Safety of the breast-feeding infant after maternal anesthesia.

There has been an increase in breast-feeding supported by the recommendations of the American Academy of Pediatrics and the World Health Organization. An anesthesiologist may be presented with a well-motivated breast-feeding mother who wishes to breast-feed her infant in the perioperative period. Administration of anesthesia entails acute administration of drugs with potential for sedation and respiratory effects on the nursing infant. The short-term use of these drugs minimizes the possibility of these effects. The aim should be to minimize the use of narcotics and benzodiazepines, use shorter acting agents, use regional anesthesia where possible and avoid agents with active metabolites. Frequent clinical assessments of the nursing infant are important. Available literature does suggest that although the currently available anesthetic and analgesic drugs are transferred in the breast milk, the amounts transferred are almost always clinically insignificant and pose little or no risk to the nursing infant.

Improving infant exposure and health risk estimates: using serum data to predict polybrominated diphenyl ether concentrations in breast milk.

Women in the United States have breast milk concentrations of polybrominated diphenyl ethers (PBDEs) that are among the highest in the world, leading to concerns over the potential health implications to breastfeeding infants during critical stages of growth and development. Developing cost-effective and sustainable methods for assessing chemical exposures in infants is a high priority to federal agencies and local communities. PBDE data are available in nationally representative serum samples but not in breast milk. As a method to predict PBDE concentrations in U.S. breast milk, we present the development of congener-specific linear regression partitioning models and their application to U.S. serum data. Models were developed from existing paired milk and serum data and applied to 2003-2004 NHANES serum data for U.S. women. Highest estimated median U.S. breast milk concentrations were for BDE-47 (30.6 ng/g lipid) and BDE-99 (6.1 ng/g lipid) with the median concentration of Σ7PBDEs estimated at 54.2 ng/g lipid. Predictions of breast milk PBDE concentration were consistent with reported concentrations from 11 similarly timed U.S. studies. When applied to NHANES data, these models provide a sustainable method for estimating population-level concentrations of PBDEs in U.S. breast milk and should improve exposure estimates in breastfeeding infants.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Coprophenomena in Tourette syndrome.

The aims of this descriptive study were to examine the prevalence and associations of coprophenomena (involuntary expression of socially unacceptable words or gestures) in individuals with Tourette syndrome. Participant data were obtained from the Tourette Syndrome International Database Consortium. A specialized data collection form was completed for each of a subset of 597 consecutive new patients with Tourette syndrome from 15 sites in seven countries. Coprolalia occurred at some point in the lifetime of 19.3% of males and 14.6% of females, and copropraxia in 5.9% of males and 4.9% of females. Coprolalia was three times as frequent as copropraxia, with a mean onset of each at about 11 years, 5 years after the onset of tics. In 11% of those with coprolalia and 12% of those with copropraxia these coprophenomena were one of the initial symptoms of Tourette syndrome. The onsets of tics, coprophenomena, smelling of non-food objects, and spitting were strongly intercorrelated. Early onset of coprophenomena was not associated with its longer persistence. The most robust associations of coprophenomena were with the number of non-tic repetitive behaviors, spitting, and inappropriate sexual behavior. Although coprophenomena are a frequently feared possibility in the course of Tourette syndrome, their emergence occurs in only about one in five referred patients. Because the course and actual impact of coprophenomena are variable, additional prospective research is needed to provide better counseling and prognostic information.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

Alternative modified infant-feeding practices to prevent postnatal transmission of human immunodeficiency virus type 1 through breast milk: past, present, and future.

Preventing mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) through breastfeeding is important to reduce the number of infected children. Research on making breastfeeding safer is a high priority. The authors reviewed the attempts to develop alternative methods, other than antiretroviral (ARV) therapy of mothers and/or babies, to decontaminate breast milk of infectious HIV-1 (free and associated with lymphocytes). They also review how these methods affect milk constituents, as well as their current and prospective status. A PubMed search for English publications on methods to prevent MTCT through breast milk was completed. Methods that have been tested, other than systemicuse or ARV or immunoprophylaxis, to reduce or prevent MTCT of HIV-1 through breast milk were broadly classified into 5 groups: (1) modified feeding practices, (2) heat treatment of milk, (3) lipolysis, (4) antimicrobial treatment of the breastfeeding mother, and (5) microbicidal treatment of infected milk. Their advantages and disadvantages are discussed, as well as future directions in the prevention of MTCT through breastfeeding.

Biochemical analysis of human milk treated with sodium dodecyl sulfate, an alkyl sulfate microbicide that inactivates human immunodeficiency virus type 1.

Reduction of transmission of human immunodeficiency virus type 1 (HIV-1) through human milk is needed. Alkyl sulfates such as sodium dodecyl sulfate (SDS) are microbicidal against HIV-1 at low concentrations, have little to no toxicity, and are inexpensive. The authors have reported that treatment of HIV-1-infected human milk with < or = 1% (10 mg/mL) SDS for 10 minutes inactivates cell-free and cell-associated virus. The SDS can be removed with a commercially available resin after treatment without recovery of viral infectivity. In this article, the authors report results of selective biochemical analyses (ie, protein, immunoglobulins, lipids, cells, and electrolytes) of human milk subjected to SDS treatment and removal. The SDS treatment or removal had no significant effects on the milk components studied. Therefore, the use of alkyl sulfate microbicides to treat milk from HIV-1-positive women may be a simple, practical, and nutritionally sound way to prevent or reduce transmission of HIV-1 while still feeding with mother's own milk.

Inactivation of HIV-1 in breast milk by treatment with the alkyl sulfate microbicide sodium dodecyl sulfate (SDS).

BACKGROUND: Reducing transmission of HIV-1 through breast milk is needed to help decrease the burden of pediatric HIV/AIDS in society. We have previously reported that alkyl sulfates (i.e., sodium dodecyl sulfate, SDS) are microbicidal against HIV-1 at low concentrations, are biodegradable, have little/no toxicity and are inexpensive. Therefore, they may be used for treatment of HIV-1 infected breast milk. In this report, human milk was artificially infected by adding to it HIV-1 (cell-free or cell-associated) and treated with or=0.1%) was virucidal against cell-free and cell-associated HIV-1 in breast milk. SDS could be substantially removed from breast milk, without recovery of viral infectivity. Viral load in artificially infected milk was reduced to undetectable levels after treatment with 0.1% SDS. SDS was virucidal against HIV-1 in human milk and could be removed from breast milk if necessary. Milk was not infectious after SDS removal. CONCLUSION: The proposed treatment concentrations are within reported safe limits for ingestion of SDS by children of 1 g/kg/day. Therefore, use of alkyl sulfate microbicides, such as SDS, to treat HIV1-infected breast milk may be a novel alternative to help prevent/reduce transmission of HIV-1 through breastfeeding.

Drugs and chemicals in human milk.

There is continuing emphasis by many professionals and organizations on the importance of breastfeeding as optimal infant nutrition. Pediatricians are frequently asked about the safety of medications taken by the nursing mother and the risk to the infant. Most drugs and many chemicals will be transferred into milk. For a vast majority of these compounds, there is no risk to the infant. It is almost always possible for the mother to continue nursing while taking the necessary medication. This article presents an introduction to the pharmacology of the transfer of drugs into milk, discusses the importance of the infant's age in assessing safety and presents a number of maternal conditions for which drugs need to be used.

Methodologic considerations for improving and facilitating human milk research.

Over the past several decades, interest in using human milk as a biomonitoring matrix has increased. However, it is not always an easy matter for a new mother to provide a milk sample. In this article, guidance on facilitating collection of human milk is provided. This includes addressing the mother's ease in expressing a milk sample, and engaging with many audiences to reduce the likelihood of negatively impacting the already low breastfeeding rates in the United States. In addition, this article covers concepts regarding long-term storage and integrity of human milk samples to maximize the utility of those samples, and proposed methods for improving public access to the full spectrum of human milk biomonitoring data, with context to understand the information presented. The environmental chemicals and chemical classes for which robust analytical methods exist are enumerated, and a process for prioritizing the development of analytical methods for additional environmental chemicals is described.

Tourette Syndrome: a general pediatrician's 35-year experience at a single center with follow-up in adulthood.

A retrospective analysis of a 35-year single-center experience with pediatric tics and Tourette syndrome was conducted. 482 charts from 1972 to 2007 were reviewed. Follow-up surveys were mailed to last known address and 83 patients responded (17%). Response rate was affected by long interval from last visit; contact information was often incorrect as it was the address of the patient as a child. Males constituted 84%. Mean tic onset was 6.6 years. At first visit, 83% had multiple motor tics and >50% had comorbidities. 44% required only 1 visit and 90% less than 12 visits. Follow-up showed positive clinical and social outcomes in 73/83 survey responses. Of those indicating a poor outcome, mean educational level was lower and attention deficit/hyperactivity disorder and learning disabilities were significantly higher. Access to knowledgeable caregivers was a problem for adult patients. A shortage of specialists may in part be addressed by interested general pediatricians.

Web-based phenotyping for Tourette Syndrome: Reliability of common co-morbid diagnoses.

Collecting phenotypic data necessary for genetic analyses of neuropsychiatric disorders is time consuming and costly. Development of web-based phenotype assessments would greatly improve the efficiency and cost-effectiveness of genetic research. However, evaluating the reliability of this approach compared to standard, in-depth clinical interviews is essential. The current study replicates and extends a preliminary report on the utility of a web-based screen for Tourette Syndrome (TS) and common comorbid diagnoses (obsessive compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD)). A subset of individuals who completed a web-based phenotyping assessment for a TS genetic study was invited to participate in semi-structured diagnostic clinical interviews. The data from these interviews were used to determine participants' diagnostic status for TS, OCD, and ADHD using best estimate procedures, which then served as the gold standard to compare diagnoses assigned using web-based screen data. The results show high rates of agreement for TS. Kappas for OCD and ADHD diagnoses were also high and together demonstrate the utility of this self-report data in comparison previous diagnoses from clinicians and dimensional assessment methods.

Sensitivity of the young infant to drug exposure through human milk.

In spite of significant exposure to drugs and chemicals through breast milk, there are very few reports of documented adverse effects on the infant. It is perhaps appropriate to consider that the presence of drugs and chemicals in milk may have a positive effect on developmental processes of the young infant. New experimental techniques coupled with increasing sensitive assays for chemical moieties present opportunities for measuring the effect of such chemicals on development processes in the neonate and young infant.

Dose-response relationship with increasing doses of dextromethorphan for children with cough.

BACKGROUND: The efficacy of dextromethorphan (DM) for treating acute cough is uncertain, and its use is not supported by the American Academy of Pediatrics. Nevertheless, DM is often administered to children as an antitussive. DM dosages are based on age rather than body weight, resulting in substantial variability in the relative amount of drug administered. OBJECTIVE: The aim of this work was to determine whether a dose-response relationship existed among a group of children administered a single nocturnal dose of DM for cough due to an upper respiratory tract infection. METHODS: As part of a larger double-blind, placebo-controlled trial of over-the-counter cough medications, children received DM. The administered doses (per manufacturer recommendations) were as follows: ages 2 to 5 years, 7.5 mg; ages 6 to 11 years, 15 mg; and ages 12 to 18 years, 30 mg. This resulted in a range of 0.35 to 0.94 mg/kg per dose. Subjective parental assessments of cough and sleep were obtained using a 7-point Likert-type scale that compared symptoms after medication with symptoms during the prior night (without medication). Three dose ranges were compared as a subset analysis of the group that received DM. RESULTS: Thirty-three patients (19 girls, 14 boys; median [interquartile range] age, 4.90 [2.90-6.80] years; age range, 2.10-16.50 years) received DM and completed the study. No significant differences were found for any of the outcome measures when comparing the effects of different doses of DM, but our observations suggested somewhat more symptomatic relief for patients receiving medium-dose DM (0.45 to <0.60 mg/kg per dose) or high-dose (HD) DM (0.60-0.94 mg/kg per dose) compared with low-dose DM (0.35 to <0.45 mg/kg per dose). Adverse events occurred most often in the HD group. CONCLUSIONS: Although no statistically significant differences were detectable for the outcomes studied, our observations suggest the potential for improved clinical symptom control with increasing doses of DM. Our findings may further suggest that a dose of 0.5 mg/kg should be considered in future assessments of the antitussive effect of DM in pediatric studies, to balance symptomatic relief with the avoidance of adverse events.

Technical workshop on human milk surveillance and research on environmental chemicals in the United States: an overview.

Interest in human milk research and monitoring for environmental chemicals is growing, and as studies of chemicals in human milk are initiated, it is of the utmost importance that these studies be conducted using harmonized methods. Due to numerous limitations in previous studies and the fact that few studies on environmental chemicals in human milk have been conducted in the United States, there is a growing need for a human milk sampling and analysis protocol in this country. The Technical Workshop on Human Milk Surveillance and Research on Environmental Chemicals in the United States was organized to develop state-of-the-science protocols describing the various aspects of such a program. An expert panel, comprised of specialists in the fields of pediatrics, family medicine, nursing, lactation, human milk sampling, analytical chemistry, epidemiology, pharmacology, toxicology, nutrition, and risk evaluation and communication, was assembled to participate in a 2-day workshop at the Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine. The expert panel was tasked with carefully describing and defining the components of well-conducted human milk surveillance and research studies, including participant selection, sample collection and analysis techniques, questionnaire development, chemical selection, and data reporting and interpretation, especially for use in the United States. The articles that follow this overview describe the results of the expert panel's deliberations on the components of human milk surveillance and research programs.

Criteria for chemical selection for programs on human milk surveillance and research for environmental chemicals.

The people of the United States is exposed to a large number of chemicals in their daily lives. In order to prioritize chemicals that should be considered for surveillance of and/or research in human milk, criteria were developed at the Technical Workshop on Human Milk Surveillance and Research on Environmental Chemicals in the United States. The criteria include (1) lipid solubility and/or persistence in the environment; (2) extensive exposure (e.g., high-production-volume chemicals and chemicals in personal care products); (3) known or suspected toxicity in a biological system; (4) historical interest, trend information; (5) chemicals of emerging concern; and (6) chemicals for medicinal use and chemicals in occupational settings. A working list of chemicals was developed for each of the criteria. It should be noted that more than one criterion may be applicable to a selected chemical, but the selected chemical should possess at least one of these designated criteria. It is hoped that by following a cohort of nursing women through their lactational cycle for a group of these chemicals, data generated will indicate the extent of infant exposure and may suggest methods for risk management to decrease inadvertent exposure for breast-feeding mothers and infants. While not the focus of this article, certain endogenous chemicals in human milk beneficial to the health of the infant warrant study as well.

Weight and height deficits in children with brain stem tumors.

Weight deficit is common among children with brain stem tumors and is often accompanied by height deficit. Among 22 consecutive children (< or =18 years) with brain stem tumor, 16 had weight deficit (< or =20th percentile) (p<1.4e-7). Eleven were at or less than the 5th percentile, and 5 were less than the 1st weight percentile. Eight also had height deficit (< or =20th percentile) (p<0.06). Misdiagnoses occurred: failure to thrive in 5, growth retardation in 2, and anorexia nervosa in 2. Delay between these diagnoses and that of brain tumor averaged 4.5 years. Detailed neuroradiologic study seems worthwhile if weight deficit is extreme and either unexplained or uncorrectable, or if the weight deficit is accompanied by an abnormality suggestive of intracranial disease.