Laurie C. Miller

Neonatal interleukin-1β, interleukin-6, and tumor necrosis factor: Cord blood levels and cellular production

In a prospective study, levels of interleukin-1 beta (IL-1 beta), interleukin-6) (IL-6), and tumor necrosis factor (TNF) were measured in a blind fashion in cord blood plasma from 92 neonates by specific immunoassays, and were correlated with the clinical courses of the infants, including type of delivery and perinatal complications. Plasma IL-1 beta concentration was undetectable in infants born by normal vaginal delivery or elective cesarean section but was significantly increased in infants born after induced vaginal deliveries (142 +/- 68 pg/ml) or urgent cesarean section (290 +/- 21 pg/ml; both p less than 0.05 compared with normal deliveries). The IL-1 beta levels were elevated in infants with severe perinatal complications (282 +/- 116 pg/ml; p less than 0.001), whereas TNF and IL-6 levels were not related to these complications. Infants with isolated perinatal infectious complications had elevated levels of plasma IL-6 compared with those of sick neonates without infection (p less than 0.001). In contrast, TNF plasma levels and IL-1 beta production by cord blood leukocytes were decreased in infants with infectious complications alone (both p less than 0.05). These studies suggest that the levels of IL-1 beta, IL-6, and TNF in the cord plasma relate differentially to clinical complications in the perinatal period.

Vitamin D and autoimmune rheumatologic disorders.

Vitamin D levels depend on many variables, including sun exposure, age, ethnicity, body mass index, use of medications and supplements. A much higher oral vitamin D intake than the current guidelines is necessary to maintain adequate circulating 25(OH)D levels in the absence of UVB radiation of the skin. In addition to the traditional known metabolic activities, vitamin D has been shown to modulate the immune system, and its deficiency has been linked to the development of several autoimmune disorders including type 1 diabetes and multiple sclerosis. Experimental use of vitamin D has revealed a novel role in the immunopathogenesis of autoimmune diseases. Disorders such as systemic lupus erythematosus, rheumatoid arthritis, Behçets, polymyositis/dermatomyositis and systemic scleroderma have all been associated to some extent to vitamin D deficiency. If vitamin D deficiency occurs at a higher rate in patients with autoimmune disorders, then appropriate supplementation may be indicated.

Health of Children Adopted From Guatemala: Comparison of Orphanage and Foster Care

Objective. Since 1986, American parents have adopted >17300 children from Guatemala. This study assessed the health, growth, and developmental status of 103 Guatemalan adopted children (48 girls; 55 boys) after arrival in the United States. Physical evidence suggestive of prenatal alcohol exposure and adequacy of vaccinations administered were also reviewed. Methods. Retrospective chart review was conducted of 103 children who were evaluated after arrival in the United States in an international adoption specialty clinic, and a case-matched study was conducted of a subgroup of 50 children who resided in either an orphanage or foster care before adoption. Mean age at arrival was 16 ± 19 months. Before adoption, 25 children resided in orphanages, 56 resided in foster care, and 22 resided in mixed-care settings. The 25 children who had resided in orphanages before adoption were matched for age at arrival, interval from arrival to clinic visit, and gender with a child adopted from foster care. Health and developmental status of these matched pairs were compared, allowing the first direct comparison of children raised in orphanages or foster care before adoption. Results. Mild growth delays were frequent among the children. Mean z scores for weight, height, and head circumference were, respectively, −1.00, −1.04, and −1.08. Children from foster care had significantly better z scores for height, weight, and head circumference than those from orphanage or mixed care. Among children who were younger than 2 years at arrival, growth measurements correlated inversely with age at arrival. Infectious diseases included intestinal parasites (8%) and latent tuberculosis infection (7%). Other medical conditions included anemia (30%), elevated lead levels (3%), and (using strict criteria) phenotypic facial features suggestive of prenatal alcohol exposure (28%). Adequacy of vaccine records from Guatemala was assessed: 28% met American Academy of Pediatrics standards for vaccine administration. Unsuspected significant medical diagnoses, including congenital anomalies and ocular, neurologic, and orthopedic problems, were found in 14%. Most children were doing well developmentally (80–92% of expected performance), but 14% had global developmental delays. Cognition, expressive and receptive language, and activities of daily living skills correlated inversely with age at arrival for children who were younger than 2 years at adoption. Among the 50 matched children, those who resided in foster care before adoption had better measurements for height, weight, and head circumference at arrival to the United States. Moreover, those who resided in foster care scored significantly better for cognitive skills than those who had previously resided in orphanages (96.3% of age-expected compared with 88.3% of age-expected); other skills did not differ between the 2 groups. No differences were found between the 2 groups of children related to prevalence of medical diagnoses or phenotypic evidence suggesting prenatal alcohol exposure. Conclusions. Guatemalan adoptees display similar overall patterns of growth and developmental delays as seen in other groups of internationally adopted children, although not as severe. Younger children had better growth and development (cognition, language, and activities of daily living skills) than older children, regardless of location of residence before adoption. Among children who were matched for age, gender, and interval from adoption to evaluation, those who had resided in foster care had better growth and cognitive scores than children who had resided in orphanages before adoption. These findings support the need for timely adoptive placement of young infants and support the placement of children in attentive foster care rather than orphanages when feasible.

Human parvovirus B19-associatedarthritis in children

Human parvovirus B19 (HPV B19) infection has been associated with chronic jointcomplaints in adult patients. We now report 22 children with joint complaints associated with recent HPV B19 infection. These children had either erythema infectiosum or serologic evidence of recent infection. Twenty children had arthritis; two had arthralgias. Eleven children had associated constitutional symptoms. Laboratory findings were generally normal. The duration of joint symptoms was less than 4 months in 14 children; however, six children have had persistent arthritis for 2 to 13 months, which would fulfill criteria for the diagnosis of juvenile rheumatoid arthritis. Although HPV B19 is usually associated with acute arthritis of brief duration, in some children infection with HPV B19 may be associated with the development of chronic arthritis.

Outcomes of children adopted from Eastern Europe

Behavioral problems are frequent among post-institutionalized Eastern European adoptees. However, risk factors related to outcomes have not been fully delineated. We evaluated 50 Eastern European adoptees, age 8—10 years, with their adoptive families for more than five years. Cognitive and behavioral outcomes and parenting stress were evaluated in relation to pre-adoptive risk factors, including arrival age, growth, and facial phenotype related to prenatal alcohol exposure. At follow-up, IQ and achievement scores were ≥ average in most children (≥74%). Behavioral and school problems were common (externalizing 44%, internalizing 18%, behavioral symptoms 50%, attention deficit hyperactivity disorder (ADHD) 46%, learning disabilities 40%, mental health disorders 28%); 38% had multiple problems. Behavioral problems correlated inversely with IQ. Parent stress was high and correlated with child externalizing behaviors and inversely to child full scale IQ. Children with “severe behavioral disturbances” (24%) were more likely to have had smaller head circumferences at arrival. Childs age at adoption related inversely to parent stress, possibly due to the longer duration of time that children resided with their families. “High/intermediate risk” phenotypic facial scores for prenatal alcohol exposure (58%) correlated with head circumference z scores at arrival and follow-up. Otherwise, arrival age, growth, and facial phenotype did not correlate with these specific outcome measures.

Interleukin-1 (IL-1) receptor blockade reduces endotoxin and Borrelia burgdorferi-stimulated IL-8 synthesis in human mononuclear cells.

Interleukin‐1 (IL‐1) is a potent stimulator of IL‐8 production by fibroblasts and monocytes. In the present study, we asked how much of endotoxin (LPS)‐induced IL‐8 production by human peripheral blood mononuclear cells was due to IL‐1 induced by LPS. Cells were stimulated with either IL‐1β, LPS, or Borrelia burgdorferi, and total IL‐8 was determined by a specific radioimmunoassay. The addition of saturating concentrations of IL‐1 receptor antagonist protein (IRAP) reduced the IL‐1β‐, LPS‐, and B. burgdorferi‐induced IL‐8 synthesis by 85, 50, and 40%, respectively. Increasing the concentration of LPS did not affect the reduction in IL‐8 synthesis observed in the presence of IRAP. Significant inhibition of the IL‐1β‐induced IL‐8 synthesis was observed when IRAP was added 60 or 90 min after IL‐1β; similarly, IL‐8 synthesis after LPS was also reduced by delayed addition of IRAP. These data suggest that the ameliorative effects of IL‐1 receptor blockade in models of inflammation and infection may be due, in part, to suppression of IL‐1‐induced IL‐8.—Porat, R.; Poutsiaka, D. D.; Miller, L. C.; Granowitz, E. V.; Dinarello, C. A. Interleukin‐1 (IL‐1) receptor blockade reduces endotoxin and Borrelia burgdorferi‐stimulated IL‐8 synthesis in human mononuclear cells. FASEB J. 6: 2482‐2486; 1992.

International Adoption: Infectious Diseases Issues

Nearly 220,000 children have been adopted from other countries by American parents since 1986. Approximately 65,000 children have arrived from China and Russia, mostly in the past 6 years. Most of these children reside in orphanages before adoption, where they may experience malnutrition, environmental deprivation, neglect, and exposure to infectious diseases. After arrival to the United States, international adoptees should undergo specialized screening evaluation for infectious diseases and other conditions. Infectious conditions of special concern include hepatitis B and C, syphilis, human immunodeficiency virus infection, tuberculosis, and presence of intestinal parasites. Before the adoption occurs, the infectious disease consultant may be asked to assist the primary care provider and the adoptive family with advice about travel and review of preadoptive medical records. After the adoption, the infectious diseases consultant may be asked to assess the adequacy of the childs vaccination record from the birth country and to assist in screening, evaluation, and management of infectious diseases.

Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist.

Lyme arthritis is one of the few forms of chronic arthritis in which the cause is known with certainty. Because cytokines are thought to contribute to the pathogenesis of chronic arthritis, we investigated the effect of the Lyme disease spirochete, Borrelia burgdorferi, on the gene expression and synthesis of IL-1 beta and the IL-1 receptor antagonist (IL-1ra) in human peripheral blood mononuclear cells. Live B. burgdorferi induced fivefold more IL-1 beta than IL-1 alpha and sevenfold more IL-1 beta than IL-1ra; LPS or sonicated B. burgdorferi induced similar amounts of all three cytokines. This preferential induction of IL-1 beta was most dramatic in response to a low passage, virulent preparation of B. burgdorferi vs. three high passage avirulent strains. No difference in induction of IL-1ra was seen between these strains. The marked induction of IL-1 beta was partially diminished by heat-treatment and abrogated by sonication; IL-1ra was not affected. This suggested that a membrane component(s) accounted for the preferential induction of IL-1 beta. However, recombinant outer surface protein beta induced little IL-1 beta. By 4 h after stimulation, B. burgdorferi induced sixfold more IL-1 beta protein than LPS. In contrast to LPS-induced IL-1 beta mRNA which reached maximal accumulation after 3 h, B. burgdorferi-induced IL-1 beta mRNA showed biphasic elevations at 3 and 18 h. B. burgdorferi-induced IL-1ra mRNA peaked at 12 h, whereas LPS-induced IL-1ra mRNA peaked at 9 h. IL-1 beta synthesis increased in response to increasing numbers of spirochetes, whereas IL-1ra synthesis did not. The preferential induction by B. burgdorferi of IL-1 beta over IL-1ra is an example of excess agonist over antagonist synthesis induced by a microbial pathogen, and may contribute to the destructive lesion of Lyme arthritis.

Prolonged fevers of unknown origin in children: Patterns of presentation and outcome

OBJECTIVE To review the presentation, clinical characteristics, and outcome of children with prolonged fevers of unknown origin who are referred for pediatric rheumatologic evaluation. METHODS We used a retrospective review of the charts of the 40 children (23 boys and 17 girls, aged 9 months to 14.6 years) with fevers persisting longer than 1 month who were referred to the Pediatric Rheumatology Clinic between 1984 and 1994, in whom evaluation did not result in diagnosis. Follow-up with childrens families, pediatricians, or both was done by telephone. RESULTS Of the 40 children, 29 had periodic fevers, and 11 had daily fevers without pattern. Patients with periodic fever were younger at onset, had longer duration of symptoms before referral, and higher maximum temperatures. The two groups did not differ in frequency of associated symptoms or signs. At follow-up (mean 60.5 +/- 5 months, n = 37), 10 children with daily fevers (within 24 months) and 23 children with periodic fevers (within 48 months) had completely recovered; three patients continue to have periodic fevers. In patients with daily fevers one had Crohn disease (7 months after initial evaluation) and another had uveitis (4 years after evaluation). One patient with periodic fevers had inflammatory bowel disease 3.5 years after the onset of fevers. Petit mal seizures developed in one patient with periodic fever, and another had mitochondrial encephalopathy. Four children with periodic fevers have attention-deficit hyperactivity disorder, and two have developmental delays. CONCLUSIONS Fevers without an obvious source usually have a benign outcome, although patients should be monitored for changes in symptoms. Of the children with periodic fevers, 29% were later found to have neurologic problems; the relation to the previous fevers is uncertain.

Time use in Russian Baby Homes.

BACKGROUND We investigated time use of Russian children residing in Baby Homes to document their opportunities and experiences during institutional care. METHODS Time use of 138 non-special needs, randomly selected children (65 female vs. 73 male, age 1 month to 4 years) in Baby Homes in Murmansk, Russia, was analysed. Baby Home specialists were trained in time-use spot observation methodology. Each child was observed every 10 min for 5 h (31 observations/child; >4000 data points). At each observation, we coded: who the child was with, adult role, what the child was doing, location and vocalizations. RESULTS Children spent 50% of their time alone, 27% with a caregiver, 15% with another adult, and 7% with another child. Infants spent significantly more time alone (65%) than toddlers (43%) or pre-schoolers (46%) [F(2,133) = 13.05, P < 0.0001]. Caregivers supervised children (58%), led group activities (16%), cared for individuals (14%), or were absent from the room (12%). Children spent the most time (32%) in activities of daily living; remaining time was spent in meaningful play (27%), non-purposeful activity (16%) or sleep (18%). The percentage of time spent in meaningful play significantly increased across age groups [infants 10%, toddlers 25%, pre-schoolers 36%, F(2,133) = 26.9, P < 0.001]. Infants (23%) and toddlers (20%) spent significantly more time than the older group (10%) in non-purposeful activity [F(2,133) = 26.9, P < 0.001]. In 12% of observations, an adult was speaking to the child, in 10% to the group, and <1% to another adult. Child vocalizations varied by age: infants 42% of observations, toddlers 56%, and pre-schoolers 59%. Older children directed more vocalizations to adults than younger children [F(2,133) = 24.47, P < 0.001]. CONCLUSION Time use of children residing in Baby Homes is limited by routinized schedules and care, at the expense of child-directed or interactive play with adults. Despite close proximity and living in group care, childrens vocalizations and interactions with others are limited.