Showing papers by "Boston Children's Hospital published in 2001"

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

Abstract: Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology A susceptibility locus for Crohn's disease has been mapped to chromosome 16 Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated

PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations.

Abstract: Background.The PedsQL (Pediatric Quality of Life Inventory) (Children’s Hospital and Health Center, San Diego, California) is a modular instrument for measuring health-related quality of life (HRQOL) in children and adolescents ages 2 to 18. The PedsQL 4.0 Generic Core Scales are multidimensional ch

Medication errors and adverse drug events in pediatric inpatients.

Abstract: ContextIatrogenic injuries, including medication errors, are an important problem in all hospitalized populations. However, few epidemiological data are available regarding medication errors in the pediatric inpatient setting.ObjectivesTo assess the rates of medication errors, adverse drug events (ADEs), and potential ADEs; to compare pediatric rates with previously reported adult rates; to analyze the major types of errors; and to evaluate the potential impact of prevention strategies.Design, Setting, and PatientsProspective cohort study of 1120 patients admitted to 2 academic institutions during 6 weeks in April and May of 1999.Main Outcome MeasuresMedication errors, potential ADEs, and ADEs were identified by clinical staff reports and review of medication order sheets, medication administration records, and patient charts.ResultsWe reviewed 10 778 medication orders and found 616 medication errors (5.7%), 115 potential ADEs (1.1%), and 26 ADEs (0.24%). Of the 26 ADEs, 5 (19%) were preventable. While the preventable ADE rate was similar to that of a previous adult hospital study, the potential ADE rate was 3 times higher. The rate of potential ADEs was significantly higher in neonates in the neonatal intensive care unit. Most potential ADEs occurred at the stage of drug ordering (79%) and involved incorrect dosing (34%), anti-infective drugs (28%), and intravenous medications (54%). Physician reviewers judged that computerized physician order entry could potentially have prevented 93% and ward-based clinical pharmacists 94% of potential ADEs.ConclusionsMedication errors are common in pediatric inpatient settings, and further efforts are needed to reduce them.

Survey of Infections Due to Staphylococcus Species: Frequency of Occurrence and Antimicrobial Susceptibility of Isolates Collected in the United States, Canada, Latin America, Europe, and the Western Pacific Region for the SENTRY Antimicrobial Surveillance Program, 1997–1999

Abstract: Between January 1997 and December 1999, bloodstream isolates from 15,439 patients infected with Staphylococcus aureus and 6350 patients infected with coagulase-negative Staphylococcus species (CoNS) were referred by SENTRY-participating hospitals in the United States, Canada, Latin America, Europe, and the Western Pacific region. S. aureus was found to be the most prevalent cause of bloodstream infection, skin and soft-tissue infection, and pneumonia in almost all geographic areas. A notable increase in methicillin (oxacillin) resistance among community-onset and hospital-acquired S. aureus strains was observed in the US centers. The prevalence of methicillin (oxacillin)-resistant S. aureus varied greatly by region, site of infection, and whether the infection was nosocomial or community onset. Rates of methicillin resistance were extremely high among S. aureus isolates from centers in Hong Kong and Japan. Uniformly high levels of methicillin resistance were observed among CoNS isolates. Given the increasing multidrug resistance among staphylococci and the possible emergence of vancomycin-resistant strains, global strategies are needed to control emergence and spread of multiply resistant staphylococci.

The trp ion channel family

Abstract: Mammalian homologues of the Drosophila transient receptor potential (TRP) channel gene encode a family of at least 20 ion channel proteins. They are widely distributed in mammalian tissues, but their specific physiological functions are largely unknown. A common theme that links the TRP channels is their activation or modulation by phosphatidylinositol signal transduction pathways. The channel subunits have six transmembrane domains that most probably assemble into tetramers to form non-selective cationic channels, which allow for the influx of calcium ions into cells. Three subgroups comprise the TRP channel family; the best understood of these mediates responses to painful stimuli. Other proposed functions include repletion of intracellular calcium stores, receptor-mediated excitation and modulation of the cell cycle.

Calcium regulation of neuronal gene expression.

Abstract: Plasticity is a remarkable feature of the brain, allowing neuronal structure and function to accommodate to patterns of electrical activity. One component of these long-term changes is the activity-driven induction of new gene expression, which is required for both the long-lasting long-term potentiation of synaptic transmission associated with learning and memory, and the activitydependent survival events that help to shape and wire the brain during development. We have characterized molecular mechanisms by which neuronal membrane depolarization and subsequent calcium influx into the cytoplasm lead to the induction of new gene transcription. We have identified three points within this cascade of events where the specificity of genes induced by different types of stimuli can be regulated. By using the induction of the gene that encodes brain-derived neurotrophic factor (BDNF) as a model, we have found that the ability of a calcium influx to induce transcription of this gene is regulated by the route of calcium entry into the cell, by the pattern of phosphorylation induced on the transcription factor cAMP-response element (CRE) binding protein (CREB), and by the complement of active transcription factors recruited to the BDNF promoter. These results refine and expand the working model of activity-induced gene induction in the brain, and help to explain how different types of neuronal stimuli can activate distinct transcriptional responses.

Practice Guidelines for the Management of Infectious Diarrhea

Abstract: The widening array of recognized enteric pathogens and the increasing demand for cost-containment sharpen the need for careful clinical and public health guidelines based on the best evidence currently available. Adequate fluid and electrolyte replacement and maintenance are key to managing diarrheal illnesses. Thorough clinical and epidemiological evaluation must define the severity and type of illness (e.g., febrile, hemorrhagic, nosocomial, persistent, or inflammatory), exposures (e.g., travel, ingestion of raw or undercooked meat, seafood, or milk products, contacts who are ill, day care or institutional exposure, recent antibiotic use), and whether the patient is immunocompromised, in order to direct the performance of selective diagnostic cultures, toxin testing, parasite studies, and the administration of antimicrobial therapy (the latter as for traveler's diarrhea, shigellosis, and possibly Campylobacter jejuni enteritis). Increasing numbers of isolates resistant to antimicrobial agents and the risk of worsened illness (such as hemolytic uremic syndrome with Shiga toxin-producing Escherichia coli O157:H7) further complicate antimicrobial and antimotility drug use. Thus, prevention by avoidance of undercooked meat or seafood, avoidance of unpasteurized milk or soft cheese, and selected use of available typhoid vaccines for travelers to areas where typhoid is endemic are key to the control of infectious diarrhea.

The mental health of young people in Australia: key findings from the child and adolescent component of the national survey of mental health and well‐being

Abstract: Objective: To identify the prevalence of three mental disorders (Depressive Disorder, Conduct Disorder and Attention-Deficit/Hyperactivity Disorder), the prevalence of mental health problems, the health-related quality of life of those with problems, and patterns of service utilisation of those with and without mental health problems, among 4–17-year-olds in Australia. To identify rates of health-risk behaviours among adolescents with mental health problems.Method: The mental disorders were assessed using the parent-version of the Diagnostic Interview Schedule for Children Version IV. Parents completed the Child Behaviour Checklist to identify mental health problems and standard questionnaires to assess healthrelated quality of life and service use. The Youth Risk Behaviour Questionnaire completed by adolescents was employed to identify health-risk behaviours.Results: Fourteen percent of children and adolescents were identified as having mental health problems. Many of those with mental health problems ha...

CARD15 mutations in Blau syndrome.

Abstract: We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Our findings indicate that, in addition to Crohn disease, CARD15 is involved in the susceptibility to a second granulomatous disorder.

Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared with TSC1, Disease in Multiple Organs

Abstract: Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features. Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2–4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

Abstract: The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Adolescents' Perceptions of Social Status: Development and Evaluation of a New Indicator

Abstract: Objective. Eliminating health disparities, including those that are a result of socioeconomic status (SES), is one of the overarching goals of Healthy People 2010. This article reports on the development of a new, adolescent-specific measure of subjective social status (SSS) and on initial exploratory analyses of the relationship of SSS to adolescents9 physical and psychological health. Methods. A cross-sectional study of 10 843 adolescents and a subsample of 166 paired adolescent/mother dyads who participated in the Growing Up Today Study was conducted. The newly developed MacArthur Scale of Subjective Social Status (10-point scale) was used to measure SSS. Paternal education was the measure of SES. Indicators of psychological and physical health included depressive symptoms and obesity, respectively. Linear regression analyses determined the association of SSS to depressive symptoms, and logistic regression determined the association of SSS to overweight and obesity, controlling for sociodemographic factors and SES. Results. Mean society ladder ranking, a subjective measure of SES, was 7.2 ± 1.3. Mean community ladder ranking, a measure of perceived placement in the school community, was 7.6 ± 1.7. Reliability of the instrument was excellent: the intraclass correlation coefficient was 0.73 for the society ladder and 0.79 for the community ladder. Adolescents had higher society ladder rankings than their mothers (μ teen = 7.2 ± 1.3 vs μ mom = 6.8 ± 1.2; P = .002). Older adolescents9 perceptions of familial placement in society were more closely correlated with maternal subjective perceptions of placement than those of younger adolescents (Spearman9s rho teens = 0.31 vs Spearman9s rho teens ≥15 years = 0.45; P society = 0.89, 95% confidence interval = 0.83, 0.95; odds ratio community = 0.91, 95% confidence interval = 0.87, 0.97). For both depressive symptoms and obesity, community ladder rankings were more strongly associated with health than were society ladder rankings in models that controlled for both domains of SSS. Conclusions. This new instrument can reliably measure SSS among adolescents. Social stratification as reflected by SSS is associated with adolescents9 health. The findings suggest that as adolescents mature, SSS may undergo a developmental shift. Determining how these changes in SSS relate to health and how SSS functions prospectively with regard to health outcomes requires additional research.

Gating of Human Theta Oscillations by a Working Memory Task

Abstract: Electrode grids on the cortical surface of epileptic patients provide a unique opportunity to observe brain activity with high temporal-spatial resolution and high signal-to-noise ratio during a cognitive task. Previous work showed that large-amplitude theta frequency oscillations occurred intermittently during a maze navigation task, but it was unclear whether theta related to the spatial or working memory components of the task. To determine whether theta occurs during a nonspatial task, we made recordings while subjects performed the Sternberg working memory task. Our results show event-related theta and reveal a new phenomenon, the cognitive "gating" of a brain oscillation: at many cortical sites, the amplitude of theta oscillations increased dramatically at the start of the trial, continued through all phases of the trial, including the delay period, and decreased sharply at the end. Gating could be seen in individual trials and varying the duration of the trial systematically varied the period of gating. These results suggest that theta oscillations could have an important role in organizing multi-item working memory.

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

Abstract: The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IκB kinase) complex, which is essential for NF-κB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-κB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-κB through the NEMO protein, indicating that EDA results from impaired NF-κB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1β, IL-18, TNFα and CD154. We thus report for the first time that impaired but not abolished NF-κB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

Mutant GABA A receptor γ2-subunit in childhood absence epilepsy and febrile seizures

Abstract: Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants. We have found a mutation in a gene encoding a GABA(A) receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Analysis and visualization of single-trial event-related potentials

Abstract: In this study, a linear decomposition technique, independent component analysis (ICA), is applied to single-trial multichannel EEG data from event-related potential (ERP) experiments. Spatial filters derived by ICA blindly separate the input data into a sum of temporally independent and spatially fixed components arising from distinct or overlapping brain or extra-brain sources. Both the data and their decomposition are displayed using a new visualization tool, the "ERP image," that can clearly characterize single-trial variations in the amplitudes and latencies of evoked responses, particularly when sorted by a relevant behavioral or physiological variable. These tools were used to analyze data from a visual selective attention experiment on 28 control subjects plus 22 neurological patients whose EEG records were heavily contaminated with blink and other eye-movement artifacts. Results show that ICA can separate artifactual, stimulus-locked, response-locked, and non-event-related background EEG activities into separate components, a taxonomy not obtained from conventional signal averaging approaches. This method allows: (1) removal of pervasive artifacts of all types from single-trial EEG records, (2) identification and segregation of stimulus- and response-locked EEG components, (3) examination of differences in single-trial responses, and (4) separation of temporally distinct but spatially overlapping EEG oscillatory activities with distinct relationships to task events. The proposed methods also allow the interaction between ERPs and the ongoing EEG to be investigated directly. We studied the between-subject component stability of ICA decomposition of single-trial EEG epochs by clustering components with similar scalp maps and activation power spectra. Components accounting for blinks, eye movements, temporal muscle activity, event-related potentials, and event-modulated alpha activities were largely replicated across subjects. Applying ICA and ERP image visualization to the analysis of sets of single trials from event-related EEG (or MEG) experiments can increase the information available from ERP (or ERF) data. Copyright 2001 Wiley-Liss, Inc.

Risk factors for cerebral edema in children with diabetic ketoacidosis.

Abstract: Background Cerebral edema is an uncommon but devastating complication of diabetic ketoacidosis in children. Risk factors for this complication have not been clearly defined. Methods In this multicenter study, we identified 61 children who had been hospitalized for diabetic ketoacidosis within a 15-year period and in whom cerebral edema had developed. Two additional groups of children with diabetic ketoacidosis but without cerebral edema were also identified: 181 randomly selected children and 174 children matched to those in the cerebral-edema group with respect to age at presentation, onset of diabetes (established vs. newly diagnosed disease), initial serum glucose concentration, and initial venous pH. Using logistic regression, we compared the three groups with respect to demographic characteristics and biochemical variables at presentation and compared the matched groups with respect to therapeutic interventions and changes in biochemical values during treatment. Results A comparison of the children i...

Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States.

Abstract: Context. Iron deficiency anemia in in- fants can cause developmental problems. However, the relationship between iron status and cognitive achieve- ment in older children is less clear. Objective. To investigate the relationship between iron deficiency and cognitive test scores among a nation- ally representative sample of school-aged children and adolescents. Design. The National Health and Nutrition Examina- tion Survey III 1988 -1994 provides cross-sectional data for children 6 to 16 years old and contains measures of iron status including transferrin saturation, free erythro- cyte protoporphyrin, and serum ferritin. Children were considered iron-deficient if any 2 of these values were abnormal for age and gender, and standard hemoglobin values were used to detect anemia. Scores from standard- ized tests were compared for children with normal iron status, iron deficiency without anemia, and iron defi- ciency with anemia. Logistic regression was used to es- timate the association of iron status and below average test scores, controlling for confounding factors. Results. Among the 5398 children in the sample, 3% were iron-deficient. The prevalence of iron deficiency was highest among adolescent girls (8.7%). Average math scores were lower for children with iron deficiency with and without anemia, compared with children with nor- mal iron status (86.4 and 87.4 vs 93.7). By logistic regres- sion, children with iron deficiency had greater than twice the risk of scoring below average in math than did chil- dren with normal iron status (odds ratio: 2.3; 95% confi- dence interval: 1.1- 4.4). This elevated risk was present even for iron-deficient children without anemia (odds ratio: 2.4; 95% confidence interval: 1.1-5.2). Conclusions. We demonstrated lower standardized math scores among iron-deficient school-aged children and adolescents, including those with iron deficiency without anemia. Screening for iron deficiency without anemia may be warranted for children at risk. Pediatrics 2001;107:1381-1386; iron deficiency, anemia, cognition, math, children, adolescence.

An etiological role for aeroallergens and eosinophils in experimental esophagitis

Abstract: Eosinophil infiltration into the esophagus is observed in diverse diseases including gastroesophageal reflux and allergic gastroenteritis, but the processes involved are largely unknown. We now report an original model of experimental esophagitis induced by exposure of mice to respiratory allergen. Allergen-challenged mice develop marked levels of esophageal eosinophils, free eosinophil granules, and epithelial cell hyperplasia, features that mimic the human disorders. Interestingly, exposure of mice to oral or intragastric allergen does not promote eosinophilic esophagitis, indicating that hypersensitivity in the esophagus occurs with simultaneous development of pulmonary inflammation. Furthermore, in the absence of eotaxin, eosinophil recruitment is attenuated, whereas in the absence of IL-5, eosinophil accumulation and epithelial hyperplasia are ablated. These results establish a pathophysiological connection between allergic hypersensitivity responses in the lung and esophagus and demonstrate an etiologic role for inhaled allergens and eosinophils in gastrointestinal inflammation.

Why Don't Low-Income Mothers Worry About Their Preschoolers Being Overweight?

Abstract: Context. Mothers are in an important position to prevent obesity in their children by shaping early diet and activity patterns. However, many mothers of overweight preschool children are not worried about their child's weight. Objective. To explore mothers' perceptions about how they determine when a child is overweight, why children become overweight, and what barriers exist to preventing or managing childhood obesity. Design. Three focus groups with 6 participants in each. Participant comments were transcribed and ana- lyzed. Themes were coded independently by the 6 au- thors who then agreed on common themes. Setting. A clinic of the Special Supplemental Nutri- tion Program for Women, Infants, and Children in Cin- cinnati, Ohio. Participants. Eighteen low-income mothers (13 black, 5 white) of preschool children (mean age of 44 months) who were at-risk for later obesity. All but 1 mother had a body mass index (BMI) >25 kg/m 2 , and 12 mothers had a BMI >30 kg/m 2 . All but 1 child had a BMI >85th per- centile for age and sex, and 7 had a BMI >95th percentile. Results. Mothers did not define overweight or obese in their children according to how height and weight measurements were plotted on the standard growth charts used by health professionals. Instead, mothers were more likely to consider being teased about weight or developing limitations in physical activity as indica- tors of their child being overweight. Children were not believed to be overweight if they were active and had a healthy diet and/or a good appetite. Mothers described overweight children as thick or solid. Mothers believed that an inherited tendency to be overweight was likely to be expressed in the child regardless of environmental factors. In trying to shape their children's eating, mothers believed that their control over the child's diet was chal- lenged by other family members. If a child was hungry, despite having just eaten, it was emotionally difficult for mothers to deny additional food. Conclusions. Health professionals should not assume that defining overweight according to the growth charts has meaning for all mothers. Despite differing percep- tions between mothers and health professionals about the definition of overweight, both groups agree that chil- dren should be physically active and have healthy diets. Health professionals may be more effective in prevent- ing childhood obesity by focusing on these goals that they share with mothers, rather than on labeling children as overweight. Pediatrics 2001;107:1138 -1146; obesity, body weight, mothers, child, preschool, mother-child rela- tions.

Prevalence of Psychiatric Disorders in Youths Across Five Sectors of Care

Abstract: Objective To examine the prevalence of psychiatric disorders among youths from the following five public sectors of care: alcohol and drug services (AD), child welfare (CW), juvenile justice (JJ), mental health (MH), and public school services for youths with serious emotional disturbance (SED) in San Diego, California. Method The Diagnostic Interview Schedule for Children was administered between October 1997 and January 1999 for 1,618 randomly selected youths aged 6–18 years who were active in at least one of the five sectors. Results Fifty-four percent of the participants met criteria for at least one study disorder. Attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (50%) were much more common than anxiety (10%) or mood (7%) disorders. Youths who were active in the MH and SED sectors were more likely than those not in these sectors to meet criteria for a disorder; youths in the CW sector were least likely. Conclusions Rates of psychiatric disorders, specifically ADHD and disruptive behavior disorders, are extremely high for youths in public sectors of care. Rates are generally higher in sectors designed to serve youths with psychiatric needs, but the prevalence of disorders was also high in sectors not specifically designed for this need (e.g., CW and JJ).

Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia.

Abstract: An abnormal pulmonary vasculature may be an important component of bronchopulmonary dysplasia (BPD). We examined human infant lung for the endothelial cell marker PECAM-1 and for angiogenic factors and their receptors. Lung specimens were collected prospectively at approximately 6 h after death. The right middle lobe was inflation fixed and part of the right lower lobe was flash frozen. We compared lungs from infants dying with BPD (n = 5) with lungs from infants dying from nonpulmonary causes (n = 5). The BPD group was significantly more premature and had more days of ventilator and supplemental oxygen support, but died at a postconceptional age similar to control infants. PECAM-1 protein and mRNA were decreased in the BPD group. PECAM-1 immunohistochemistry showed the BPD group had decreased staining intensity and abnormal distribution of alveolar capillaries. The dysmorphic capillaries were frequently in the interior of thickened alveolar septa. The BPD group had decreased vascular endothelial growth factor (VEGF) mRNA and decreased VEGF immunostaining, compared with infants without BPD. Messages for the angiogenic receptors Flt-1 and TIE-2 were decreased in the BPD group. We conclude that infants dying with BPD have abnormal alveolar microvessels and that disordered expression of angiogenic growth factors and their receptors may contribute to these abnormalities.

Evolution and transmission of stable CTL escape mutations in HIV infection

Abstract: Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.