La Rabida Children's Hospital

Exposure to multiple traumas, particularly in childhood, has been proposed to result in a complex of symptoms that includes posttraumatic stress disorder (PTSD) as well as a constrained, but variable group of symptoms that highlight self-regulatory disturbances. The relationship between accumulated exposure to different types of traumatic events and total number of different types of symptoms (symptom complexity) was assessed in an adult clinical sample (N = 582) and a child clinical sample (N = 152). Childhood cumulative trauma but not adulthood trauma predicted increasing symptom complexity in adults. Cumulative trauma predicted increasing symptom complexity in the child sample. Results suggest that Complex PTSD symptoms occur in both adult and child samples in a principled, rule-governed way and that childhood experiences significantly influenced adult symptoms.

Children with medical complexity (CMC) have medical fragility and intensive care needs that are not easily met by existing health care models. CMC may have a congenital or acquired multisystem disease, a severe neurologic condition with marked functional impairment, and/or technology dependence for activities of daily living. Although these children are at risk of poor health and family outcomes, there are few well-characterized clinical initiatives and research efforts devoted to improving their care. In this article, we present a definitional framework of CMC that consists of substantial family-identified service needs, characteristic chronic and severe conditions, functional limitations, and high health care use. We explore the diversity of existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. Finally, we suggest a research agenda that uses a uniform definition to accurately describe the population and to evaluate outcomes from the perspectives of the child, the family, and the broader health care system.

Monoclonal antibody GK1.5 recognizes a previously undescribed murine T cell surface molecule, designated L3T4, which migrates on SDS-PAGE under reducing conditions as a single band with an apparent m.w. of 52,000. L3T4 is expressed by approximately 80% of thymocytes and by approximately 20% of spleen cells. There appears to be poor correlation between expression of L3T4 by functional T cell clones and expression of Lyt-2, expression of the cytolytic phenotype, and class I MHC antigen reactivity. On the other hand, both a class II MHC antigen-reactive HTL clone and an Lyt-1- Mls-reactive HTL clone express L3T4. Analysis of the effect of mAb GK1.5 on PFC responses in adoptive transfer suggests that L3T4 is expressed by the helper/inducer subset of murine T cells. Expression of L3T4 by murine T cells, however, may correlate primarily with class II MHC antigen reactivity rather than with functional phenotype; mAb GK1.5 profoundly blocks antigen-specific cytolysis by the cloned class II MHC antigen-reactive CTL line A15-1.17. Antigen-specific cytolysis by A15-1.17 is blocked by mAb GK1.5 at a step before the lethal hit. Collectively, the flow cytometric, functional, and biochemical data indicate that L3T4 is similar to the human Leu-3/T4 molecule.

Childhood exposure to victimization is prevalent and has been shown to contribute to significant immediate and long-term psychological distress and functional impairment. Children exposed to interpersonal victimization often meet criteria for psychiatric disorders other than posttraumatic stress disorder (PTSD). Therefore, this article summarizes research that suggests directions for broadening current diagnostic conceptualizations for victimized children, focusing on findings regarding victimization, the prevalence of a variety of psychiatric symptoms related to affect and behavior dysregulation, disturbances of consciousness and cognition, alterations in attribution and schema, and interpersonal impairment. A wide range of symptoms is common in victimized children. As a result, in the current psychiatric nosology, multiple comorbid diagnoses are necessary-but not necessarily accurate-to describe many victimized children, potentially leading to both undertreatment and overtreatment. Related findings regarding biological correlates of childhood victimization and the treatment outcome literature are also reviewed. Recommendations for future research aimed at enhancing diagnosis and treatment of victimized children are provided.

This study provides a summary of the results of an expert opinion survey initiated by the International Society for Traumatic Stress Studies Complex Trauma Task Force regarding best practices for the treatment of complex posttraumatic stress disorder (PTSD). Ratings from a mail-in survey from 25 complex PTSD experts and 25 classic PTSD experts regarding the most appropriate treatment approaches and interventions for complex PTSD were examined for areas of consensus and disagreement. Experts agreed on several aspects of treatment, with 84% endorsing a phase-based or sequenced therapy as the most appropriate treatment approach with interventions tailored to specific symptom sets. First-line interventions matched to specific symptoms included emotion regulation strategies, narration of trauma memory, cognitive restructuring, anxiety and stress management, and interpersonal skills. Meditation and mindfulness interventions were frequently identified as an effective second-line approach for emotional, attentional, and behavioral (e.g., aggression) disturbances. Agreement was not obtained on either the expected course of improvement or on duration of treatment. The survey results provide a strong rationale for conducting research focusing on the relative merits of traditional trauma-focused therapies and sequenced multicomponent approaches applied to different patient populations with a range of symptom profiles. Sustained symptom monitoring during the course of treatment and during extended follow-up would advance knowledge about both the speed and durability of treatment effects.

Activated macrophages (aM phi) destroy more effectively cancer cells than normal cells. The mechanism by which macrophages destroy cancer cells is not known. We report here that tumor cells susceptible to aM phi were killed by recombinant (r) tumor necrosis factor type alpha (TNF-alpha), whereas variant tumor cells resistant to aM phi after selection in vitro or in vivo were resistant to killing by rTNF-alpha. The converse selection for rTNF-alpha-resistant variants resulted in cells that were also resistant to killing by aM phi. The sensitivity of macrophage-resistant variants was not changed to other tumoricidal cells or soluble mediators, except that the macrophage-resistant variants were also resistant to the effects of another cytotoxic protein, B-cell lymphotoxin, which is structurally related to rTNF-alpha. Similar results were obtained regardless of whether short-term or long-term cytotoxic effects of aM phi were measured. Finally, it was shown that killing of tumor cells by murine aM phi was completely inhibited with a polyclonal antibody that neutralizes the effects of murine TNF-alpha. These results suggest a major role for TNF-alpha in tumor cell destruction by aM phi in vitro and in vivo.

A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying approximately 5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 gene showed disease association (P values reaching 10(-10), odds ratio >1.5) in both adult- and childhood-onset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity" associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.

When injected into mice, the synthetic double-stranded polynucleotide poly(inosinic) X poly(cytidylic) acid induces high natural killer (NK) cell activity within 4 to 12 hours. Induction of NK activity in mice immunized 2 or 3 days previously, or the addition of NK cells to cultures immunized in vitro 2 or 3 days previously, promotes early termination of the ongoing primary immunoglobulin M antibody response. A target for NK cells is a population of accessory cells that has interacted with antigen and is necessary for sustaining the antibody response. The inference is strong that NK cells induced normally by immunization also terminate the usual antibody response in vivo by elimination of antigen-exposed accessory cells.

1. The interaction of acid mucopolysaccharides of connective tissue with solubilized collagen of native, or near-native, structure was investigated by free solution electrophoresis at pH7·0. 2. Complex-formation was detected by the appearance of a third peak in the ascending limb only, indicating reversible association. 3. Complex-formation was destroyed by prior heating of solubilized collagen, indicating a probable requirement for high molecular weight or internal structure of the protein. 4. Hyaluronate and chondroitin sulphate of mol.wt. 50000 gave complexes with soluble collagen at I 0·4, whereas heparin and chondroitin sulphate of mol.wt. 15000–18000 did not. All mucopolysaccharides yielded complexes at I 0·1. The stability of the complex appears mainly dependent on electrostatic forces and is increased with increase in chain length of the polysaccharide. 5. Solubilized collagen interacted to yield gels with the `native' chondroitin sulphate–protein macro-molecule from cartilage. 6. A schematic model for the interaction of collagen and chondroitin sulphate–protein macromolecules shows parallel-ordered interaction of collagen fibrils with chondroitin sulphate side chains of the chondroitin sulphate–protein macromolecule. The biological implications of this model are discussed, particularly in relation to the ordered structures and the ionic-network properties of the intercellular components of connective tissue.

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.

OBJECTIVES: The purpose of this pilot study is to describe the use of the Kinesio Taping method for the upper extremity in enhancing functional motor skills in children admitted into an acute rehabilitation program. METHOD: Fifteen children (10 females and 5 males; 4 to 16 years of age), who were receiving rehabilitation services at the Rehabilitation Institute of Chicago participated in this study. For 13 of the inpatients, this was the initial rehabilitation following an acquired disability, which included encephalitis, brain tumor, cerebral vascular accident, traumatic brain injury, and spinal cord injury. The Melbourne Assessment of Unilateral Upper Limb Function (Melbourne Assessment) was used to measure upper-limb functional change prior to use of Kinesio Tape, immediately after application of the tape, and 3 days after wearing tape. Children's upper-limb function was compared over the three assessments using analysis of variance. RESULTS: The improvement from pre- to posttaping was statistically significant, F(1, 14) = 18.9; p < .02. CONCLUSION: These results suggest that Kinesio Tape may be associated with improvement in upper-extremity control and function in the acute pediatric rehabilitation setting. The use of Kinesio Tape as an adjunct to treatment may assist with the goal-focused occupational therapy treatment during the child's inpatient stay. Further study is recommended to test the effectiveness of this method and to determine the lasting effects on motor skills and functional performance once the tape is removed.

Abstract Background This study assessed the concurrent validity of the Ages and Stages Questionnaire (ASQ) compared with Bayley Scales of Infant Development II (BSID II) amongst children aged 24 months. Methods Data were collected from 53 infants and mothers who participated in the New York State Angler Cohort Child Development Study. Parents completed the 24-month ASQ to assess communication, personal-social, problem-solving ability, and fine and gross motor control. The BSID II was administered by a clinical psychologist at the 24-month home visit for cognitive and psychomotor assessment. The ASQ was scored using age-specific norms of <2 SDs below any domain mean to define failure. A BSID II score of <85 indicated mild or severe delay, while a score of <70 suggested a severe delay. Results Scores on the ASQ communication and personal-social domains were moderately correlated with the BSID II Mental Scale (R= 0.52, P < 0.001; R= 0.45, P < 0.01) and ASQ gross motor with the BSID II Motor Scale (R= 0.46, P < 0.01), whereas ASQ problem-solving and fine motor domains were not significantly correlated with BSID II scores. The ASQ had a sensitivity of 100% and specificity of 87% at 24 months (n= 40) for severely delayed status. Conclusions Results suggest the ASQs provide a simple, valid, and cost-effective method for clinicians and field-based researchers to reduce the number of standardized assessments required to identify developmentally delayed infants at age 24 months. Future studies should further assess the validity of the ASQs in larger, more diverse populations of infants.

OBJECTIVE: Acute lymphocytic leukemia (ALL) often presents with musculoskeletal concerns such as pain or swelling, even before appearance of blasts in the peripheral blood. Such presentation may lead to misdiagnosis of a child with juvenile rheumatoid arthritis (JRA). This study was designed to identify the predictive factors for leukemia using basic clinical and laboratory information. METHODS: A retrospective chart review was performed using a simple questionnaire to compare the clinical and laboratory findings present during the initial visit to a pediatric rheumatology clinic for 277 children who were ultimately diagnosed with either JRA (n = 206) or ALL (n = 71). Sensitivity and specificity analysis of a variety of parameters, both singly and in combination, was performed to identify predictive value for ALL. RESULTS: The majority (75%) of children with ALL did not have blasts in the peripheral blood at the time of evaluation by pediatric rheumatologists. In children presenting with unexplained musculoskeletal complaints, the 3 most important factors that predicted a diagnosis of ALL were low white blood cell count (< 4 x 10(9)/L), low-normal platelet count (150-250 x 10(9)/L), and history of nighttime pain. In the presence of all 3, the sensitivity and specificity for a diagnosis of ALL were 100% and 85%, respectively. Other findings, including antinuclear antibody, rash, and objective signs of arthritis, were not helpful in differentiating between these diagnoses because they occurred at similar rates in both groups. CONCLUSIONS: When a child develops new-onset bone-joint complaints, the presence of subtle complete blood count changes combined with nighttime pain should lead to consideration of leukemia as the underlying cause.

Band 3 is the predominant membrane-spanning polypeptide and the mediator of anion transport in the human erythrocyte. In addition, it provides the sites of association for fructose 1,6-bisphosphate aldolase and other cytoplasmic proteins with the membrane. The aldolase-binding activity of water-soluble fragments of band 3 was measured by their inhibition of aldolase catalytic activity and by their displacement of aldolase from ghosts. At saturation, the binding of one band 3 or certain of its fragments per aldolase molecule partially inhibited the catalytic activity and band 3 binding of the unliganded subunits of the tetramer through an apparently cooperative mechanism. An NH2-terminal 23,000-dalton fragment generated by S-cyanylation of the cytoplasmic pole of band 3 was approximately 20% as avid in binding aldolase as was native band 3. Several fragments cleaved from the NH2-terminal portion of the 23,000-dalton peptide by trypsin, mild acid hydrolysis, and cyanogen bromide digestion all bound aldolase, while fragments from the rest of the polypeptide were essentially inactive. The first 31 residues of band 3 contained 16 Asp plus Glu, no basic residues, and a blocked alpha-amino terminus. The highly acidic composition of this region is consistent with the strongly electrostatic character of the interaction between band 3 and aldolase, presumably at the strongly basic catalytic center of the enzyme. We conclude that the NH2-terminal region of band 3 bears the membrane-binding site for aldolase.

Culture supernatants generated by alloantigenic or lectin stimulation of a cloned helper T lymphocyte, designated L2, contain interleukin 2 (IL 2), granulocyte/macrophage colony-stimulating factor (CSF), B cell stimulating factor (BCSF), macrophage (Ia+)-recruiting factor (MIRF), (Ia+)-inducing activity, gamma-interferon, Fc receptor-enhancing activity, macrophage migration inhibitory factor (MIF), macrophage activation factor (MAF), interleukin 3 (IL 3), and a factor responsible for prolonging the synthesis and secretion of the fourth and second components of complement by guinea pig peritoneal macrophages. Erythropoietin was not detected. A spontaneously arising variant of L2, designated L2V, produces much lower quantities of macrophage-stimulating activities, IL 2, and interferon. However, when compared to L2, L2V produces much higher levels of BCSF, equivalent amounts of IL 3, and slightly smaller amounts of CSF. Unlike L2V, a cytolytic clone, designated L3, secretes lymphokines that primarily affect macrophage function. The time course of lymphokine production by L2 cells indicates that for the six lymphokine activities studied there are three different times at which maximal or near maximal levels are reached, as follows: 1) IL 2, 12 to 24 hr; 2) IL 3 and CSF, 24 to 48 hr; and 3) (Ia+)-inducing activity, MAF, and interferon, 48 hr or later. Only IL 2 activity disappears during the 8-day culture cycle. The time course data and the differential production of activities by the three types of lymphocyte clones suggest that at least four terminal effector lymphokine molecules account for the ten biologic activities tested.

BALB/c mice repeatedly immunized with Pneumococcus R36A vaccine produce antibodies to phosphorylcholine having the TEPC-15 myeloma idiotype (murine IgA myeloma protein that binds phosphorylcholine). The plaque-forming cell response to phosphorylcholine shows a decrease with repeated immunizations. In contrast, spleen cells from multiply immunized mice responded better in vitro than spleen cells from nonimmunized mice. The serum of animals immunized four or five times agglutinates TEPC-15-coated sheep erythrocytes. Inhibition of hemagglutination shows that the agglutinating activity is directed against the TEPC-15 idiotype. Sera from these mice, when added to cultures of normal spleen cells, specifically suppress the response to phosphorylcholine. The suppressive activity in the serum can be removed by solid absorption with TEPC-15. Evidently, repeated immunization with antigen induces two kinds of antibody responses: one directed against antigen and the other directed against the antibody to the antigen. It is proposed that this "auto" antibody against receptor is involved in the regulation of the immune response.

Abstract The presence of d-glucuronic acid in dermatan sulfate preparations has previously been reported from several laboratories. It has not been clear whether the d-glucuronic acid represents a contamination with another polymer or whether it is actually part of the dermatan sulfate molecule. The present studies were undertaken in order to evaluate this problem more definitively. It is demonstrated that highly purified dermatan sulfate is partially degraded by testicular hyaluronidase yielding polysaccharide fragments with d-glucuronic acid in the newly formed nonreducing termini. The conclusion is therefore reached that d-glucuronic acid is an integral part of the dermatan sulfate molecule. As a result of the presence of hyaluronidase-susceptible linkages to d-glucuronic acid residues in the close vicinity of the polysaccharide-bound peptide, a large proportion of the polysaccharide fragments reisolated after enzyme treatment are devoid of amino acids.

OBJECTIVE: Symptoms of posttraumatic stress disorder (PTSD) after life-threatening medical illness have been found to predict poor outcome in preliminary studies of adults and children. However, these symptoms are rarely recognized in general medical or pediatric settings. Here we report on the first large investigation to assess prevalence and correlates of self-reported symptoms of posttraumatic stress in a nonreferred sample of adolescent liver, heart, and kidney transplant recipients. METHODS: One hundred four adolescents, ages 12 to 20 years (mean: 15.7; SD: 2.1), completed and returned the University of California, Los Angeles, PTSD Index for the Diagnostic and Statistical Manual of Mental Disorders. All participants were at least 1 year post-initial transplant and were fluent speakers of English and/or Spanish. RESULTS: More than 16% of the adolescents met all symptom criteria for PTSD, and an additional 14.4% met 2 of 3 symptom-cluster criteria. Regression analysis indicated no effect of gender, ethnicity, age at interview, organ type, time since transplant, or age at transplant. CONCLUSIONS: As has been found with other life-threatening pediatric conditions, solid organ transplantation can precipitate symptoms of posttraumatic stress. Symptoms are not predicted by what would be considered objective factors increasing life threat, suggesting a greater salience of subjective appraisal of threat, as has been seen in studies of childhood cancer survivors.

Biological activities of monoclonal A/J antibodies to the T15 idiotype in BALB/c mice were compared to heterogeneous antibodies raised by conventional immunization procedures. Two monoclonal antibodies, AB1-2 and GB4-10, which are of the gamma 1, chi class, appeared to have identical specificities by binding criteria and reacted similarly to conventional antibodies in their abilities to induce neonatal suppression, inhibit plaque-forming cell induction by phosphorylcholine (PC) antigens and to inhibit specifically, anti-PC plaque-forming cells. However, in functional analyses of anti-PC responses in various strains of mice, discrepancies were noted in the T15 responses as defined by monoclonal antibodies and conventional antisera. This heterogeneity was also observed in adult mice suppressed with the GB4-10 monoclonal antibody. These animals eventually produced an anti-PC responses of AB1-2 idiotype but lacking the GB4-10 marker. These results show that the T15 IgM anti-PC response in BALB/c and other strains of mice is heterogeneous and probably consists of a family of clones. Particular clones can be precisely eliminated by the use of appropriate monoclonal antibodies, and the anti-PC response that eventually recovers is still T15+ but lacking the suppressed clones.

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