Clarifying the role of neuroticism in suicidal ideation and suicide attempt among women with major depressive disorder.

BACKGROUND: Prior research consistently demonstrates that neuroticism increases risk for suicidal ideation, but the association between neuroticism and suicidal behavior has been inconsistent. Whereas neuroticism is recommended as an endophenotype for suicidality, the association of neuroticism with attempted suicide warrants clarification. In particular, prior research has not distinguished between correlates of attempted suicide, correlates of suicidal ideation, and correlates of comorbid psychopathology. METHODS: The present study used the CONVERGE study, a sample of 5864 women with major depressive disorder (MD) and 5783 women without MD throughout China. Diagnoses, suicidal ideation, and attempted suicide were assessed with the Composite International Diagnostic Interview (CIDI). Neuroticism was assessed with the neuroticism portion of the Eysenck Personality Questionnaire. RESULTS: Results replicate prior findings on the correlates of suicidal ideation, particularly elevated neuroticism among individuals who report prior suicidal ideation. Moreover, as compared with individuals who reported having experienced only suicidal ideation, neuroticism was associated with decreased likelihood of having attempted suicide. CONCLUSIONS: The association of neuroticism with suicidality is more complicated than has been previously described. Whereas neuroticism increases risk for suicidal ideation, neuroticism may decrease risk for a suicide attempt among individuals with suicidal ideation. These results have implications for the assessment of risk for a suicide attempt among individuals who report suicidal ideation and addresses prior discordant findings by clarifying the association between neuroticism and attempted suicide.

Peripheral blood gene expression signature differentiates children with autism from unaffected siblings.

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders with high heritability, yet a majority of genetic contribution to pathophysiology is not known. Siblings of individuals with ASD are at increased risk for ASD and autistic traits, but the genetic contribution for simplex families is estimated to be less when compared to multiplex families. To explore the genomic (dis-) similarity between proband and unaffected sibling in simplex families, we used genome-wide gene expression profiles of blood from 20 proband-unaffected sibling pairs and 18 unrelated control individuals. The global gene expression profiles of unaffected siblings were more similar to those from probands as they shared genetic and environmental background. A total of 189 genes were significantly differentially expressed between proband-sib pairs (nominal p < 0.01) after controlling for age, sex, and family effects. Probands and siblings were distinguished into two groups by cluster analysis with these genes. Overall, unaffected siblings were equally distant from the centroid of probands and from that of unrelated controls with the differentially expressed genes. Interestingly, five of 20 siblings had gene expression profiles that were more similar to unrelated controls than to their matched probands. In summary, we found a set of genes that distinguished probands from the unaffected siblings, and a subgroup of unaffected siblings who were more similar to probands. The pathways that characterized probands compared to siblings using peripheral blood gene expression profiles were the up-regulation of ribosomal, spliceosomal, and mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune response and calcium signaling pathways. Further integrative study with structural genetic variations such as de novo mutations, rare variants, and copy number variations would clarify whether these transcriptomic changes are structural or environmental in origin.

General health status of children with D-transposition of the great arteries after the arterial switch operation.

BACKGROUND: To study the long-term impact on general health status of D-transposition of the great arteries (D-TGA) after the arterial switch operation (ASO) during infancy, we asked parents to complete the Child Health Questionnaire, Parent Form-50 when their children were 8 years old. METHODS AND RESULTS: Of 160 eligible patients, questionnaires were completed for 155 subjects (96%). Median age at surgery was 6 days (range 1 to 67 days), and median age at completion of the Child Health Questionnaire was 8.1 years (7.6 to 10.0 years). Subsequent to questionnaire completion, children underwent psychometric testing. Mean Physical Health Summary and Psychosocial Summary scores were 54.0+/-6.1 and 49.7+/-9.9, respectively, which were similar to those of normal subjects. Compared with the normative sample, parents of D-TGA patients reported more problems with attention, learning, and speech, as well as greater frequency of developmental delay (P<0.001 for each). Worse Psychosocial Summary scores were significantly associated with lower full-scale IQ (P=0.001) and lower achievement in reading (P=0.005) and math (P=0.007). Worse Physical Health Summary scores were associated with longer hospital stay after the ASO (P=0.02). General health status scores were not significantly related to presence of ventricular septal defect, age at surgery, perfusion variables during the ASO, sex, or history of cardiac reoperation. CONCLUSIONS: At age 8 years, children with D-TGA after ASO have an overall physical and psychosocial health status similar to that of the general population. Lower IQ and academic achievement are associated with worse psychosocial health status, whereas longer hospital course after initial surgery is associated with worse physical health status.

Developmental and neurologic effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants.

OBJECTIVES: In a randomized single-center trial, we compared developmental and neurologic outcomes at 1 and 2 to 4 years of age in children who underwent reparative cardiac operations at less than 9 months of age after use of the alpha-stat versus pH-stat strategy during deep hypothermic cardiopulmonary bypass. METHODS: Among 168 children eligible for follow-up, 1-year developmental evaluations were carried out on 111, neurologic evaluations on 110, and electroencephalographic evaluations on 102. Parents of 122 children completed questionnaires on behavior and development when children were 2 to 4 years of age. RESULTS: The Psychomotor Development Index scores of the alpha-stat and pH-stat groups did not differ significantly (P =.97). For Mental Development Index scores, the treatment group effect differed according to diagnosis (P =.007). In the D -transposition of the great arteries (n = 59) and tetralogy of Fallot (n = 36) subgroups, the pH-stat group had slightly higher Mental Development Index scores than the alpha-stat group, although these differences were not statistically significant. In the ventricular septal defect subgroup (n = 16), the alpha-stat group had significantly higher scores. Psychomotor Development Index and Mental Development Index scores were significantly higher in the group with D -transposition of the great arteries than in the other 2 groups (P =.03 and P =.01, respectively). Across all diagnoses, Mental Development Index scores were significantly higher than Psychomotor Development Index scores (P <.001). Treatment group assignment was not significantly associated with abnormalities on neurologic examination (P =.70) or electroencephalographic examination (P =.77) at 1 year or with parents' ratings of children's development (P =.99) or behavior (P =.27) at age 2 to 4 years. CONCLUSIONS: Use of alpha-stat versus pH-stat acid-base management strategy during reparative infant cardiac operations with deep hypothermic cardiopulmonary bypass was not consistently related to either improved or impaired early neurodevelopmental outcomes.

Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life.

The development of cardiac hypertrophy during neonatal life and in adults implies different processes. The angiotensin II (Ang II) system is involved in the development of cardiac hypertrophy in adults, but its role in neonates remains unclear. The aim of this study was to estimate the influence of increased hemodynamic load on the developmental pattern of the AT1/AT2 receptor expression in the heart. Two-day-old rats submitted to abdominal aortic constriction (AC) or sham operation were sacrificed 2 h, and 1, 3, and 8 days after surgery. Ang II was evaluated in sera and immunohistology was performed to define the cardiac hypertrophy process. The Ang II receptor subtypes 1 and 2 were quantified at the receptor and mRNA levels by(125)I-Ang II binding and RT-PCR, respectively. Ang II content in sera increased transiently 2 h after surgery in the AC group. In sham-operated, AT1 and AT2 decreased throughout the period studied at both mRNA and receptor levels. However, the AT1 mRNA level decrease was more pronounced than that of AT2 (by 57% and 27%, respectively). AC not only prevented the postnatal decrease in AT mRNA level but resulted in an increase in AT1 mRNA 8 days after surgery (P<0.05). Besides in the AC groups, AT2 mRNA levels but not those of AT1 mRNA were linearly correlated with the left ventricular mass. At the receptor level, a significant transient (1 day after surgery) increase in both AT1 and AT2 was observed. In conclusion, our data demonstrated that imposition of pressure overload soon after birth altered the pattern of AT receptor expression.

Reliability and validity of a DSM-IV based ADHD screener.

The Diagnostic Rating Scale (DRS) was completed by the parents and teachers of 82 children referred for clinical evaluations, 73 referred children seen twice, and 218 non-referred children from the community. The DRS, which uses a categorical rather than a dimensional rating approach, was 70% to 90% sensitive to diagnoses of Attention Deficit/Hyperactivity Disorder (ADHD) made by blind clinical teams. In research and clinical applications, the DRS could improve screening efficiency, especially in situations where it would be desirable to exclude all children who might have ADHD or identify all children with Hyperactive-Impulsive symptoms. Because of its objectivity and consistency with the Diagnostic and Statistical Manual (DSM)-IV criteria, the DRS could facilitate comparison of participant samples across studies.

An evaluation of an innovative multimedia educational software program for asthma management: report of a randomized, controlled trial.

BACKGROUND: Asthma continues to be a substantial cause of morbidity in pediatric populations. New strategies are needed to provide cost-effective educational interventions for children with asthma, particularly those in the inner city. OBJECTIVE: To assess the effectiveness of a multimedia educational software program about asthma. SETTING: A hospital-based primary care clinic and an affiliated neighborhood health center. DESIGN: Randomized, controlled trial. POPULATION: Children 3 to 12 years old with physician-diagnosed asthma. INTERVENTION: An interactive educational computer program, Asthma Control, designed to teach children about asthma and its management. Using a graphic display of a child going through simulated daily events, the game emphasizes: 1) monitoring; 2) allergen identification; 3) use of medications; 4) use of health services; and 5) maintenance of normal activity. Control group participants reviewed printed educational materials with a research assistant. OUTCOMES: Acute health care use (emergency department and outpatient) was the primary outcome. Secondary outcome measures included maternal report of asthma symptom severity, child functional status and school absences, satisfaction with care, and parental and child knowledge of asthma. RESULTS: A total of 137 families were enrolled in the study (76 intervention, 61 control). Both intervention and control groups showed substantial improvement in all outcomes during the 12-month follow-up period. Aside from improvement in knowledge after use of the computer program, no differences were demonstrated between the 2 groups in primary or secondary outcome measures. Children reported enjoyment of program use. CONCLUSIONS: This trial of an educational software program found that it did not produce greater improvement than occurred with review of traditional written materials. Because both groups showed substantial improvement over baseline, computer-based education may be more cost-effective. Alternatively, improvements in illness severity over time may overshadow the effects of such interventions. Rigorous comprehensive evaluations such as this are necessary to assess new interventions intended to improve management and outcomes of asthma.

Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function.

OBJECTIVES: Transplantation of fetal cardiomyocytes improves function of infarcted myocardium but raises availability, immunologic, and ethical issues that justify the investigation of alternate cell types, among which skeletal myoblasts are attractive candidates. METHODS: Myocardial infarction was created in rats by means of coronary artery ligation. One week later, the animals were reoperated on and intramyocardially injected with culture growth medium alone (controls, n = 15), fetal cardiomyocytes (5 x 10(6) cells, n = 11), or neonatal skeletal myoblasts (5 x 10(6) cells, n = 16). The injections consisted of a 150-microL volume and were made in the core of the infarct, and the animals were immunosuppressed. Left ventricular function was assessed by echocardiography immediately before transplantation and 1 month thereafter. Myoblast-transplanted hearts were then immunohistologically processed for the expression of skeletal muscle-specific embryonic myosin heavy chain and cardiac-specific connexin 43. RESULTS: The left ventricular ejection fraction markedly increased in the fetal and myoblast groups from 39.3% +/- 3.9% to 45% +/- 3.4% (P =.086) and from 40.4% +/- 3.6% to 47.3% +/- 4.4% (P =.034), respectively, whereas it decreased in untreated animals from 40.6% +/- 4% to 36.7% +/- 2.7%. Transplanted myoblasts could be identified in all animals by the positive staining for skeletal muscle myosin. Conversely, clusters of connexin 43 were not observed on these skeletal muscle cells. CONCLUSIONS: These results support the hypothesis that skeletal myoblasts are as effective as fetal cardiomyocytes for improving postinfarction left ventricular function. The clinical relevance of these findings is based on the possibility for skeletal myoblasts to be harvested from the patient himself.

Expression of laminin alpha2 chain during normal and pathological growth of myocardium in rat and human.

OBJECTIVES: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin alpha2 chain) together with that of fibronectin (FN) is modified in the diseased human heart. Laminin alpha2 chain expression was also investigated during physiological and pathological cardiac growth in the rat. METHODS: In ten normal human hearts and ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-alpha2 and FN mRNA levels were quantified by slot-blot using total RNA and the protein distribution was analysed using an immunofluorescence approach. In Wistar rats, laminin alpha2 and FN mRNA expression was analyzed using RNase protection assay (RPA) and slot-blot assays. RESULTS: The amount of laminin alpha2 mRNA did not vary in normal and pathological human hearts whereas it was significantly decreased in renovascular hypertensive rats (-20%) P<0.05 versus normal tissue). The amount of fibronectin mRNA increased in IDMC patients (x2, P<0.05 versus normal tissue), but was unchanged in hypertensive rats. A negative correlation was found between the cardiac laminin-alpha2 level and the age of the patients whatever the cardiac status. During postnatal development in the rat, a similar decrease in cardiac laminin-alpha2 level was observed between 3 and 30 weeks of age. Finally, the immunofluorescent approach failed to detect any alteration in laminin alpha2 distribution within the human myocardium. CONCLUSION: These data indicate that an imbalance between myocyte hypertrophy and the level of laminin-alpha2 might contribute to alterations in sarcolemmal properties, which occur during the development of cardiac hypertrophy and its transition to cardiac failure.

Thyroid hormones differentially modulate enolase isozymes during rat skeletal and cardiac muscle development.

During muscle development, an isozymic transition of the glycolytic enzyme enolase occurs from the embryonic and ubiquitous alphaalpha-isoform to the muscle-specific betabeta-isoform. Here, we demonstrate a stimulatory role of thyroid hormones on these two enolase genes during rat development in hindlimb muscles and an inhibitory effect on the muscle-specific enolase gene in cardiac muscle. In hindlimb muscles the ubiquitous alpha-transcript level is diminished by hypothyroidism, starting at birth. On the contrary, the more abundant muscle-specific beta-transcript is insensitive to hypothyroidism before establishment of the functional diversification of fibers and is greatly decreased thereafter. Our data support the hypothesis of a role of thyroid hormones in coordinating the expressions of contractile proteins and metabolic enzymes during muscle development. The subcellular localization of isoenolases, established here, is not modified by hypothyroidism. Our results underline the specificity of action of thyroid hormones, which modulate differentially two isozymes in the same muscle and regulate, in opposite directions, the expression of the same gene in two different muscles.

Extracellular matrix and growth factors during heart growth.

The effects of growth factors on tissue remodeling and cell differentiation depend on the nature of the extracellular matrix, the type and organization of integrins, the activation of metalloproteinases and the presence of secreted proteins associated to the matrix. These interactions are actually poorly known in the cardiovascular system. We describe here: 1) the main components of extracellular matrix within the cardiovascular system; 2) the role of integrins in the transmission of growth signals; 3) the shift in the expression of the components of the extracellular matrix (fibronectin and collagens) and the stimulation of the synthesis of metalloproteinases during normal and hypertrophic growth of the myocardium; 4) the effects of growth factors, such as Angiotensin II, Fibroblast Growth Factors (FGF), Transforming Growth Factor-beta (TGF-beta), on the synthesis of proteins of the extracellular matrix in the heart.

The extracellular matrix and the cytoskeleton in heart hypertrophy and failure.

Cell characteristics and phenotype depend on the nature of the extracellular matrix, the type and organization of integrins and cytoskeleton. The interactions between these components are poorly known at the myocyte level and during cardiac remodeling associated with cardiac hypertrophy and heart failure. We analyze here the nature and organization of extracellular matrix (ECM) proteins, cytoskeleton and integrins and their regulation by growth factors, such as angiotensin II, in normal myocyte growth and in pathological growth (hypertrophy) of the myocardium and heart failure.

Self-protection by cardiac myocytes against hypoxia and hyperoxia.

Cardiac muscle must maintain a continuous balance between its energy supply and work performed. An important mechanism involved in achievement of this balance is cross talk via chemical signals between cardiac myocytes and the cardiac muscle vascular system. This has been demonstrated by incubating isolated cardiac myocytes in different concentrations of oxygen and then assaying the conditioned media for vasoactive substances on isolated aortic rings and small-resistance arteries. With increasing oxygen concentrations above 6%, cardiac myocytes produce increasing amounts of angiotensin I, which is converted to angiotensin II by the blood vessel. The angiotensin II stimulates vascular endothelial cells to secrete endothelin and increase vascular tone. Below 6% oxygen, cardiac myocytes secrete adenosine, which acts directly on vascular smooth muscle to block the effect of alpha-adrenergic agonists and reduce vascular tone. In an intact heart, the net effect of these 2 regulatory systems would be the maintenance of oxygen concentration within a narrow range at the cardiac myocytes. By acting as oxygen sensors, cardiac myocytes modulate vascular tone according to the needs of the myocytes and reduce potential problems of hypoxia and extensive formation of reactive oxygen species.

Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass.

BACKGROUND: It is not known whether developmental and neurological outcomes in the preschool period differ depending on whether the predominant vital organ support strategy used in infant heart surgery was total circulatory arrest (CA) or low-flow cardiopulmonary bypass. METHODS AND RESULTS: Infants with D-transposition of the great arteries who underwent an arterial-switch operation were randomly assigned to a support method consisting predominantly of CA or low-flow cardiopulmonary bypass. Developmental and neurological status were evaluated blindly at 4 years of age in 158 of 163 eligible children (97%). Neither IQ scores nor overall neurological status were significantly associated with either treatment group or duration of CA. The CA group scored lower on tests of motor function (gross motor, P=0.01; fine motor, P=0.03) and had more severe speech abnormalities (oromotor apraxia, P=0.007). Seizures in the perioperative period, detected either clinically or by continuous electroencephalographic monitoring, were associated with lower mean IQ scores (12.6 and 7.7 points, respectively) and increased risk of neurological abnormalities (odds ratios, 8.4 and 5.6, respectively). The performance of the full cohort was below expectations in several domains, including IQ, expressive language, visual-motor integration, motor function, and oromotor control. CONCLUSIONS: Use of CA to support vital organs during open heart surgery in infancy is associated, at the age of 4 years, with worse motor coordination and planning but not with lower IQ or with worse overall neurological status.

Addressing sexual abuse in the primary care setting.

OBJECTIVE: To describe factors that prompt pediatric practitioners to suspect child sexual abuse, the barriers to inquiry, and the approach to management of cases of possible abuse. DESIGN: Qualitative, descriptive, and case-based. METHODS: Six focus group interviews were conducted. Maternal and Child Health Bureau-sponsored collaborative office rounds groups nationwide participated in discussions of five vignettes. Each group interview lasted 1.5 hours and had 7 to 16 participants (n = 65). Audiotaped data were transcribed and analyzed independently for themes by two reviewers. RESULTS: Five themes emerged from the group interviews: anticipatory guidance, red flags, approach to management, terminology used in discussions, and barriers to inquiry. All groups discussed giving anticipatory guidance about sexual abuse. Half (3/6) believed girls were more likely to be victimized, and some (2/6) gave more anticipatory guidance to girls for this reason. Although some groups reported giving anticipatory guidance about sexual abuse, many reported inconsistencies in their practice. All groups identified historical, behavioral, and physical red flags for sexual abuse but believed that they were not trained in residency to recognize these signs. There was no consensus regarding the approach to management of cases of possible sexual abuse, and many participants did not know the types of questions that they should be asking children when they suspect abuse. Members of all groups reported using imprecise terms when they discuss sexual issues with families. Most (4/6) believed that it was a practitioner's responsibility to inquire about abuse but believed that their discomfort with sexual topics was a barrier to inquiry. All believed that the most significant barrier to inquiry was inadequate training in the area of sexual abuse and that cases are missed because of lack of training. CONCLUSIONS: Highly motivated pediatric practitioners reported that they give anticipatory guidance about sexual abuse inconsistently, that they were not trained to recognize red flags for sexual abuse, and that they do not have a consistent approach to cases of suspected abuse. Additionally, they reported that they are not comfortable discussing sexual issues and that they miss cases of sexual abuse primarily because of lack of training. Educational interventions that target these themes are essential to improve the ability of pediatricians to screen children and to intervene when sexual abuse is identified.

[Cellular cardiomyoplasty: state of the art, evaluation, and future possibilities]. / Cardiomyoplastie cellulaire. Etat des lieux, évaluation et avenir.

Cellular cardiomyoplasty, or the transplantation of myogenic cells into the myocardial tissues, could emerge as a therapeutic alternative in patients with cardiac failure. It depends on several procedures: implantation of cell types, syngenic embryonic cardiomycocytes, allogenic and autogenic cardiac muscle cells. These cells carne into contact with host cardiomyocytes and could contract in a synchronous fashion. Experimental data suggests that this technique could improve global left ventricular function in the post-infarction period or in dilated cardiomyopathy even though the precise mechanism of this improvement is not fully understood. Many difficulties remain, the cell types have an oncogenic potential; syngenic foetal cells are weakly immunogenic but their use is limited by ethical and problems of supply. Therefore, auto-transplantation either of cardiomycocytes obtained by endomyocardial biopsy or of adult skeletal muscle, could be a potential clinical option.