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Weight is the foremost marker of health outcomes in infants; however, the majority of community workers and health care providers in remote, resource-constrained settings have limited access to functional scales. This study develops and validates a simple weight estimation strategy for infants that addresses the limitations of current approaches. Circumferential and segmental anthropometric measures were evaluated for their relationship to infant weight and length. Data derived from 2097 US infants (n = 1681 for model development, n = 416 for validation). Statistical and practical considerations informed final measurement selection. Head circumference and chest circumference demonstrated the best correlations with weight ( r = 0.89) and length ( r = 0.94 and 0.93), and were among the most reproducible as reflected by intraclass correlation coefficients (>0.98). The head circumference and chest circumference combination offered better goodness-of-fit and smaller limits of agreement than did either measure alone. The final model predicted weight within 10% and 15% of actual for 84% and 94% of infants, respectively, with no bias for postnatal age ( P = .76), gestational age ( P = .10), and sex ( P = .25). The model requires simple summation to generate a weight estimate and can be embodied as a low-cost, paper-based device.

This article describes a new free extensive reading resource for learning the mid-frequency words of English and for reading well known texts with minor vocabulary adaptation. A gap exists between the end of graded readers at around 3,000 word families and the vocabulary size needed to read unsimplified texts at around 8,000 word families. Mid-frequency readers are designed to fill this gap. They consist of texts from Project Gutenberg adapted for learners with a vocabulary size of 4,000 word families, 6,000 word families and 8,000 word families. Each text is available at these three different levels. The goal is to have at least fifty such texts at each of the three different levels freely available. The adaptation is done using the BNC/COCA word family lists and the AntWordProfiler program. The article also discusses research that needs to be done on learning mid-frequency vocabulary and on creating and using mid-frequency readers.

Objective: To compare anticipatory guidance delivery at primary care office and Home Nursing Visits (HNV) in the first week after birth. Methods: As part of a randomized, controlled trial comparing office-based care with a model where the initial outpatient encounter was a HNV, data were collected on visit content. During the study’s 2 week telephone interview, mothers were asked whether selected items from the textbook, Bright Futures, were covered at their initial postdischarge visit. Questions covered each of the first week anticipatory guidance categories: newborn sleep, newborn care, safety, and nutritional adequacy. Chi-squared tests were used to compare frequency of anticipatory guidance delivery between randomized groups. Results: Of the 1154 mothers enrolled, 1077 (93.3%) completed the telephone interview. Mothers in the HNV group were significantly more likely to report receiving information on anticipatory guidance topics: Infant Sleep Position (67.4% vs. 84.9%; p

Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGFβ were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.

Importance Rapid infant weight gain is associated with later obesity, but interventions to prevent rapid infant growth and reduce risk for overweight status in infancy are lacking. Objective To examine the effect of a responsive parenting (RP) intervention on infant weight gain between birth and 28 weeks and overweight status at age 1 year. Design, Setting, and Participants The Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study is an ongoing randomized clinical trial comparing an RP intervention designed to prevent childhood obesity with a safety control. The study includes primiparous mother-newborn dyads (n = 291) and was conducted at the Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, in addition to home visits. Enrollment was initiated in January 2012, and evaluable population analyses for this study were conducted between April 2015 and November 2015. Interventions At 2 weeks post partum, initial intervention materials appropriate to the assigned treatment group were mailed to the participant’s home. Research nurses conducted home visits at 3 weeks, 16 weeks, 28 weeks, and 40 weeks, and a research center visit occurred at 1 year. The Intervention Nurses Start Infants Growing on Healthy Trajectories curriculum included messages about infant feeding, sleep hygiene, active social play, emotion regulation, and growth record education. The control group received a developmentally appropriate home safety intervention also delivered by nurse home visitors. Main Outcomes and Measures Conditional weight gain from birth to 28 weeks was calculated. General linear models examined intervention effect on conditional weight gain. The intervention’s effect on infant weight-for-length percentiles was tested using analysis of variance. Logistic regression compared the odds of overweight status (weight for length ≥95th percentile) at 1 year as a function of conditional weight gain. Results Of the mothers included in the study, 246 were white (88%), 260 were non-Hispanic (93%), 210 were married (75%), and 201 were working full time (72%) at time of enrollment. The mean conditional weight gain score was lower among infants in the RP group compared with the control group (−0.18; 95% CI, −0.36 to −0.001), reflecting that the RP infants gained weight more slowly than control group infants (0.18; 95% CI, 0.02-0.34); this effect did not differ by feeding mode (predominantly fed breast milk or not). Infants in the RP group also had lower mean weight-for-length percentiles at 1 year than infants in the control group (57.5%; 95% CI, 52.56%-62.37% vs 64.4%; 95% CI, 59.94%-69.26%; P = .04) and were less likely to be overweight at age 1 year (5.5% vs 12.7%; P = .05). Conclusions and Relevance An RP intervention is associated with reduced rapid weight gain during the first 6 months after birth and overweight status at age 1 year. Trial Registration clinicaltrials.gov Identifier:NCT01167270.

Calorimetric studies of the inclusion complexes of straight and branched alcohols and of diols with alpha-cyclodextrin (α-CD) have been carried out in water solvent. The data suggest that straight and branched chain alcohols enter the cavity of α-CD alkyl end first. The hydroxyl group hydrogen bonds to the outer oxygen ring of the cyclodextrin. For branched chain alcohols the longer alkyl part of the molecule penetrates the α-CD cavity up to the hydroxyl group. Diols form two hydrogen bonds to the outer oxygen ring of the cyclodextrin with some penetration into its interior.

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Obesity prevalence among infants and young children has increased rapidly during the past 4 decades, a disturbing trend given early obesity's association with later life obesity and its comorbidities. Fortunately, infancy is a period of great behavioral and metabolic plasticity offering numerous targets for preventive interventions. Modifiable factors that may affect early rapid weight gain and obesity risk include infant sleep duration, feeding to soothe infant distress, and the introduction of solid foods and transitional feeding. We discuss evidence linking these factors to weight outcomes, as well as results from behavioral obesity interventions in infancy, from our laboratory and others'. For example, in a recent pilot intervention, we focused on helping new mothers address three areas of infant behavior hypothesized to affect weight gain and early obesity risk: infant sleeping, crying, and feeding. First-time mothers were randomly assigned to receive either a Soothe/Sleep intervention, an Introduction of Solids intervention, both interventions, or no interventions. The interventions were delivered via home visits and showed positive effects on infant behaviors and weight outcomes at 1 year. Based on evidence from such pilot interventions, we assess the plausibility of targeting behavioral factors in infancy and suggest next steps for early prevention research.

Background Gut flora are important immunomodulators that may be disrupted in individuals with atopic conditions. Probiotic bacteria have been suggested as therapeutic modalities to mitigate or prevent food allergic manifestations. We wished to investigate whether perinatal factors known to disrupt gut flora increase the risk of IgE-mediated food allergies. Methods Birth records obtained from 192 healthy children and 99 children diagnosed with food allergies were reviewed retrospectively. Data pertaining to delivery method, perinatal antibiotic exposure, neonatal nursery environment, and maternal variables were recorded. Logistic regression analysis was used to assess the association between variables of interest and subsequent food allergy diagnosis. Results Retrospective investigation did not find perinatal antibiotics, NICU admission, or cesarean section to be associated with increased risk of food allergy diagnosis. However, associations between food allergy diagnosis and male gender (66 vs. 33; p=0.02) were apparent in this cohort. Additionally, increasing maternal age at delivery was significantly associated with food allergy diagnosis during childhood (OR, 1.05; 95% CI, 1.017 to 1.105; p=0.005). Conclusions Gut flora are potent immunomodulators, but their overall contribution to immune maturation remains to be elucidated. Additional understanding of the interplay between immunologic, genetic, and environmental factors underlying food allergy development need to be clarified before probiotic therapeutic interventions can routinely be recommended for prevention or mitigation of food allergies. Such interventions may be well-suited in male infants and in infants born to older mothers.

Amyloid-beta peptides (Aβ) can trigger apoptotic cascades in neurons. We found previously that memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors approved for the treatment of moderate to severe Alzheimer's disease, can prevent neurodegeneration induced by intracranial Aβ(1-40) injection. In this study, we tested the hypothesis that memantine prevents Aβ(1-40)-mediated cognitive impairment, neurodegeneration, and apoptosis of hippocampal neurons in rats. In addition, we hypothesized that Aβ(1-40) injection would induce changes in the levels of one or more apoptosis-related proteins, and that these changes would be attenuated by memantine treatment. Female Sprague-Dawley rats were administered memantine (continuous subcutaneous application, 9.6-14.4mg/kg/day; n=8) or vehicle (water; n=8) for 9 days. Two days after treatment initiation, the animals were bilaterally injected with Aβ(1-40) into the CA1/DG region of the hippocampus, subjected to active avoidance testing for 7 days, and sacrificed for immunohistochemical examination of four caspases (3, 6, 8, and 9) and three proteins of the Bcl-2 family (Bcl-2, Bax, and Bad). Injection of Aβ resulted in neurodegeneration, DNA fragmentation, increased Bcl-2 immunostaining, and significantly impaired performance in an active avoidance task, all which were significantly attenuated in rats treated with memantine. No differences in immunoreactivity of caspases 3, 6, 8, and 9 were discovered between groups after 7 days. Additional experiments demonstrated that an increase in caspase 8 immunostaining, observed 3 days after Aβ(1-40) injection, was significantly attenuated in memantine-treated rats. These data suggest that, in rats, memantine can prevent amyloid-triggered expression of apoptosis-related markers and concomitant cognitive deficits.

Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives. Copyright © 2012 by the American Academy of Pediatrics.

Obesity prevalence among infants and young children has increased rapidly during the past 4 decades, a disturbing trend given early obesity's association with later life obesity and its comorbidities. Fortunately, infancy is a period of great behavioral and metabolic plasticity offering numerous targets for preventive interventions. Modifiable factors that may affect early rapid weight gain and obesity risk include infant sleep duration, feeding to soothe infant distress, and the introduction of solid foods and transitional feeding. We discuss evidence linking these factors to weight outcomes, as well as results from behavioral obesity interventions in infancy, from our laboratory and others'. For example, in a recent pilot intervention, we focused on helping new mothers address three areas of infant behavior hypothesized to affect weight gain and early obesity risk: infant sleeping, crying, and feeding. First-time mothers were randomly assigned to receive either a Soothe/Sleep intervention, an Introduction of Solids intervention, both interventions, or no interventions. The interventions were delivered via home visits and showed positive effects on infant behaviors and weight outcomes at 1 year. Based on evidence from such pilot interventions, we assess the plausibility of targeting behavioral factors in infancy and suggest next steps for early prevention research.

Complex formation between 15-crown-5 and malononitrile was studied in twelve solvents by calorimetry. Thermodynamic parameters for the crown ether adduct were determined and used in a LFER analysis to ascertain the solvent effects on the complexation process. Enthalpy of solution data show that malononitrile is solvated by electron pair donation by the solvents and the crown ether is solvated by donating electron pairs to the solvents. The complex is more solvated than the monomers.

The effect of chronic administration of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) on N-methyl-D-aspartate (NMDA)-evoked seizures was studied in C57BL/6 mice (20/group). Animals were injected i.p. for 9 days with either 1.0 mg/kg CPA or 1.0 mg/kg CPX followed by 2 injection-free days (the washout period) and subsequent administration of a single dose of 60 mg/kg NMDA. As in our previous study, this dose of NMDA caused clonic/tonic seizures resulting in high (60%) mortality within 3 h after injection of the drug. Despite insignificant changes in seizure latency, chronic pretreatment with CPA increased the incidence of clonic/tonic episodes and end-point mortality. Conversely; chronic exposure to CPX completely eliminated clonic/tonic episodes, significantly increased average survival time, and reduced end-point mortality (P < 0.05). The results indicate that chronic treatment with adenosine A1 receptor antagonist may protect against NMDA-evoked seizures to the same degree as previously observed following a single, acute exposure to CPA. Since the density of adenosine receptor binding sites was unchanged after chronic treatment with either CPX or CPA, it is likely that the mechanism behind the observed protection may rest at the level of second messenger systems coupled to adenosine A1 receptors.

The characteristics of the low affinity component of 1,3-di(2-[5-3H]tolyl)guanidine binding to the guinea pig cerebellum were investigated. Saturation binding assays where sigma 1 receptors were masked with dextrallorphan indicated that 1,3-di(2-[5-3H]tolyl)guanidine bound to cerebellar membranes in a fashion best described by a 1 site+non-specific binding model with a low density of specific binding sites (Bmax approximately 200 fmol/mg protein). Boiling the cerebellar membranes before addition to the saturation assay had no effect on the density of 1,3-di(2-[5-3H]tolyl)guanidine binding. In contrast, both the Kd and Bmax for 1,3-di(2-[5-3H]tolyl)guanidine binding to liver membranes was significantly reduced by boiling, as was the density of [3H](+)-pentazocine binding to cerebellum and liver. Thus, a substantial component of 1,3-di(2-[5-3H]tolyl)guanidine binding in the guinea pig cerebellum is to non-specific, proteinaceous binding sites with some of the pharmacological characteristics of the sigma 2 binding site.

Objective To compare office-based care (OBC) with a care model using a home nursing visit (HNV) as the initial postdischarge encounter for “well” breastfeeding newborns and mothers. Design Randomized controlled trial. Setting A single academic hospital. Participants A total of 1154 postpartum mothers intending to breastfeed and their 1169 newborns of at least 34 weeks' gestation. Interventions Home nursing visits were scheduled no later than 2 days after discharge; OBC timing was physician determined. Outcome Measures Mothers completed telephone surveys at 2 weeks, 2 months, and 6 months. The primary outcome was unplanned health care utilization for mothers and newborns within 2 weeks of delivery. Other newborn outcomes were proportion seen within 2 days after discharge and breastfeeding duration. Maternal mental health, parenting competence, and satisfaction with care outcomes were assessed. Analyses followed an intent-to-treat paradigm. Results At 2 weeks, hospital readmissions and emergency department visits were uncommon, and there were no study group differences in these outcomes or with unplanned outpatient visit frequency. Newborns in the HNV group were seen no more than 2 days after discharge more commonly than those in the OBC group (85.9% vs 78.8%) (P = .002) and were more likely to be breastfeeding at 2 weeks (92.3% vs 88.6%) (P = .04) and 2 months (72.1% vs 66.4%) (P = .05) but not 6 months. No group differences were detected for maternal mental health or satisfaction with care, but HNV group mothers had a greater parenting sense of competence (P Conclusions Home nursing visits are a safe and effective alternative to OBC for the initial outpatient encounter after maternity/nursery discharge with similar patterns of unplanned health care utilization and modest breastfeeding and parenting benefits. Trial Registration clinicaltrials.gov Identifier: NCT00360204

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

In rodents, noradrenergic (NE) locus coeruleus (LC) neurons are well known to express tyrosine hydroxylase (TH) immunoreactivity. However, due to its very low enzyme activity, NE cortical fibers do not typically express TH immunoreactivity, thus dopamine-beta-hydroxylase (DBH) immunoreactivity is commonly utilized as a marker for NE cortical fibers. In this study, we performed double and/or triple immunofluorescent staining using antibodies against TH, DBH, and/or norepinephrine transporter (NET) to investigate the altered noradrenergic TH expression of cortical fibers in citalopram (CTM) exposed rats and monoamine oxidase (MAO) A knock out (KO) mice. We have noted the following novel findings: 1) neonatal exposure to the selective serotonin reuptake inhibitor (SSRI) CTM enhanced noradrenergic TH immunoreactive fibers throughout the entire neocortex, and a few of them appeared to be hypertrophic; 2) slightly enhanced noradrenergic cortical TH immunoreactive fibers were also noted in MAO A KO mice, and many of them revealed varicosities compared to the rather smooth noradrenergic cortical TH immunoreactive fibers in wild type (WT) mice; 3) LC dendrites of MAO A KO mice exhibited beaded morphology compared to the smooth LC dendrites in WT mice. Our findings suggest that both genetic and environmental factors during early development may play a critical role in the regulation and proper function of noradrenergic TH expression in the neocortex.

The molecular mechanisms for the discrepancy in outcome of initiating estrogen therapy (ET) around peri-menopause or several years after menopause in women are unknown. We hypothesize that the level of expression of a dominant negative estrogen receptor (ER) β variant, ERβ2, may be a key factor determining the effectiveness of ET in post-menopausal women. We tested this hypothesis in ovariectomized nine month-old (an age when irregular estrous cycles occur) female Sprague Dawley rats. Estradiol treatment was initiated either 6 days (Early ET, analogous to 4 months post-menopause in humans), or 180 days (Late ET, analogous to 11 years post-menopause in humans) after ovariectomy. Although ERβ2 expression increased in all OVX rats, neurogenic and neuroprotective responses to estradiol differed in Early and Late ET. Early ET reduced ERβ2 expression in both hippocampus and white blood cells, increased the hippocampal cell proliferation as assessed by Ki-67 expression, and improved mobility in the forced swim test. Late ET resulted in either no or modest effects on these parameters. There was a close correlation between the degree of ERβ2 expression and the preservation of neural effects by ET after OVX in rats, supporting the hypothesis that persistent elevated levels of ERβ2 are a molecular basis for the diminished effectiveness of ET in late post-menopausal women. The correlation between the expression of ERβ2 in circulating white blood cells and brain cells suggests that ERβ2 expression in peripheral blood cells may be an easily accessible marker to predict the effective window for ET in the brain.

Cough due to upper respiratory tract infections (URIs) is one of the most frequent complaints encountered by pediatric health-care providers, and one of the most disruptive symptoms for children and families. Despite the frequency of URIs, there is limited evidence to support the few therapeutic agents currently available in the United States (US) to treat acute cough due to URI. Published, well-designed, contemporary research supporting the efficacy of narcotics (codeine, hydrocodone) and US Food and Drug Administration (FDA)-approved over-the-counter (OTC) oral antitussives and expectorants (dextromethorphan, diphenhydramine, chlophedianol, and guaifenesin) is absent for URI-associated pediatric cough. Alternatively, honey and topically applied vapor rubs may be effective antitussives.

Background: Originally believed to be a rare phenomenon, heteroplasmy - the presence of more than one mitochondrial DNA (mtDNA) variant within a cell, tissue, or individual - is emerging as an important component of eukaryotic genetic diversity. Heteroplasmies can be used as genetic markers in applications ranging from forensics to cancer diagnostics. Yet the frequency of heteroplasmic alleles may vary from generation to generation due to the bottleneck occurring during oogenesis. Therefore, to understand the alterations in allele frequencies at heteroplasmic sites, it is of critical importance to investigate the dynamics of maternal mtDNA transmission. Results: Here we sequenced, at high coverage, mtDNA from blood and buccal tissues of nine individuals from three families with a total of six maternal transmission events. Using simulations and re-sequencing of clonal DNA, we devised a set of criteria for detecting polymorphic sites in heterogeneous genetic samples that is resistant to the noise originating from massively parallel sequencing technologies. Application of these criteria to nine human mtDNA samples revealed four heteroplasmic sites. Conclusions: Our results suggest that the incidence of heteroplasmy may be lower than estimated in some other recent re-sequencing studies, and that mtDNA allelic frequencies differ significantly both between tissues of the same individual and between a mother and her offspring. We designed our study in such a way that the complete analysis described here can be repeated by anyone either at our site or directly on the Amazon Cloud. Our computational pipeline can be easily modified to accommodate other applications, such as viral re-sequencing.

OBJECTIVE: National guidelines do not recommend antibiotics as an asthma therapy. We sought to examine the frequency of inappropriate antibiotic prescribing during US ambulatory care pediatric asthma visits as well as the patient, provider, and systemic variables associated with such practice. PATIENTS AND METHODS: Data from the National Ambulatory Medical Care Surveys and National Hospital Ambulatory Medical Care Survey were examined to assess office and emergency-department asthma visits made by children (aged RESULTS: From 1998 to 2007, an estimated 60.4 million visits occurred for asthma without another ICD-9 code justifying antibiotic prescription. Antibiotics were prescribed during 16% of these visits, most commonly macrolides (48.8%). In multivariate analysis, controlling for patient age, gender, race, insurance type, region, and controller medication use, systemic corticosteroid prescription (odds ratio [OR]: 2.69 [95% confidence interval (CI): 1.68–4.30]) and treatment during the winter (OR: 1.92 [95% CI: 1.05–3.52]) were associated with an increased likelihood of antibiotic prescription, whereas treatment in an emergency department was associated with decreased likelihood (OR: 0.48 [95% CI: 0.26–0.89]). A second multivariate analysis of only office-based visits demonstrated that asthma education during the visits was associated with reduced antibiotic prescriptions (OR: 0.46 [95% CI: 0.24–0.86]). CONCLUSIONS: Antibiotics are prescribed during nearly 1 in 6 US pediatric ambulatory care visits for asthma, ∼1 million prescriptions annually, when antibiotic need is undocumented. Additional education and interventions are needed to prevent unnecessary antibiotic prescribing for asthma.

Background This study (NCT00197236) evaluated the safety and immunogenicity of a hepatitis A virus (HAV) vaccine when coadministered with diphtheria-tetanus-acellular pertussis (DTaP) and Haemophilus influenzae type b (Hib) vaccines in children 15 months of age. Methods This was an open-labeled, multicenter study with healthy subjects enrolled and randomized (1:1:1) into 3 treatment groups. A total of 394 subjects received the first study vaccinations at 15 months of age. Group HAV (N = 135) received 2 doses of HAV vaccine 6 to 9 months apart. Group HAV+DTaP+Hib (N = 127) received HAV vaccine coadministered with DTaP and Hib vaccines and the second dose of HAV vaccine, 6 to 9 months later. Group DTaP+Hib→HAV (N = 132) received the DTaP and Hib vaccines at 15 months of age, followed by HAV vaccine 30 days later and the second dose of HAV vaccine 7 to 10 months after the DTaP+Hib vaccines. Immune responses were evaluated before the first study vaccination and 30 days after each vaccine dose. Solicited, unsolicited, and serious adverse events were collected. Results After 2 doses of the HAV vaccine, all subjects in the 3 groups were seropositive. The geometric mean concentration of anti-HAV antibodies ranged between 1625.1 and 1904.4 mIU/mL. Coadministration of the 3 vaccines did not impact immunogenicity of the HAV, DTaP, or Hib vaccines. Vaccines were well tolerated in all groups. Conclusions A 2-dose schedule of HAV vaccine was well tolerated and immunogenic when administered to children starting at 15 months of age. Immune responses to the DTaP or Hib vaccines were similar whether they were administered alone or were coadministered with the HAV vaccine.

Direct pharmacological targeting of the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is an attractive therapeutic strategy for treating cancer. Obatoclax is a pan-BCL-2 family inhibitor currently in clinical development. Here we show that, although obatoclax can induce mitochondrial apoptosis dependent on BCL-2 associated x protein/BCL-2 antagonist killer (BAX/BAK) consistent with its on-target pharmacodynamics, simultaneous silencing of both BAX and BAK did not abolish acute toxicity or loss of clonogenicity. This is despite complete inhibition of apoptosis. Obatoclax dramatically reduced viability without inducing loss of plasma membrane integrity. This was associated with rapid processing of light chain-3 (LC3) and reduction of S6 kinase phosphorylation, consistent with autophagy. Dramatic ultrastructural vacuolation, not typical of autophagy, was also induced. Silencing of beclin-1 failed to prevent LC3 processing, whereas knockout of autophagy-related (Atg)7 abolished LC3 processing but failed to prevent obatoclax-induced loss of clonogenicity or ultrastructural changes. siRNA silencing of Atg7 in BAX/BAK knockout mouse embryonic fibroblasts did not prevent obatoclax-induced loss of viability. Cells selected for obatoclax resistance evaded apoptosis independent of changes in BCL-2 family expression and displayed reduced LC3 processing. In summary, obatoclax exhibits BAX- and BAK-dependent and -independent mechanisms of toxicity and activation of autophagy. Mechanisms other than autophagy and apoptosis are blocked in obatoclax resistant cells and contribute significantly to obatoclax's anticancer efficacy.

To examine how urban parents’ perceptions of healthy infant size and growth relate to objective weight-for-length percentiles of their children, parents of 222 (69% minority) 6- to 27-month-old infants were surveyed. In all, 41% of parents said growth charts had never been explained to them, and 31% were not confident they understood the meaning of chart percentiles. A total of 20% of parents preferred their child weigh ≥75th percentile, and these children had higher mean weight-for-length percentiles than their peers ( P = .05). Similarly, 37% of parents agreed that “a chubby baby is a healthy baby,” and these children had higher mean weight-for-length percentiles than others in the cohort ( P = .02). Additionally, 58% of parents ranked a growth curve with consistent growth at the 10th percentile as the “least healthy” of 6 infant growth curves. Growth charts are not consistently explained to or understood by urban parents, and many prefer early life growth patterns associated with later obesity.

The effect of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) on N-methyl-D-aspartate (NMDA)-evoked seizures was studied in C57BL/6 mice (20/group). Animals were injected i.p. either with CPA (0.5, 1, 2 mg/kg) or CPX (1, 2 mg/kg) 15 min prior to administration of NMDA (30, 60, 125 mg/kg). Administration of NMDA alone resulted in a complete locomotor arrest at 30 mg/kg, while clonic/tonic seizures and progressively increasing mortality were seen at higher doses. Prior administration of CPA resulted either in a delay of seizure onset and unchanged mortality (0.5 mg/kg CPA, 60 mg/kg NMDA) or in elimination of tonic episodes and a significant reduction in postictal mortality (1, 2 mg/kg CPA; 60, 125 mg/kg NMDA). Pretreatment with CPX at either 1 or 2 mg/kg eliminated locomotor depression in animals injected with NMDA at 30 mg/kg. At 60 mg/kg NMDA, the effect of CPX administration resulted in mortality equivalent to that seen with 125 mg/kg NMDA administered alone. The results indicate that A1 receptor agonists may protect against NMDA-evoked seizures and that the adenosine A1 receptor may be directly involved in these actions.

Chronic (14 days) administration of either imipramine or electroconvulsive shock effected significant changes in the ligand binding properties of the NMDA (N-methyl-D-aspartate) receptor complex in rat cortex. These changes were manifested as: (1) a reduction in the potency of glycine to inhibit the binding of 5,7-dichloro[3H]kynurenic acid to strychnine-insensitive glycine receptors; and (2) a reduction in the proportion of high affinity, glycine-displaceable [3H]CGP-39653 binding to NMDA receptors. Chronic electroconvulsive shock, but not imipramine treatment also reduced the density of [3H]CGP-39653 binding sites in cortical membranes. These findings demonstrate that the ability of chronic antidepressant treatments to induce adaptive changes in the glycine and glutamate regulatory sites of the NMDA receptor is not species specific, since it obtains in rats as well as mice.

Correlation of the isopotential contours of the optimized conformations of a series of alpha-amino acids, in their neutral and zwitterionic forms, with their potencies to inhibit [3H]glycine binding and to enhance [3H]10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, leads to the following conclusions: (a) steric congestion at the amino group is detrimental to binding potency; (b) a zwitterionic amino acid is required for high affinity to the receptor; (c) a conformation in which the carboxylate group is at a 90 degrees dihedral angle to the ammonium nitrogen is preferred for high affinity; and (d) placing the carbon backbone of the zwitterionic alpha-amino acid, in its preferred conformation, above the plane defined by the ammonium nitrogen and the carboxylate oxygen atoms, and viewing the molecule along the nitrogen to carboxylate carbon axis, there is a space forbidden to the ligand (receptor-required-space) to the left.

This study examined variations in gene expression between FFPE blocks within tumors of individual patients. Microarray data were used to measure tumor heterogeneity within and between patients and disease states. Data were used to determine the number of samples needed to power biomarker discovery studies. Bias and variation in gene expression were assessed at the intrapatient and interpatient levels and between adenocarcinoma and squamous samples. A mixed-model analysis of variance was fitted to gene expression data and model signatures to assess the statistical significance of observed variations within and between samples and disease states. Sample size analysis, adjusted for sample heterogeneity, was used to determine the number of samples required to support biomarker discovery studies. Variation in gene expression was observed between blocks taken from a single patient. However, this variation was considerably less than differences between histological characteristics. This degree of block-to-block variation still permits biomarker discovery using either macrodissected tumors or whole FFPE sections, provided that intratumor heterogeneity is taken into account. Failure to consider intratumor heterogeneity may result in underpowered biomarker studies that may result in either the generation of longer gene signatures or the inability to identify a viable biomarker. Moreover, the results of this study indicate that a single biopsy sample is suitable for applying a biomarker in non–small-cell lung cancer.

Objectives To systematically analyze growth data from infant health maintenance records to characterize infant weight gain increasing risk for childhood overweight, and to identify additional information from those records that could refine risky infant weight gain as a screening tool. Design Retrospective cohort study. Setting A pediatric office in central Pennsylvania. Participants Children aged 6 to 8 years (n = 129) born in 2000 or later who attended health maintenance visits. Main Exposures Risky infant weight gain was a cutoff selected after considering its sensitivity and specificity during the interval best predicting childhood overweight risk as determined with receiver operating characteristic curve analysis. We identified demographic, growth pattern, and parental feeding choice differences between at-risk infants who did and did not become overweight children. Main Outcome Measure Childhood overweight, defined as a sex- and age-specific body mass index of the 85th percentile or higher at ages 6 to 8 years according to 2000 Centers for Disease Control and Prevention growth charts. Results Childhood overweight prevalence was 24.8%. At-risk infants gained at least 8.15 kg from ages 0 to 24 months. While 31.4% of at-risk infants became overweight children, 68.6% were resilient. At-risk, resilient participants had parents with more education, had lower weight gain from ages 18 to 24 months and 0 to 24 months and a smaller area under the weight-gain curve from ages 0 to 24 months, were more often exclusively breastfed for 6 months or longer, and were introduced to solid foods later than at-risk, overweight participants. Conclusions While most researchers would not recognize weight gain of 8.15 kg or more from ages 0 to 24 months as rapid growth, it was a fair screening tool for childhood overweight in our sample and had the potential to be refined using information about demographic characteristics, growth patterns, and parental feeding choices.

OBJECTIVE: To determine if a single application of a vapor rub (VR) or petrolatum is superior to no treatment for nocturnal cough, congestion, and sleep difficulty caused by upper respiratory tract infection. METHODS: Surveys were administered to parents on 2 consecutive days—on the day of presentation when no medication had been given the previous evening, and the next day when VR ointment, petrolatum ointment, or no treatment had been applied to their child's chest and neck before bedtime according to a partially double-blinded randomization scheme. RESULTS: There were 138 children aged 2 to 11 years who completed the trial. Within each study group, symptoms were improved on the second night. Between treatment groups, significant differences in improvement were detected for outcomes related to cough, congestion, and sleep difficulty; VR consistently scored the best, and no treatment scored the worst. Pairwise comparisons demonstrated the superiority of VR over no treatment for all outcomes except rhinorrhea and over petrolatum for cough severity, child and parent sleep difficulty, and combined symptom score. Petrolatum was not significantly better than no treatment for any outcome. Irritant adverse effects were more common among VR-treated participants. CONCLUSIONS: In a comparison of VR, petrolatum, and no treatment, parents rated VR most favorably for symptomatic relief of their child's nocturnal cough, congestion, and sleep difficulty caused by upper respiratory tract infection. Despite mild irritant adverse effects, VR provided symptomatic relief for children and allowed them and their parents to have a more restful night than those in the other study groups.

More than 20% of US children between ages 2 and 5 years are overweight suggesting efforts to prevent obesity must begin earlier. This study tested the independent and combined effects of two behavioral interventions delivered to parents, designed to promote healthy infant growth in the first year. Mother-newborn dyads intending to breastfeed were recruited from a maternity ward. With a 2 × 2 design, 160 dyads were randomized into one of four treatment cells to receive both, one, or no interventions delivered at two nurse home visits. The first intervention ("Soothe/Sleep") instructed parents on discriminating between hunger and other sources of infant distress. Soothing strategies were taught to minimize feeding for non-hunger-related fussiness and to prolong sleep duration, particularly at night. The second intervention ("Introduction of Solids") taught parents about hunger and satiety cues, the timing for the introduction of solid foods, and how to overcome infants' initial rejection of healthy foods through repeated exposure. A total of 110 mother-infant dyads completed the year-long study. At 1 year, infants who received both interventions had lower weight-for-length percentiles (P = 0.009). Participants receiving both interventions had a mean weight-for-length in the 33rd percentile; in contrast, those in other study groups were higher first intervention only--50th percentile; second intervention only--56th percentile; control group--50th percentile).This suggests that multicomponent behavioral interventions may have potential for long-term obesity prevention (ClinicalTrials.gov number, NCT00359242).

Repeated administration of psychostimulants to rodents can lead to behavioral sensitization. Previous studies, using nonspecific opioid receptor (OR) antagonists, revealed that ORs were involved in modulation of behavioral sensitization to methamphetamine (METH). However, the contribution of OR subtypes remains unclear. In the present study, using mu-OR knockout mice, we examined the role of mu-OR in the development of METH sensitization. Mice received daily intraperitoneal injection of drug or saline for 7 consecutive days to initiate sensitization. To express sensitization, animals received one injection of drug (the same as for initiation) or saline on day 11. Animal locomotor activity and stereotypy were monitored during the periods of initiation and expression of sensitization. Also, the concentrations of METH and its active metabolite amphetamine in the blood were measured after single and repeated administrations of METH. METH promoted significant locomotor hyperactivity at low doses and stereotyped behaviors at relative high doses (2.5 mg/kg and above). Repeated administration of METH led to the initiation and expression of behavioral sensitization in wild-type mice. METH-induced behavioral responses were attenuated in the mu-OR knockout mice. Haloperidol (a dopamine receptor antagonist) showed a more potent effect in counteracting METH-induced stereotypy in the mu-OR knockout mice. Saline did not induce behavioral sensitization in either genotype. No significant difference was observed in disposition of METH and amphetamine between the two genotypes. Our study indicated that the mu-opioid system is involved in modulating the development of behavioral sensitization to METH. (c) 2010 Wiley-Liss, Inc.

Background Activation of the extrinsic apoptosis pathway by tumour necrosis factor related apoptosis inducing ligand (TRAIL) is a novel therapeutic strategy for treating cancer that is currently under clinical evaluation. Identification of molecular biomarkers of resistance is likely to play an important role in predicting clinical anti tumour activity. The involvement of the mitochondrial type 1 voltage dependent anion channel (VDAC1) in regulating apoptosis has been highly debated. To date, a functional role in regulating the extrinsic apoptosis pathway has not been formally excluded. Methods We carried out stable and transient RNAi knockdowns of VDAC1 in non-small cell lung cancer cells, and stimulated the extrinsic apoptotic pathway principally by incubating cells with the death ligand TRAIL. We used in-vitro apoptotic and cell viability assays, as well as western blot for markers of apoptosis, to demonstrate that TRAIL-induced toxicity is VDAC1 dependant. Confocal microscopy and mitochondrial fractionation were used to determine the importance of mitochondria for caspase-8 activation. Results Here we show that either stable or transient knockdown of VDAC1 is sufficient to antagonize TRAIL mediated apoptosis in non-small cell lung cancer (NSCLC) cells. Specifically, VDAC1 is required for processing of procaspase-8 to its fully active p18 form at the mitochondria. Loss of VDAC1 does not alter mitochondrial sensitivity to exogenous caspase-8-cleaved BID induced mitochondrial depolarization, even though VDAC1 expression is essential for TRAIL dependent activation of the intrinsic apoptosis pathway. Furthermore, expression of exogenous VDAC1 restores the apoptotic response to TRAIL in cells in which endogenous VDAC1 has been selectively silenced. Conclusions Expression of VDAC1 is required for full processing and activation of caspase-8 and supports a role for mitochondria in regulating apoptosis signaling via the death receptor pathway.

We have demonstrated that neonatal exposure to selective serotonin reuptake inhibitors has lasting effects on behavior and serotonergic neurons in Long Evans rats. Hyperserotoninemia and altered sensory processing are reported in autistic spectrum disorders (ASD). We hypothesized that early life exposure to SSRIs alters sensory processing, disrupts responses to novelty and impairs social interactions in a manner similar to that observed in ASD. Male and female Long-Evans rat pups were administered citalopram, buproprion, fluoxetine, or saline from postnatal day (P) 8 to 21. Rats were tested for response to a novel tone before weaning (P25). Later, rats were tested 2× for response to a novel object (P39), and to a novel conspecific (P78, P101). In addition, rats were assessed for juvenile play behaviors (P32–P34) and later, we assessed sexual response to an estrus female in male rats (P153–184). Antidepressant exposure increased freezing after tone, diminished novel object exploration and reduced conspecific interaction up to 3× compared to saline exposed rats. Juvenile play was profoundly reduced in antidepressant-exposed males when compared to saline exposed groups. Exposure to the SSRIs, but not bupropion disrupted male sexual behaviors. Moreover, specific male responses to female proceptive behaviors were disrupted in SSRI, but not bupropion exposed rats. We conclude that neonatal exposure to antidepressants in rats results in sensory and social abnormalities that parallel many of those reported in ASD.

Cost-effectiveness analyses of asthma controller regimens for adults exist, but similar evaluations exclusively for children are few.We sought to compare the cost-effectiveness of 2 commonly used asthma controllers, fluticasone and montelukast, with data from the Pediatric Asthma Controller Trial.We compared the cost-effectiveness of low-dose fluticasone with that of montelukast in a randomized, controlled, multicenter clinical trial in children with mild-to-moderate persistent asthma. Analyses were also conducted on subgroups based on phenotypic factors. Effectiveness measures included (1) the number of asthma-control days, (2) the percentage of participants with an increase over baseline of FEV(1) of 12% or greater, and (3) the number of exacerbations avoided. Costs were analyzed from both a US health care payer's perspective and a societal perspective.For all cost-effectiveness measures studied, fluticasone cost less and was more effective than montelukast. For example, fluticasone treatment cost $430 less in mean direct cost (P.01) and resulted in 40 more asthma-control days (P.01) during the 48-week study period. Considering sampling uncertainty, fluticasone cost less and was more effective at least 95% of the time. For the high exhaled nitric oxide (eNO) phenotypic subgroup (eNO ≥25 ppb) and more responsive PC(20) subgroup (PC(20)2 mg/mL), fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures, whereas not all the effectiveness measures were statistically different for the other 2 phenotypic subgroups.For children with mild-to-moderate persistent asthma, low-dose fluticasone had lower cost and higher effectiveness compared with montelukast, especially in those with more airway inflammation, as indicated by increased levels of eNO and more responsivity to methacholine.

OBJECTIVE: Despite data suggesting that routine urine screening for chronic kidney disease (CKD) has low diagnostic yield and the American Academy of Pediatrics 2007 recommendation to discontinue this screening, pediatricians may not have recognized this change. Because the new recommendation marks a major alteration in the practice guidelines, we sought to evaluate the cost-effectiveness of dipstick urinalysis for detection of CKD from the primary care practitioner's perspective. METHODS: Decision analysis was used to model a screening dipstick urinalysis strategy relative to a no-screening strategy. Data on the incidence of hematuria and proteinuria in children were derived from published reports of large cohorts of school-aged children. Direct costs were estimated from the perspective of the primary care practitioner. The measure of effectiveness was the rate of diagnoses of CKD. Cost-effectiveness was evaluated by using an incremental cost-effectiveness ratio. RESULTS: Expected costs and effectiveness for the no-screening strategy were $0 because no resources were used and no cases of CKD were diagnosed. The screening strategy involved a cost per dipstick of $3.05. Accounting for both true-positive and false-positive initial screens, 14.2% of the patients required a second dipstick as per typical clinical care, bringing the expected cost of the screening strategy to $3.47 per patient. In the screening strategy, 1 case of CKD was diagnosed per 800 screened, and the incremental cost-effectiveness ratio was $2779.50 per case diagnosed. CONCLUSIONS: Urine dipstick is inexpensive, but it is a poor screening test for CKD and a cost-ineffective procedure for the primary care provider. These data support the change in the American Academy of Pediatrics guidelines on the use of screening dipstick urinalysis. Clinicians must consider the cost-effectiveness of preventive care procedures to make better use of available resources.

Mice infected with an immunosuppressive murine leukemia virus (MuLV) mixture, LP-BM5, displayed profound and selective deficits in spatial learning in a modified Morris water maze. These deficits appeared before the appearance of gross neurological impairment or histopathological changes in the central nervous system. Thus, LP-BM5-infected mice displayed deficits in several aspects of trained performance compared to controls. Furthermore, a failure to exhibit any evidence of task acquisition in this maze was observed almost twice as frequently (P less than 0.0005) in infected mice as in uninfected controls. Moreover, in the absence of gross visual, motoric, or motivational impairment, LP-BM5 MuLV-infected animals exhibited neither the target directed search pattern nor the spatial preference characteristic of controls. The spatial learning and memory deficit described here is the first report of cognitive impairment accompanying viral-induced immunosuppression in a nonprimate species.

We hypothesized that parents of infants prefer growth at higher percentiles and are averse to growth at lower percentiles. Of 279 participating parents, only 10% desired their child’s weight to be in the lowest quartile. For children weighing in the lowest quartile, 57% of parents thought their child’s weight was “too low.” In contrast, 66% of parents whose child’s weight was in the top quartile preferred their child weigh that much. When viewing hypothetical infant growth trajectories, 47% ranked a growth chart demonstrating growth along the 10th percentile for weight as “least healthy” of 6 growth patterns, and 29% chose charts showing an infant at the 90th percentile for weight at age 1 as “healthiest.” In conclusion, parents are averse to growth at the bottom of the weight growth chart but are much less likely to feel negatively about growth at higher percentiles. This is troubling given the childhood obesity epidemic.

Background Conventional wisdom regarding exposures to persistent organic chemicals via breast-feeding assumes that concentrations decline over the course of lactation and that the mother’s body burden reflects her cumulative lifetime exposure. Two important implications stemming from these lines of thought are, first, that assessments of early childhood exposures should incorporate decreasing breast milk concentrations over lactation; and, second, that there is little a breast-feeding mother can do to reduce her infant’s exposures via breast-feeding because of the cumulative nature of these chemicals. Objectives We examined rates of elimination and milk/serum partition coefficients for several groups of persistent organic chemicals. Methods We collected simultaneous milk and blood samples of 10 women at two times postpartum and additional milk samples without matching blood samples. Results Contrary to earlier research, we found that lipid-adjusted concentrations of polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins and furans, and organochlorine pesticides in serum and milk do not consistently decrease during lactation and can increase for some women. Published research has also suggested an approximate 1:1 milk/serum relationship (lipid adjusted) on a population basis for 2,3,7,8-tetrachlorodibenzo-p-dioxin; however, our results suggest a more complex relationship for persistent, lipophilic chemicals with the milk/serum relationship dependent on chemical class. Conclusions Decreases in concentration of lipophilic chemicals on a lipid-adjusted basis during lactation should no longer be assumed. Thus, the concept of pumping and discarding early milk as means of reducing infant exposure is not supported. The hypothesis that persistent lipophilic chemicals, on a lipid-adjusted basis, have consistent concentrations across matrices is likely too simplistic.

Many parents, grandparents, and clinicians have associated a baby’s ability to eat and gain weight as a sign of good health, and clinicians typically only call significant attention to infant growth if a baby is failing to thrive or showing severe excesses in growth. Recent evidence, however, has suggested that pediatric healthcare providers should pay closer attention to growth patterns during infancy. Both higher weight and upward crossing of major percentile lines on the weight-for-age growth chart during infancy have long term health consequences, and are associated with overweight and obesity later in life. Clinicians should utilize the numerous available opportunities to discuss healthy growth and growth charts during health maintenance visits in the first two years after birth. Further, providers should instruct parents on strategies to promote healthy behaviors that can have long lasting obesity preventive effects.

This article describes the visual nature of the reading process as it relates to reading speed. It points out that there is a physical limit on normal reading speed and beyond this limit the reading process will be different from normal reading where almost every word is attended to. The article describes a range of activities for developing reading fluency, and suggests how the development of fluency can become part of a reading programme.

Using high resolution autoradiographic techniques, the distribution of radioactivity in forebrain and brainstem was assessed after IV injection of 3H-impramine or 3H-desipramine. Results were compared with regional binding of the drugs to brain sections in vitro. Similar topographic binding of 3H-imipramine and 3H-desipramine was observed in vitro among brain regions, except in the paraventricular nucleus of the hypothalamus and locus coeruleus, where binding was greater for 3H-desipramine. For both 3H-desipramine and 3H-imipramine, some brain regions that exhibited high binding in vitro also showed high accumulation after in vivo injection. However, certain regions that contained high densities of binding sites for the antidepressant drugs as measured by in vitro binding showed very low accumulation of radioactivity after in vivo treatment. Such regions included the dentate gyrus of the hippocampus, layer 1 of piriform cortex, caudate-putamen, pontine and midbrain central gray, and cerebellar granular layer. Compared to in vitro binding of the drugs, the distribution of imipramine and desipramine in vivo appears more anatomically selective. For imipramine, primary sites of action in vivo, as indicated by the topographic distribution in brain, appear to be the locus coeruleus, hippocampus, lateral septal nucleus, and amygdala. For desipramine, the greatest accumulation in vivo was found in the locus coeruleus, paraventricular nucleus of the hypothalamus, and anterior thalamic nuclei.

Two goals when counseling breastfeeding mothers taking medication are protecting the infant from adverse events and permitting necessary maternal therapy. Madadi et al. report a case–control study of neonatal and maternal opioid toxicity after codeine administration. Therapeutic considerations in counseling breastfeeding mothers include susceptibility to drug toxicity of the very young and/or premature infant, significant interindividual variations in drug response, the dose–response relationship with respect to drug toxicity, and the role of pharmacogenetics in both the mother and the infant. These host factors may combine in a particular patient to act synergistically to produce an adverse reaction. Clinical Pharmacology & Therapeutics (2009); 85, 1, 20–22 doi:10.1038/clpt.2008.209

Background Clinical trials in children with moderate-to-severe persistent asthma are limited. Objective We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing. Methods The budesonide dose (with salmeterol [50 μg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 μg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction. Results Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated. Conclusion Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid–sparing alternative in children with moderate-to-severe persistent asthma.