr-1 using catalytic deoxyribonucleic acid molecules (DNAzymes, DZs) delivered via the clinically relevant coronary route in a large animal model of myocardial IR. It was hypothesized that Egr-1 inhibition with intracoronary DZ would reduce infarction size by modulating its downstream effector molecules. Egr-1 DZs inhibited the adherence of THP-1 monocytes to IL-1β-activated endothelial cells in vitro and retained its catalytic activity up to 225 min after in vivo administration. In a porcine model of myocardial IR (45 min ischaemia/3 h reperfusion), DZ was taken up in the cytoplasm and nuclei of cardiomyocytes and endothelial cells in the myocardium after intracoronary delivery. Egr-1 DZs reduced infarct size and improved cardiac functional recovery following intracoronary delivery at the initiation of IR in this large animal model of MI. This was associated with inhibition of pro-inflammatory Egr-1 and ICAM-1 expression, and the reduced expression of TNF-α, PAI-1, TF, and myocardial MPO activity in tissue derived from the border zone of the infarct. Taken together, these data suggest that strategies targeting Egr-1 via the intracoronary route after IR injury in pigs have potential therapeutic implications in human MI.     

Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF(V600E)-induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF(V600E)-driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15(INK4B). This treatment also eliminated subpopulations resistant to targeted BRAF(V600E) inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF(V600E) inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.     

Neither single-marker nor haplotype analyses support an association between genetic variation near NOTCH4 and bipolar disorder.

Markers near the NOTCH4 locus on chromosome 6p21.3 have been reported to be associated with schizophrenia in some studies. Since schizophrenia and bipolar affective disorder (BPAD) may share genetic determinants, we tested markers in and near NOTCH4 in a sample of 153 parent-offspring triads ascertained through a sibling pair with BPAD for evidence of association. This sample would have 80% power to detect an association at or above a genotype relative risk of 2.4 at the 10(-7) level of significance. In addition to the two markers previously showing the most significant association with schizophrenia, three additional nearby markers were studied. The five markers were genotyped using validated methods. Both single-marker and 3-marker haplotype data was analyzed using family-based association methods. No genome-wide significant association was detected between any of the five SNP-markers and BPAD in this sample. One marker showed nominal evidence of association (P = 0.049), but this evidence was not supported by haplotype analyses including nearby flanking markers or by case-control analysis using 93 Caucasian controls. These results do not support an association between genetic variation near NOTCH4 and BPAD in this sample.     

The controversial role of phosphodiesterase type 5 inhibitors in the treatment of premature ejaculation

IntroductionIt is controversial whether or not the most frequent male sexual dysfunctions, premature ejaculation (PE) and erectile dysfunction (ED), share pathogenetic mechanisms and treatments.MethodsThree scientists (C.McM., J.C., and A.A.), together with the Controversy's Editor (E.A.J.), with expertise in the area of medical treatment of PE, present different perspectives on the use of phosphodiesterase type 5 inhibitors (PDE5is) in PE. The psychological point of view is discussed by an expert in sexology (M.P.).Main Outcome MeasureOutcome measures used are expert opinions supported by the critical review of the currently available literature.ResultsThis Controversy examines the role of nitric oxide (NO) as a neurotransmitter involved in the central and peripheral control of ejaculation, the adherence of methodology to the contemporary consensus of ideal PE drug trial design, the impact of methodology on treatment outcomes, and the role of PDE5i drugs (sildenafil, tadalafil, and vardenafil) in the treatment of PE.ConclusionsWhile it is evident that PDE5is are the first choice in patients with comorbid ED and PE (where one may be secondary to the other), well‐designed studies on the possible use of PDE5is in PE patients without ED are still limited. The issue will be less controversial when further evidence on the role of NO and PDE5 in the mechanism of ejaculation is available. Jannini EA, McMahon C, Chen J, Aversa A, and Perelman M. The controversial role of PDE5 inhibitors in the treatment of premature ejaculation. J Sex Med 2011;8:2135–2143.     

Mothering from the Inside Out: results of a pilot study testing a mentalization-based therapy for mothers enrolled in mental health services

Mothers who are involved with mental health services (for themselves or their children) rarely receive adequate support for their role as parents. Mental illness in a parent or child often exacerbates the challenges of managing psychological distress that is germane to the parenting roll. Mentalization-based approaches to psychotherapy for parents have the potential to address challenges of emotional regulation in parents by supporting their capacity to recognize and modulate negative affect during stressful parenting situations. In this study, we piloted Mothering from the Inside Out (MIO) with 17 mothers receiving services at a community-based mental health clinic. MIO is a 12-week, mentalization-based parenting intervention that demonstrated efficacy in two previous randomized controlled trials with substance using mothers. In this study, we were interested in determining whether community-based clinicians could deliver MIO with sustained fidelity. We were also interested in examining the preliminary feasibility, acceptability and efficacy of MIO when delivered by clinicians in a community mental health center. Finally, we were interested in replicating prior tests of the proposed treatment mechanisms. Treatment outcomes included maternal reflective functioning, psychiatric and parenting stress, and mother–child interaction quality. Our findings indicated that MIO was feasible and acceptable when delivered in the community-based setting and that all maternal indices improved. However, no improvement in mother–child interaction quality was found, possibly because of insufficient time for these changes to consolidate.     

Pharmacological characterization of glycine-gated chloride currents recorded in rat hippocampal slices

An inhibitory role for strychnine-sensitive glycine-gated chloride channels (GlyRs) in mature hippocampus has been overlooked, largely due to the misconception that GlyR expression ceases early during development and to few functional studies demonstrating their presence. As a result, little is known regarding the physiological and pharmacological properties of native GlyRs expressed by hippocampal neurons. In this study, we used pharmacological tools and whole cell patch-clamp recordings of CA1 pyramidal cells and interneurons in acutely prepared hippocampal slices from 3- to 4-wk old rats to characterize these understudied receptors. We show that glycine application to recorded pyramidal cells and interneurons elicited strychnine-sensitive chloride-mediated currents (I(gly)) that did not completely desensitize in the continued presence of agonist but reached a steady state at 45-60% of the peak amplitude. Additionally, the inhibitory amino acid, taurine, which has been shown to activate GlyRs in other systems, activated GlyRs expressed by both pyramidal cells and interneurons, although with much less potency than glycine, having an EC(50) 10-fold higher. To examine the potential subunit composition of hippocampal GlyRs, we tested the effect of the GABA(A) receptor antagonist, picrotoxin, on I(gly) recorded from both cell types. At low micromolar concentrations of picrotoxin (< or =100 microM), which selectively block alpha homomeric GlyRs, I(gly) was partially attenuated in both cell types, indicating that alpha homomeric receptors are expressed by pyramidal cells and interneurons. At picrotoxin concentrations < or =1 mM, approximately 10-20% of the whole cell current remained, suggesting that alphabeta heteromeric GlyRs are also expressed because this subtype of GlyR is relatively resistant to picrotoxin antagonism. Finally, we examined whether hippocampal GlyRs are modulated by zinc. Consistent with previous reports in other preparations, zinc elicited a bidirectional modulation of GlyRs, with physiological zinc concentrations (1-100 microM) increasing whole cell currents and concentrations >100 microM depressing them. Furthermore, the same concentration of zinc that potentiates I(gly) suppressed currents mediated by the N-methyl-D-aspartate subtype of the glutamate receptor. Thus we provide a pharmacological characterization of native GlyRs expressed by both major neuron types in hippocampus and show that these receptors can be activated by taurine, an amino acid that is highly concentrated in hippocampus. Furthermore, our data suggest that at least two GlyR subtypes are present in hippocampus and that GlyR-mediated currents can be potentiated by zinc at concentrations that suppress glutamate-mediated excitability.     

Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: Chromosomes 3, 5, 15, 16, 17, and 22

As part of the four-center NIMH Genetics Initiative on Bipolar Disorder we carried out a genomic scan of chromosomes 3, 5, 15, 16, 17, and 22. Genotyping was performed on a set of 540 DNAs from 97 families, enriched for affected relative pairs and parents where available. We report here the results of the initial 74 markers that have been typed on this set of DNAs. The average distance between markers (θ) was 12.3 cM. Nonparametric analysis of excess allele sharing among affected sibling pairs used the SIBPAL program of the S.A.G.E. package to test three hierarchical models of affected status. D16S2619 gave some evidence of linkage to bipolar disorder, with P = 0.006 for Model II (in which bipolar 1, bipolar 2 and schizoaffective-bipolar type individuals are considered affected). Nearby markers also showed increased allele sharing. A second interesting region was toward the telomere of chromosome 5q, where D5S1456 and nearby markers showed increased allele sharing; for D5S1456, P = 0.05, 0.015 and 0.008 as the models of affected status become more broad. MOD score analysis also supported the possible presence of a susceptibility locus in this region of chromosome 5. A pair of adjacent markers on chromosome 3, D3S2405 and D3S3038, showed a modest increased allele sharing in the broad model. Several isolated markers had excess allele sharing at the P < 0.05 level under a single model. D15S217 showed a MOD score of 2.37 ( P < 0.025). Multipoint analysis flagged the region of chromosome 22 around D22S533 as the most interesting. Thus, several regions showed modest evidence for linkage to bipolar disorder in this initial genomic scan of these chromosomes, including broad regions near previous reports of possible linkage. Am. J. Med. Genet. 74:238–246, 1997. © Wiley-Liss, Inc.     

Role of radial glia in cytogenesis, patterning and boundary formation in the developing spinal cord

Radial glial fibres provide a transient scaffold and impose constraints in the developing central nervous system (CNS) that facilitate cell migration and axon growth. Recent reports have raised doubts about the distinction between radial glia and precursor cells by demonstrating that radial glia are themselves neuronal progenitor cells in the developing cortex, indicating a dual role for radial glia in both neurogenesis and migration guidance. Radial glia shift toward exclusive generation of astrocytes after neurogenesis has ceased. Radial progenitor cell differentiation and lineage relationships in CNS development are complex processes depending on genetic programming, cell-cell interaction and microenvironmental factors. In the spinal cord, radial cells that arise directly from the neuroepithelium have been identified. At least in the spinal cord, these radial cells appear to be the precursors to radial glia. It remains unknown whether radial glial cells or their precursors, the radial cells, or both can give rise to neurons in the spinal cord. Radial glial cells are also important in regulating the axon out-growth and pathfinding processes that occur during white matter patterning of the developing spinal cord.