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The aim of this 12-month prospective study was to compare reports describing the health-related quality of life (HRQL) of children with Juvenile idiopathic arthritis (JIA) obtained from parents and children, to investigate the extent to which the children's HRQL changed over a 12-month period, and to describe the relationship between children's HRQL, and their experience of pain and use of pain coping strategies. Fifty-four children aged 8-18 years with JIA and their parents completed standard questionnaires assessing children's HRQL, pain intensity, and pain coping strategies at baseline, 6 months, and 12 months. In general, children reported that their HRQL was better than was reported by parents. Both informants described children's HRQL as being very stable over the 12 months of the study. Consistent with the Biobehavioural Model of Pain, there was a significant negative relationship between children's HRQL and their experience of pain. However, there was little evidence that pain coping strategies mediated the relationship between children's experience of pain and their HRQL.

Objectives: To investigate the relationship between health-related quality of life (HRQL), experience of pain and pain coping strategies in children with juvenile idiopathic arthritis (JIA). To compare reports describing these variables obtained from children and their parents., Methods: Participants were 59 children aged 8 to 18 yr with JIA and their parents. Parents and children completed the PedsQL generic core scales and arthritis module, the visual analogue scale of the Varni-Thompson Pediatric Pain Questionnaire, and the Waldron/Varni Pediatric Pain Coping Inventory. Parents rated children's functional disability using the Childhood Health Assessment Questionnaire., Results: Parents reported significantly lower scores (indicating worse HRQL) than children on five of the eight PedsQL scales rating children's HRQL. Parents and children reported a significant negative relationship between pain levels and the PedsQL scores assessing children's physical, emotional and social functioning. They also reported a significant negative relationship between scores on several pain coping scales and scores on the PedsQL scales. However, the pattern of these relationships varied for reports from parents and children., Conclusions: Pain intensity and pain coping strategies have a significant and independent relationship with several domains that comprise the HRQL of children with JIA. However, parents and children have differing perceptions of the nature of these relationships. The differences emphasize the importance of clinicians obtaining information about children's HRQL, pain levels and pain coping strategies from both parents and children.

The ability of neutrophils to degrade cartilage proteoglycan suggests that the neutrophils that accumulate in the joints of rheumatoid arthritis patients are mediators of tissue damage. The regulatory mechanisms which are relevant to the proteoglycan-degrading activity of neutrophils are poorly understood. Since phosphatidylinositol 3-kinase (PI3-K), protein kinase C (PKC), the extracellular signal-regulated protein kinase (ERK)1/ERK2 and cyclic adenosine monophosphate (cAMP) have been reported to regulate neutrophil respiratory burst and/or degranulation, a role for these signalling molecules in regulating proteoglycan degradation was investigated. Preincubation of human neutrophils with GF109203X (an inhibitor of PKC), PD98059 (an inhibitor of MEK, the upstream regulator of ERK1/ERK2) or with forskolin or dibutyryl cAMP, failed to suppress proteoglycan degradation of opsonized bovine cartilage. In contrast, preincubation of neutrophils with wortmannin or LY294002, specific inhibitors of PI3-K, inhibited proteoglycan degradation. Incubation of neutrophils with cartilage resulted in the activation of PI3-K in neutrophils, consistent with a role for PI3-K in proteoglycan degradation. Activation of PI3-K and proteoglycan degradation was enhanced by tumour necrosis factor-alpha. Degradation caused by neutrophils from the synovial fluid of rheumatoid arthritis patients was also inhibited by wortmannin. These data demonstrate that the proteoglycan degradative activity of neutrophils required PI3-K but not PKC or the ERK1/ERK2/ERK5 cascades and was insensitive to increases in intracellular cAMP concentrations.

The antibody response in the young infant is limited in several ways; in particular, responses generally are of low affinity and restricted to IgM. This raises the question whether the affinity maturation process, consisting of somatic mutation of immunoglobulin genes coupled with selection of high-affinity variants, is operative in the neonate. Re-arranged V(H)6 genes were amplified by polymerase chain reaction (PCR) from cord blood and from peripheral blood of infants. Heteroduplex analysis detected mutation in only 2/18 cord blood samples, while mutations were seen from about 10 days of age onwards. Cloning and sequencing of mutated neonatal V(H)6 genes showed that mutated sequences contained relatively few mutations (one to three mutations per sequence) compared with published values of about 10 in adult IgM sequences. Selection was not evident in the majority of neonatal samples. Thus mutation can occur in the human neonate, but is minimal and generally not accompanied by selection. The age at which affinity maturation develops effectively is yet to be defined.

The neonatal immune system responds to a restricted range of antigens, producing largely IgM antibody of low affinity. Comparison of the components of the B-cell antigen receptor complex shows significantly elevated membrane levels of IgM in neonatal B cells, compared with adult cells. CD79, which acts as the signal transducer for membrane immunoglobulin, is elevated in parallel with IgM, while IgD is elevated to a lesser degree. CD19, CD21, CD22 and CD81, which are all involved in transmitting activation signals when immunoglobulin is engaged, are not elevated. CD32, which is involved in negative regulation of activation, is present at reduced levels on cord B cells. The elevation of B-cell membrane IgM persists during infancy. Neonatal B cells respond in vitro to interleukin-4 (IL-4) by further elevation of membrane IgM levels. The elevated level of membrane IgM may make neonatal B cells easier to trigger by low concentrations of antigen, but in vitro activation and immunoglobulin modulation experiments did not show significant differences between cord and adult B-cell responses to anti-IgM.

Mutation of the interleukin-2 (IL-2) receptor gamma chain, which also serves as a component of the receptor complexes for IL-4, 7, 9 and 15, results in severe immune deficiency. We hypothesized that the immunological immaturity of healthy neonates might be associated with low levels of expression of this receptor molecule. Using monoclonal antibody and a highly sensitive immunofluorescence method, we showed that IL-2 receptor gamma chain is expressed at significantly lower levels on cord blood cells compared with adult cells. IL-2-dependent T-cell activation in vitro was reduced in cord blood cells compared with adult cells, but B-cell responses to IL-4 were not obviously impaired. The lower level of expression of the gamma chain and some other cytokine receptor chains may contribute to the immunological immaturity of the newborn, by selectively depressing particular immunological mechanisms.

Previous studies have suggested that, in vivo, activated T lymphocytes and neutrophils are important in immunity to nontypable Haemophilus influenzae. We now extend this work by showing that neutrophils pretreated with products of activated T lymphocytes or activated macrophages show significantly enhanced killing of nontypable H. influenzae. Lymphotoxin, a product of activated T lymphocytes, significantly enhanced the neutrophil-mediated killing of nontypable H. influenzae, and tumor necrosis factor, produced by activated T lymphocytes as well as macrophages stimulated by activated T lymphocytes, also significantly increased the bactericidal activity of neutrophils. These cytokine-induced effects were seen with short pretreatment times of neutrophils and were maximal by 30 min. The killing of H. influenzae by neutrophils required the presence of heat-labile opsonins. In the absence of these opsonins, both tumor necrosis factor and lymphotoxin were unable to promote the killing of the bacteria by neutrophils. Furthermore, the results showed that tumor necrosis factor-primed neutrophils displayed significantly increased expression of CR3 and CR4 that was associated with increased phagocytosis of complement-opsonized nontypable H. influenzae. These cytokines may play an important role in immunity toward nontypable H. influenzae by stimulating neutrophil bactericidal activity.

The humoral and mucosal immune responses to oral immunization with xenogeneic antibodies were studied using an animal model in which female rabbits were fed daily doses of the MOPC-315 murine IgA antibody, and were mated during the course of the feeding programme. Serum and colostrum samples were assayed for the presence of anti-idiotypic antibodies by ELISA assay, before and after depletion of anti-IgA antibodies, by affinity chromatography using another murine IgA idiotype. It was shown that all animals responded to exposure to the MOPC-315 idiotype with the production of serum anti-murine immunoglobulin antibodies and that four of six animals produced serum anti-idiotypic antibodies. That the immune response included antibodies directed against the antigen-binding site was confirmed by competition ELISA assay. Mucosal IgG and IgA anti-immunoglobulin antibodies were present in milk from all antibody-fed rabbits tested, and IgA anti-idiotypic antibodies were detectable in the colostrum of one rabbit. The results provide some support for the hypothesis that human exposure to xenogeneic antibodies, most commonly bovine milk immunoglobulins, may provoke the production of anti-idiotypic antibodies, and that such exposure may lead to disturbances of immune regulation.

Polymeric IgA (PIgA) and immune complex concentrations in IgA-related renal disease were measured in cross sectional and longitudinal studies to establish the relationship between these parameters and both mucosal infection and renal dysfunction. These studies were performed in 50 patients with IgA nephropathy (IgAN), 17 patients with Henoch Schönlein purpura nephritis (HSPN), 11 control patients with IgA negative, diffuse mesangial proliferative glomerulonephritis (DMPGN) and 50 healthy controls. Total PIgA (PIgAT) and PIgA subclass concentrations were measured using a secretory component binding enzyme immunoassay and isotype specific immune complex concentrations were measured using conglutinin (K) binding immunoassays. In cross sectional studies patients with IgAN were found to have increased concentrations of PIgAT, PIgA1, K-IgA1 and K-IgA2 compared to controls. In the longitudinal studies controls and patients had significant increases in PIgAT and PIgA1 concentrations during infection. However, in patients with IgAN, the increases were greater, persisted for longer, and PIgA2 concentrations were also increased. K-IgA1 and K-IgA2 concentrations increased significantly during episodes of infection in IgAN patients in contrast to controls. Patients with HSPN had results similar to those of IgAN patients. No significant correlation was found between PIgA or K-IgA concentrations, and either serum creatinine concentrations or the degree of hematuria. The results indicate that patients with IgA-related renal disease have abnormal regulation of PIgA and immune complexed IgA, and that these abnormalities are exaggerated during mucosal infection.

Six hundred and eighty two assessments were performed on 641 babies under 6 months of age who presented to the emergency department of the Royal Children's Hospital, Melbourne, to try and determine the best markers of serious illness in young infants. Detailed, specific questions that quantified a baby's functional response to illness gave the most useful information. As a group, the six most common predictive symptoms of serious illness were: taking less than half the normal amount of feed over the preceding 24 hours, breathing difficulty, having less than four wet nappies in the preceding 24 hours, decreased activity, drowsiness, and a history of being both pale and hot. The presence of the corresponding sign on examination increased the predictive value of the symptom by 10-20%. Specific, highly predictive (though less common) signs included moderate to severe chest wall recession, respiratory grunt, cold calves, and a tender abdomen. A list of low, medium, and high risk symptoms has been constructed and the five measurements that were most useful in predicting serious illness in young infants have been detailed.

Total IgG concentrations, IgG antibody concentrations to pooled Escherichia coli antigens, and IgG anti-E. coli antibody avidity were measured in cord and maternal serum samples collected from 52 mother-infant pairs after premature delivery (mean gestational age 28 wk, range 23-33 wk). The mean IgG anti-E. coli antibody concentration in cord serum (1.86 relative units/mL) was markedly lower than in maternal serum (5.42 relative units/mL) at this gestation (p less than 0.0001). Cord serum IgG anti-E. coli antibody concentrations correlated closely with maternal IgG anti-E. coli concentrations when controlled for the effect of gestational age (partial correlation coefficient 0.89; p less than 0.001) but only weakly with gestational age when controlled for maternal IgG antibody concentrations (partial correlation coefficient 0.23; p = 0.06). The mean ratio of cord to maternal IgG anti-E. coli antibody concentrations was considerably lower than the mean ratio for total IgG concentrations (0.34 versus 0.72; p less than 0.001). The mean avidity of IgG antibody for the pooled E. coli antigens was significantly greater in cord serum than in maternal serum (2.45 versus 1.99M; p less than 0.0001). There was a close correlation between cord and maternal antibody avidity (r = 0.70; p less than 0.001), but cord IgG antibody avidity did not correlate with gestational age (r = -0.07; p = 0.61), nor with cord IgG anti-E. coli antibody concentrations (r = 0.10; p = 0.50).(ABSTRACT TRUNCATED AT 250 WORDS)

Concentrations of immunoglobulins and anti-Escherichia coli antibody were studied longitudinally in tracheobronchial aspirates from 33 premature intubated neonates, median gestational age 27 weeks. Aspirates collected at birth contained IgG, IgA, and IgM in 100%, 93%, and 79% of samples, respectively. The median IgA concentration at birth was 0.7 micrograms/mg total protein and increased to 5.8 micrograms/mg protein by the sixth week. IgG and IgM antibodies to E coli were present in 90% and 30%, respectively, of tracheobronchial aspirates collected at birth. Samples from three of 28 neonates (11%) contained IgA anti-E coli antibody at birth, and the proportion with IgA antibody rose to 50% during the sixth week. Secretory component associated IgA and IgM were detectable in samples tested at birth and at 4 weeks of age, and secretory component associated anti-E coli antibody was present in aspirates from three of nine neonates studied at 4 weeks of age, but had not been detectable at birth.

We describe a child with primary defect of polymorph bacterial killing associated with systemic lungs erythematosus. We suggest that her autoimmune disease results from chronic bacterial antigen stimulation and propose a hypothetical model linking immunodeficiency with autoimmunity.

A simple enzyme immunoassay has been developed to allow the quantitation of the human response to immunization with pneumococcal polysaccharide. The assay uses the 14-valent vaccine (Pneumovax) as a convenient antigen to adsorb to the solid-phase microdilution plate wells and commercially available isotype-specific antibody conjugates. The results have been expressed as arbitrary pneumococcal polysaccharide antibody units by reading off a standard curve constructed by using heterogeneous pooled serum. All nonimmunized subjects tested had immunoglobulin G (IgG) antibodies present in serum. All six control subjects who were immunized with Pneumovax demonstrated an IgG response, and the majority responded with a rise in IgA- and IgM-specific antibody concentrations at a mean of 6 weeks postimmunization. Five out of six cord sera tested contained IgG antibodies only, which were present in concentrations similar to those seen in adults, whereas in 6- to 12-month-old infants only low levels of IgG and IgM and no IgA antibodies were detected. Serum taken from 10 hypogammaglobulinemic patients immediately prior to infusion of immunoglobulin showed low to negative IgG antibody concentrations, and no IgA or IgM antibody was present.

Polymorphonuclear neutrophil iodide uptake can be used as a measure of yeast opsonization and optimal assay conditions are described for the identification of sera defective in this function. The use of standard normal and defective sera permits correction of inter-assay variations resulting from the use of different cell donors. The iodination assay correlated well (r = 0.74, P less than 0.001) with a direct assay of yeast opsonization when both were used to measure this function in a panel of 72 sera. Differences in results between the two assay systems for some sera may be explained by a requirement for two different surface-associated opsonic molecules in the initiation of neutrophil metabolic activity.

Serum IgG subclass-specific antibody concentrations to pneumococcal polysaccharides (PnPs) 1 and 14 were measured in 13 adult patients with isolated IgA deficiency and nine healthy adults immediately before and 4 weeks following immunization with polyvalent pneumococcal vaccine. Samples were analysed by enzyme immunoassay using pooled human serum as a reference preparation. A significant rise in median post-immunization antibody concentrations to PnPs14 was seen for all IgG subclasses, for IgA-deficient patients and for controls. For PnPs1, post-immunization IgG2 and IgG4 antibody concentrations rose significantly in the patient group, and IgG4 antibody concentrations rose significantly in the controls. The median IgG1 and IgG3 antibody concentrations to PnPs1 were significantly higher pre- and post-immunization in IgA-deficient individuals in comparison with controls, as were post-immunization IgG3 antibody concentrations to PnPs14. This enhancement of IgG1 and IgG3 antibody responses to pneumococcal polysaccharide antigens in IgA-deficient patients suggests an alteration in regulation of the normal switching processes in the generation of subclass and isotype diversity or could possibly be due to alteration in the affinity of subclass specific antibody.

This study compares the efficiency of different methods of separation of human bone marrow in vitro prior to transplantation. Separation on Ficoll-paque resulted in a median recovery of 11.3 X 10(4) CFU-c/10(9) nucleated cells harvested. The recovery from the major CFU-c containing fraction following separation on a discontinuous Percoll gradient was 10.8 X 10(4) CFU-c/10(9) nucleated cells. The CFU-c recovered from Percoll were contained in a smaller number of cells, resulting in enrichment for CFU-c of 1.6 times that of Ficoll-paque. Further CFU-c enrichment to approximately three times that of Ficoll-paque separation was possible by treatment of Percoll fractionated cells with soybean agglutinin (SBA). However this caused an overall loss of 67% of CFU-c. Cells remaining after SBA treatment of the CFU-c containing Percoll fraction had increased spontaneous DNA synthesis and decreased PHA responses. There was no significant change in the mixed lymphocyte reaction in comparison with Ficoll-paque.

Two male siblings with transient diabetes mellitus were of normal birth weight, were asymptomatic, and did not require treatment with insulin. This may be a previously undescribed disorder or part of the range of transient diabetes mellitus of infancy. Previously reported infants with transient diabetes mellitus of infancy have usually been small for gestational age and have presented with glycosuric dehydration, infections, or growth failure. Insulin concentrations after oral glucose challenge showed inadequate insulin secretion with respect to the degree of hyperglycaemia in these children. Autosomal dominant inheritance may occur in some families with this disorder, and parents of some affected children may also have had asymptomatic or unrecognised transient diabetes mellitus of infancy. Leucocyte histocompatibility antigen typing of this family did not show any association of specific antigens with transient diabetes mellitus of infancy in the affected children.

Seven murine monoclonal antibodies (MoAbs) to antigenic determinants present on human lymphocytes did not promote phagocytosis of allogeneic human lymphocytes by human peripheral blood polymorphonuclear leucocytes (PML). Similarly there was no significant metabolic activation of PML as determined by incorporation of radiolabelled iodide. The opsonic activity of MoAbs was not enhanced by addition of human or rabbit complement nor by the use of sheep anti-mouse IgG, rabbit anti-mouse immunoglobulin or goat anti-mouse immunoglobulin as second antibody. Whole serum from mice immunized with human lymphocytes did not act as an opsonin when tested with human PML. Hyperimmune mouse antiserum to Bordetella pertussis antigen acted only weakly as an opsonin. Human PML may not have an in vivo role in the removal of allogeneic lymphocytes treated with murine anti-lymphocyte MoAbs.

Four hundred normal children aged between 2 weeks and 11 years were examined to determine the prevalence and site of recent injury of any type. There was evidence of injury in 37% with a steady increase in prevalence to 60% by the end of the third year of life. Bruising of the hands and feet and of the lower legs was the most frequent type of injury. Head and facial injuries were most common between 18 months and 3 years (17% of children) but were rare at other ages. Injury to the lumbar region was unusual before 5 years but was present in 14% of children of school age. In 84 children of similar age where non-accidental injury was proved or suspected a different pattern of injury was present. Sixty per cent had injuries to the head and face; this increase in prevalence was seen at all ages. These children also had more frequent injuries in the lumbar region, particularly before the age of 5 years.

To investigate the relationship between mucosal and systemic immunity we analysed the specific anti-Escherichia coli antibody concentration and avidity of IgA in colostrum and IgG in paired blood samples from 47 mothers giving birth to premature neonates. The avidity of each sample, expressed as an avidity index, was determined using a novel enzyme immunoassay (EIA)-based procedure, while specific antibody determinations were performed by means of conventional sandwich EIA techniques. All subjects had detectable antibody to E. coli in serum and breast milk. The median avidity index for specific IgA antibody in breast milk (3.53 M NH4SCN, range 2.77-4.90) was significantly higher (P less than 0.0001) than that for specific IgG antibody in serum (median 2.03 M NH4SCN, range 1.15-3.65). Using Spearman correlation analysis, a weak but significant association was found between the avidity of colostral IgA antibody and the avidity of systemic IgG antibody to pooled E. coli polysaccharides (rs = 0.29, P = 0.02). There was also a weak correlation between the concentrations of specific serum IgG antibody and of specific colostral IgA antibody (rs = 0.36, P = 0.006). There was no correlation between the concentration of IgA anti-E. coli antibody in colostrum and the avidity of colostral IgA antibody (rs = 0.14, P less than 0.05). Similarly, there was no correlation between the concentration and the avidity of serum IgG anti-E. coli antibody (rs = 0.23, P less than 0.05). The findings of this study suggest independent regulation of concentration and avidity of specific IgA antibody in preterm breast milk. Similar results were seen for specific IgG antibody in serum. The correlations between systemic and mucosal antibody with respect to both concentration and avidity were significant, but are relatively weak and therefore suggest that there also may be independent factors which afford differential regulation of systemic and mucosal antibody responses.

The concentrations of beta-lactoglobulin was measured in the sera of 47 preterm an term neonates during the first few days of life under standardised conditions after feeding with a cows' milk'based formula. Preterm neonates, particularly those of less than 33 weeks' gestation, had higher serum concentrations of beta-lactoglobulin than term neonates given an equivalent mild feed. Prior feeding with breast milk did not diminish the amount of beta-lactoglobulin absorbed. Our results suggest tha te ability of the gastrointestinal tract to exclude antigenically intact food proteins increases with gestational age and that gut closure occurs normally before birth in man.

Neonatal breast milk from 50 babies aged between 2 and 39 days was studied for the presence of antibody to the cows' milk protein beta lactoglobulin. Specific IgA antibody and specific secretory antibody to beta lactoglobulin were detectable towards the end of the second week of life in milk secreted by neonates fed cows' milk formula. Specific antibody concentrations were independent of total IgA concentrations. Babies receiving little or no cows' milk protein did not produce antibody in neonatal breast milk. Antigen specific mucosal immune responses develop in tissues distant from the site of primary mucosal exposure by the end of the second week of life in term human neonates, suggesting that prophylactic immunisation against enteric or other mucosal pathogens within a few days of birth may provide antibody responses in secretions, which may protect against mucosal infection.

A boy with congenital hypogammaglobulinaemia died at the age of 12 years after a viral meningoencephalitis of two and a half years duration due to an untypable picornavirus. He had received intravenous immunoglobulin every four weeks from the time of the start of immunoglobulin replacement treatment at the age of 3 years. The encephalitis did not respond to high dose intravenous gammaglobulin (2500 g during 22 months). The virus could not be isolated during the administration of intraventricular immunoglobulin (38.15 g) and intraventricular recombinant alpha interferon (121 X 10(6) units), but recurred rapidly each time intraventricular treatment was stopped. Further modes of treatment are still required for prevention and treatment of this disorder.