Continuous exposure to brain-derived neurotrophic factor is required for persistent activation of TrkB receptor, the ERK signaling pathway, and the induction of neuropeptide Y production in cortical cultures

We have previously demonstrated that brain-derived neurotrophic factor (BDNF) induces persistent neuropeptide Y (NPY) production in cortical cultures in an ERK1/2-dependent manner. In some studies, it was shown that BDNF leads to the downregulation of TrkB receptor and some of its downstream responses, whereas in others it does not. We examined whether the BDNF requirement for induction of persistent NPY production correlates with that for induction of phosphorylation of TrkB and ERK1/2. Continuous 24-h exposure to BDNF led to a 2- to 3-fold increase in NPY production (maximal level). While 1 h of BDNF exposure induced NPY production at a half maximal level, 8 h was required for induction of a maximal level. BDNF-induced NPY production was completely inhibited by co-exposure to TrkB-Fc fusion protein (TrkB extracellular domain fused to Fc) and partially inhibited by TrkB-Fc added 1 h after BDNF; TrkC-Fc did not do so. Activation of TrkB receptor was analyzed at two potential tyrosine phosphorylated sites, the activation loop and the Shc binding. BDNF led to coordinated phosphorylation of the two sites that persisted for 6-8 h, and this was not associated with changes in the content of TrkB protein. The presence of BDNF throughout the 6- to 8-h period was required for the persistent phosphorylation of TrkB and ERK1/2. Thus, continuous BDNF activation of TrkB is required for persistent activation of the ERK1/2 pathway and induction of NPY production. We propose that, within the time frame analyzed in this study, BDNF does not lead to the downregulation of TrkB receptor or of the biological responses leading to NPY production.     

Relationship between education and delay discounting in smokers

Smokers are less educated and are more likely to discount future rewards than nonsmokers. We assessed the relationship between delay discounting and education level in 77 smokers entering smoking cessation treatment. There was an effect of education on computer task and the questionnaire measures of discounting, with participants having no college discounting delayed rewards significantly (P < .01) more than those attending college. Subjects discounted small rewards more than large rewards for both tasks (P < .001). Results show that education level is inversely associated with discounting in smokers.     

Clinical and epidemiologic burden of chronic myelogenous leukemia

Chronic myelogenous leukemia represents 7-20% of all leukemia cases, with a worldwide incidence projected at less than one to two per 100,000 people. Approximately 85% of patients are diagnosed with chronic-phase chronic myelogenous leukemia and up to 40% are asymptomatic. Treatment strategies include chemotherapy, interferon-alpha therapy, transplantation (bone marrow/stem cell transplant) and imatinib mesylate (Gleevec), with the impact of treatment best realized during the chronic phase of the disease. Only transplantation has been clinically demonstrated to eradicate the Philadelphia chromosome, alter the natural course of the disease and cure patients diagnosed with chronic myelogenous leukemia. Interferon-alpha is currently considered for first-line treatment, however, the recent introduction of targeted therapy may change clinical practice. Ongoing research focused on new drug combinations and target therapies may eventually expand the armamentarium available to cure this disease.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure

Aims: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Methods: Unmatched case-control study in the UK and Eire 1992–2001 and Victoria, Australia 1988–1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Results: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 µg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 µg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 µg/ml (2.78 to 5.15); unvaccinated GMC 1.48 µg/ml (0.90 to 2.21); p = 0.003). Conclusions: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

Hib vaccination in infants born prematurely

Aims: To document the immunogenicity and persistence of antibody to polyribosyl-ribitol phosphate (PRP) as well as the clinical protection against invasive Haemophilus influenzae type b (Hib) disease in premature infants immunised at the routine schedule. Methods: Blood was obtained at 2, 5, 12, and 64 months of age from a cohort of prematurely born infants (≤32 weeks gestation). Anti-PRP antibody concentrations were compared with those of a control cohort of infants born at full term and vaccinated at the same schedule. Hib vaccine failures occurring between October 1992 and October 2000 were reported by paediatricians through an active, prospective, national survey in the UK and Republic of Ireland. The number of prematurely born children with vaccine failure was compared with the corresponding number born at term. Results: Twenty seven prematurely born infants were followed to 5 years of age. Compared with term infants they had a significantly lower geometric mean concentration of anti-PRP antibody and/or a significantly lower proportion above one or both of the conventional protective antibody concentrations (0.15 and 1.0 µg/ml) at all ages. A total of 165 cases of invasive Hib disease were identified over eight years of national surveillance. Eighteen were premature (<37 weeks); approximately 12 would be expected. The relative risk of UK premature infants developing disease compared with term infants was 1.5 (95% CI 0.9 to 2.6). Conclusions: Premature infants develop lower antibody concentrations than term infants following Hib conjugate vaccination. Premature infants may also have an increased risk of clinical vaccine failure, but interpretation is limited by the small number of premature infants developing invasive Hib disease over eight years of national surveillance. Overall, vaccination with Hib conjugate vaccines affords a high level of protection to premature babies.     

Behavioral responses to tactile stimuli in children with cerebral palsy

Children with cerebral palsy often have difficulty processing tactile information. Assessment of tactile processing in children with cerebral palsy frequently relies on the use of informal clinical observations, checklists, and sensory histories without established psychometric properties. It is proposed that a formal approach to the assessment of behavioral responses to tactile stimuli will provide a better understanding of the tactile processing of children with cerebral palsy. This approach also has potential to assist with the development of intervention strategies and the evaluation of progress. The purposes of this article are to review the literature on the tactile processing difficulties of children with cerebral palsy, examine the suitability of existing assessments of tactile processing for children with cerebral palsy, and provide a rationale for a new assessment tool being developed by the authors.     

The impact of maternal depression on adolescent adjustment: the role of expressed emotion

The present study evaluated the role of expressed emotion (EE) as a predictor of child symptomatology and functional impairment in a sample of nearly 800 adolescent children of mothers with varying histories of depression or who were nondepressed. Structural equation modeling was used to test the hypothesized associations in half of the sample, and all models were cross-validated on the other half of the study sample. Results indicated that EE criticism and degree of maternal depression both had independent predictive associations with youths' externalizing symptoms and functional impairment. In addition, high EE criticism served as an intervening variable between maternal depression and child functioning (externalizing symptoms and functional impairment). Results are discussed in terms of the mutual effects of depressed mothers and dysfunctional youths on each other.     

The 1996 welfare law: key elements and reauthorization issues affecting children

The Personal Responsibility and Work Opportunity Reconciliation Act of 1996 changed the social policy landscape for children in many ways. It replaced the prior welfare program with block grants to the states entitled Temporary Assistance for Needy Families, and modified a broad array of other programs and initiatives affecting low-income children. This article describes the key themes dominating the debate over welfare reform in 1996, specifically: Increased state discretion in program design, leading to more variability in states' eligibility requirements and services provided to low-income families; More stringent work requirements even for parents of very young children; Time limits on the use of federal funds for cash assistance, and a strong focus on caseload reduction; Increased emphasis on parental responsibility, with stronger child support requirements; and Increased emphasis on reducing out-of-wedlock births, including bonuses to states with the largest reductions, and special requirements for unmarried teen parents who seek welfare. Although child well-being received little attention during the congressional debates in 1996, the authors conclude with the hope that improving child outcomes and child well-being will emerge as a key theme when the law is reauthorized in 2002.     

Estimating Haemophilus influenzae type b vaccine effectiveness in England and Wales by use of the screening method

In October 1992, Haemophilus influenzae type b (Hib) conjugate vaccine was introduced to infants in the United Kingdom with a "catch-up" program for those aged <4 years. Initially, the rate of invasive Hib disease decreased dramatically but has been increasing since 1999. To determine possible reasons for this increase, the effectiveness of Hib conjugate vaccine was estimated by use of the screening method. Between October 1993 and December 2001, a total of 443 cases of Hib infection occurred in children eligible for vaccination; 363 (82%) were fully vaccinated. Vaccine effectiveness was estimated to be 56.7% (95% confidence interval, 42.5-67.4). Effectiveness was lower in children vaccinated during infancy, compared with those who were vaccinated during the catch-up campaign (P=.0033), declined with time since vaccination (P=.0008), and was lower in children born during 2000-2002, compared with other children scheduled for infant vaccination (P=.0041). Use of a catch-up vaccination program enhanced the control of Hib infection in England and Wales. Since 1999, however, low effectiveness in infants, declining effectiveness with age, and the use of lower-efficacy vaccines have contributed to increased rates of Hib infection. The potential role of boosters needs to be considered.