Shriners Hospitals for Children - Houston

OBJECTIVE: To develop a North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) international consensus on the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population. METHODS: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which developed these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-available evidence from PubMed, Cumulative Index to Nursing and Allied Health Literature, and bibliographies. The committee convened in face-to-face meetings 3 times. Consensus was achieved for all recommendations through nominal group technique, a structured, quantitative method. Articles were evaluated using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Using the Oxford Grades of Recommendation, the quality of evidence of each of the recommendations made by the committee was determined and is summarized in appendices. RESULTS: More than 600 articles were reviewed for this work. The document provides evidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population. CONCLUSIONS: This document is intended to be used in daily practice for the development of future clinical practice guidelines and as a basis for clinical trials.

Previous genetic studies of idiopathic talipes equinovarus (ITEV) suggest an environmental and genetic component to the etiology of ITEV. The present study was undertaken to assess the role of causal factors in the development of ITEV. A total of 285 propositi were ascertained, with detailed family history information available in 173 cases and medical records on the remaining 112 propositi. Information was collected on specific prenatal, parental, and demographic factors. No racial heterogeneity was noted among any of the factors. The overall ratio of affected males to females was 2.5:1. The incidence of twinning among all propositi was significantly increased (P=0.006) above the expected population frequency. A family history of ITEV was noted in 24.4% of all propositi studied. These findings, in addition to the detailed analysis of 53 pedigrees with ITEV history, suggest the potential role of a gene or genes operating in high-risk families to produce this foot deformity.

CONTEXT: Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. OBJECTIVE: The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. DESIGN AND PARTICIPANTS: We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. MAIN OUTCOME MEASURES: Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. RESULTS: ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. CONCLUSIONS: Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

Recent research and theorizing suggest that narcissism may predict both positive and negative leadership behaviors. We tested this hypothesis with data on the 42 U.S. presidents up to and including George W. Bush, using (a) expert-derived narcissism estimates, (b) independent historical surveys of presidential performance, and (c) largely or entirely objective indicators of presidential performance. Grandiose, but not vulnerable, narcissism was associated with superior overall greatness in an aggregate poll; it was also positively associated with public persuasiveness, crisis management, agenda setting, and allied behaviors, and with several objective indicators of performance, such as winning the popular vote and initiating legislation. Nevertheless, grandiose narcissism was also associated with several negative outcomes, including congressional impeachment resolutions and unethical behaviors. We found that presidents exhibit elevated levels of grandiose narcissism compared with the general population, and that presidents' grandiose narcissism has been rising over time. Our findings suggest that grandiose narcissism may be a double-edged sword in the leadership domain.

Achondroplasia (ACH) is the most common dwarfing condition having a prevalence of 1/25,000 live births. An increase in overall mortality, age specific mortality up to age 34 years and heart disease-related mortality was first reported in a 1987 study of a large population of ACH individuals. Since this study, concern about premature death, particularly in young adults, has persisted in the ACH population. The present study was undertaken to follow-up the patterns of mortality in a more contemporaneous ACH population. The vital status of 718 ACH individuals from the original study and 75 new ACH individuals was determined through the search of two computerized mortality database. The results showed that the overall mortality and age-specific mortality at all ages remained significantly increased. Rates of death were similar across all 42 years of follow-up suggesting that higher death rates were still occurring in the contemporary ACH population. Accidental, neurological, and heart disease-related deaths were increased in adults. Heart disease-related mortality, between ages 25 and 35, was more than 10 times higher than the general population. Overall survival and the average life expectancy for this ACH population were decreased by 10 years. These results demonstrate that despite advances in the knowledge of the natural history of ACH and health care needs of this population, mortality remains significantly increased. The high rate of heart disease related deaths illustrates the need to identify risk factors in the ACH population and develop treatment interventions accordingly.

Studies were undertaken first to describe the invariant characteristics of gait initiation and second to better understand the function of each limb in the process of gait initiation. Analysis of variance indicated significant main effects for speed for time to onset of EMG activity and force plate recordings, time to swing toe-off and heel-strike and stance toe-off. However, when the dependent variables were expressed as a percentage of the initiation cycle, no significant main effects were noted. For the second study, two force plates were utilized, and reflective markers were placed on the sacrum and anterior superior iliac spines. The timing of heel-strike of the swing limb and toe-off of the stance limb showed a high degree of coordination in both experiments (r = 0.95 and 0.98). It was concluded that the relative invariance of selected parameters indicates that gait initiation is centrally programmed. It also appears that the swing limb, although forces were very small, is responsible for the initial weight shift to the stance limb and that the stance limb is then primarily responsible for the generation of momentum.

STUDY DESIGN: A prospective, randomized, double-blind Institutional Review Board-approved study evaluating the efficacy of Amicar (epsilon aminocaproic acid), an antifibrinolytic agent, in decreasing perioperative blood loss in idiopathic scoliosis. OBJECTIVES: To compare the perioperative (intraoperative and postoperative) blood loss and the need for autologous and homologous blood replacement in two groups of essentially identical patients undergoing a posterior spinal fusion for idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Reducing perioperative blood loss and the need for transfusion in patients undergoing spinal surgery is important to orthopedic surgeons. Recently, there has been interest in pharmacologic agents, particularly Amicar and Aprotinin, to assist in decreasing perioperative blood loss. In 2001, in a preliminary study, we demonstrated that Amicar appeared to be effective in reducing perioperative blood loss in patients with idiopathic scoliosis undergoing a posterior spinal fusion and segmental spinal instrumentation. This was a study of 28 consecutive patients receiving Amicar compared to a historical control group of the 31 previous consecutive patients with the same study criteria. The current study was performed to confirm our preliminary findings. METHODS: We analyzed the perioperative blood loss of 36 patients with idiopathic scoliosis who were blindly randomized by the operating room pharmacy into an Amicar and control group. The criteria to be included in the study was the same as the preliminary study: diagnosis of idiopathic scoliosis, age at surgery 11 to 18 years, posterior spinal fusion and segmental spinal instrumentation only, autogenous iliac crest bone graft or homologous cancellous bone graft, and a signed agreement to participate in the study. The patients in both groups had the same anesthetic technique, intraoperative procedure, instrumentation, postoperative management, and standardized indications for transfusions. RESULTS: Before surgery, the patients in both groups were essentially identical. The distribution of patients and their results was not known until the completion of the study. Patients in the Amicar group demonstrated a statistically significant decrease in perioperative blood loss and the need for autologous blood transfusion. Interestingly, this decrease was predominantly in the postoperative suction drainage. This may be due to elevated fibrinogen levels induced by Amicar. The patients taking Amicar had no intraoperative or postoperative thromboembolic complications. CONCLUSIONS: The results of this study confirmed that the use of intraoperative Amicar is a safe, effective, and inexpensive method to significantly reduce perioperative blood loss in patients with idiopathic scoliosis undergoing posterior spinal fusion and segmental spinal instrumentation. The results have allowed us to reduce our recommendation for perioperative autologous blood donation, thereby further decreasing costs.

Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system. Although COMP/TSP5 abnormalities are associated with several pathological conditions, its normal function remains unclear. This study was undertaken to delineate the function(s) of COMP/TSP5 in cartilage, especially regarding its interaction with chondrocytes. We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. Chondrocyte attachment to COMP/TSP5 in the calcium-replete conformation was inhibited by function-blocking integrin alpha5 and beta1 antibodies, suggesting the involvement of the alpha5beta1 integrin. Under this condition, a function-blocking antibody against alphaVbeta3 did not have any effect on cell attachment. On the other hand, chondrocyte attachment to reduced COMP/TSP5 was instead sensitive to alphaVbeta3 function-blocking antibodies, suggesting that COMP/TSP5 mediates attachment through chondrocyte alphaVbeta3 integrin under this condition. Cell attachment to reduced COMP/TSP5 was not inhibited by beta1 antibodies. These data indicate that COMP/TSP5 in different conformations can utilize different integrin receptors. These results are the first to demonstrate that COMP/TSP5 can mediate chondrocyte attachment through interactions with integrins. Through these interactions, COMP/TSP5 may be able to regulate cellular activities and respond to environment in the surrounding cartilage matrix.

Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix (ECM) of the musculoskeletal system. Its importance is underscored by its association with several growth disorders. In this report, we investigated its interaction with aggrecan, a major component of cartilage ECM. We also tested a COMP/TSP5 mutant, designated MUT3 that accounts for 30% of human pseudoachondroplasia cases, to determine if the mutation affects function. Using a solid-phase binding assay, we have shown that COMP/TSP5 can bind aggrecan. This binding was decreased with MUT3, or when COMP/TSP5 was treated with EDTA, indicating the presence of a conformation-dependent aggrecan binding site. Soluble glycosaminoglycans (GAGs) partially inhibited binding, suggesting that the interaction was mediated in part through aggrecan GAG side chains. Using affinity co-electrophoresis, we showed that COMP/TSP5, in its calcium-replete conformation, bound to heparin, chondroitin sulfates, and heparan sulfate; this binding was reduced with EDTA treatment of COMP/TSP5. MUT3 showed weaker binding than calcium-repleted COMP/TSP5. Using recombinant COMP/TSP5 fragments, we found that the "signature domain" could bind to aggrecan, suggesting that this domain can mediate the interaction of COMP/TSP5 and aggrecan. In summary, our data indicate that COMP/TSP5 is an aggrecan-binding protein, and this interaction is regulated by the calcium-sensitive conformation of COMP/TSP5; interaction of COMP with aggrecan can be mediated through the GAG side chains on aggrecan and the "signature domain" of COMP/TSP5. Our results suggest that COMP/TSP5 may function to support matrix interactions in cartilage ECM.

We have identified a novel missense mutation in a pseudoachondroplasia (PSACH) patient in one of the type III repeats of cartilage oligomeric matrix protein (COMP). Enlarged lamellar rough endoplasmic reticulum vesicles were shown to contain accumulated COMP along with type IX collagen, a cartilage-specific component. COMP was secreted and assembled normally into the extracellular matrix of tendon, demonstrating that the accumulation of COMP in chondrocytes was a cell-specific phenomenon. We believe that the intracellular storage of COMP causes a nonspecific aggregation of cartilage-specific molecules and results in a cartilage matrix deficient in required structural components leading to impaired cartilage growth and maintenance. These data support a common pathogenetic mechanism behind two clinically related chondrodysplasias, PSACH and multiple epiphyseal dysplasia.

A cohort of 93 patients with developmental dysplasia of the hip (DDH) treated with a Pavlik harness were evaluated to determine predictors of treatment failure. Failure was defined as failure to achieve or maintain hip reduction in the Pavlik harness. Of 93 patients (137 hips), 17 (26 hips) failed Pavlik harness treatment. Univariate risk factors for failure included bilaterality, initial clinical exam, and initial ultrasound (US) percent coverage. Clinical exam and initial percent coverage were multivariate risk factors for failure. Among initially clinically dislocatable hips, a low initial US alpha angle correlated with an increased likelihood of failure. All (6/6) patients with an initially irreducible hip and an initial coverage of <20% by US eventually failed treatment. Gender, side of pathology, and age at diagnosis and initiation of treatment did not correlate with failure. Irreducibility by physical exam combined with US coverage of <20% identified a patient group that uniformly failed Pavlik harness treatment. These patients may be candidates for alternative bracing, traction, or closed or open reduction.

Several questionnaires have been developed in an attempt to measure real-life functional levels of pediatric orthopaedic patients. One in particular was developed by the Pediatric Orthopaedic Society of North America (POSNA) in 1994. This POSNA instrument yields four functional assessment scores, a global function score, and a happiness score (each having a possible range from 0 to 100). In this study, the POSNA questionnaire was administered to the parents of 57 normal children and 27 normal adolescents to determine how normal respondents can be expected to score. Means, standard deviations, and other statistics were derived for the functional scores. It was concluded that normal children should respond quite high on all the scores, possibly 100. These results allow us to understand that a child scoring in the low 80s or less is functioning at a different level than the normal child.

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent in clinical and research communities. A definition of AMC was recently developed using a modified Delphi consensus method involving 25 experts in the field of AMC from 8 countries. Participants included health care professionals, researchers, and individuals with AMC. An annotation of the definition provides more in-depth explanations of the different sentences of the AMC definition and is useful to complement the proposed definition. The aim of this study was to provide an annotation of the proposed consensus-based AMC definition. For the annotation process, 17 experts in AMC representing 10 disciplines across 7 countries participated. A paragraph was developed for each sentence of the definition using an iterative process involving multiple authors with varied and complementary expertise, ensuring all points of view were taken into consideration. The annotated definition provides an overview of the different topics related to AMC and is intended for all stakeholders, including youth and adults with AMC, their families, and clinicians and researchers, with the hopes of unifying the understanding of AMC in the international community.

Summary An evaluation of ankle function in gait after 22 Vulpius lengthenings of the gastrocnemius fascia and 27 Z-lengthenings of the Achilles tendon was performed in 33 ambulatory cerebral palsy patients. Simultaneous hip or knee surgeries or both were performed in most instances. Gait analysis including ankle motion, moment, and power data was obtained before surgery and ≈ 1 year after. The ankle moments were improved and approached normal in the majority of cases in each group. There were no significant differences between the Vulpius and Z-lengthening groups at follow-up in any of the parameters. There were significant differences between the initial and follow-up measurements of each group. The Vulpius group showed a notable presence of abnormal midstance work initially and had a significant decrease at follow-up. The Z-lengthening group showed a notable presence of equinus and a notable lack of push-off work initially and had a significant decrease in equinus and a significant increase in push-off work at follow-up. Each procedure appears to give satisfactory results because the follow-up results were similar.

STUDY DESIGN: Retrospective analysis of pelvic incidence and other radiographic parameters as a predictor of progression of isthmic spondylolisthesis. OBJECTIVES: To evaluate the predictive value of various radiographic parameters, including pelvic incidence, in determining the risk for progression of lumbosacral isthmic spondylolisthesis. SUMMARY OF BACKGROUND DATA Although pelvic incidence has recently been shown to be positively correlated to the severity of spondylolisthesis, it has not been confirmed as a predictor of spondylolisthetic progression. MATERIALS AND METHODS: Thirty-six patients who have undergone primary posterior lumbosacral fusion for isthmic spondylolisthesis at our institution from 1977 to 2001 were retrospectively analyzed. There were 24 females and 12 males with a mean age of 21.3 +/- 2.0 years (range, 12 to 53 y). Twenty-two patients had high-grade (Meyerding class III, IV, V) and 14 patients had low-grade (Meyerding class I, II) spondylolisthesis, respectively. Factors evaluated included age, gender, neurologic deficits, reason for surgery, and documented evidence of progression. Slip percentage, high-grade or low-grade slip, slip angle, sacral inclination, sacral rounding, trapezoidal L5 vertebra, and pelvic incidence were measured from immediate preoperative standing lateral radiographs. These factors were statistically analyzed for risk of progression. Continuous variables were analyzed using one-way analysis of variance. Nominal variables were analyzed using chi2 test. RESULTS: Pelvic incidence (P = 0.66) was not predictive of spondylolisthetic progression. Of the other radiographic measurements, slip percentage (P < 0.001), slip angle (P = 0.016), and high-grade spondylolisthesis (P < 0.0001) were highly predictive of progression. Interestingly, sacral inclination (P = 0.33) was not predictive of progression. CONCLUSIONS: Pelvic incidence cannot adequately predict the probability of spondylolisthetic progression. Analysis of the other clinical and radiographic parameters revealed that slip percentage and high-grade spondylolisthesis remain the most positive predictors of progression.

BACKGROUND: It is generally accepted that the presence of angular deformity about the knee that persists into the preadolescent years will not correct spontaneously. The goal of this study was to review our experience with hemiepiphysiodesis and physeal stapling for the correction of angular deformity to establish the efficacy of these procedures and to determine their indications and the rate of correction. METHODS: A retrospective review of 48 patients undergoing hemiepiphysiodesis or physeal stapling about the knee was performed. Patients were included if they had at least 2 years of documented follow-up without an osteotomy. RESULTS: The average follow-up was 30.4 months (range, 24-52 months). Genu varum was identified in 33 patients, genu valgum in 14 patients, and a windswept deformity in 1. Of the 52 limbs with genu varum, 35 were secondary to Blount disease. The group with genu varum unrelated to Blount disease presented a change in the mechanical axis from a mean of -32 degrees at surgery to a mean of - 13 degrees. The patients with Blount disease presented a change in the mechanical axis from a mean of -19 degrees at surgery to a mean of -16 degrees. The group with genu valgum presented a change in the mechanical axis from a mean of 20 degrees at surgery to a mean of 2 degrees. CONCLUSIONS: Hemiepiphysiodesis is an effective means for correcting angular deformity about the knee in skeletally immature patients with both genu valgum and genu varum, so long as the genu varum is unrelated to Blount disease. Hemiepiphysiodesis is effective in preventing the progression of deformity in patients with Blount disease. LEVEL OF EVIDENCE: Therapeutic-Level IV.

Several questionnaires have been developed in an attempt to measure real-life functional levels of pediatric orthopaedic patients. One in particular was developed by the Pediatric Orthopaedic Society of North America (POSNA) in 1994. This POSNA instrument yields four functional assessment scores, a global function score, and a happiness score (each having a possible range from 0 to 100). In this study, the POSNA questionnaire was administered to the parents of 57 normal children and 27 normal adolescents to determine how normal respondents can be expected to score. Means, standard deviations, and other statistics were derived for the functional scores. It was concluded that normal children should respond quite high on all the scores, possibly 100. These results allow us to understand that a child scoring in the low 80s or less is functioning at a different level than the normal child.

In 1976, an epidemic caused by infections with an influenza virus antigenically similar to A/Victoria/75 (H3N2) occurred in Houston, Texas. During this outbreak, 37 families (155 members) enrolled in the Houston Family Study were under observation. The families lived throughout the metropolitan area (Houston, Texas), and were representative of low income groups. The overall frequency of infection in family members was 27.7%. The frequency of infection was the highest for infants under one year of age and for their older siblings, 14 (37.8%) of 37 and 17 (33.3%) of 51, respectively. Eighteen (48.6%) of the 37 families had at least one infected member. Twelve of the 18 'infected' families had school aged children, whereas only three of the 19 'non-infected' families had school aged children (P less than 0.01). These infected families were also larger and had increased household density (persons/rooms). The levels of pre-existing HI antibodies to A/Victoria/75 and A/Port Chalmers/73 were inversely related to frequencies of infection and illness associated with A/Victoria/75 virus. Three children required hospitalization as direct consequence of their infection with this H3N2 influenza virus. Antibody response to infection was related to previous experience with antigenically-related influenza A (H3N2) viruses according to Francis', 'doctrine of original antigenic sin.'

Cartilage oligomeric matrix protein (COMP) is a large extracellular matrix protein expressed in cartilage, ligament and tendon. Mutations in the COMP gene cause two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH) and Multiple Epiphyseal Dysplasia (MED/EDM1). We report on a novel point mutation D511Y in the seventh calcium-binding repeat of the COMP gene and the resulting iliac crest growth plate pathology. The PSACH iliac crest growth plate is comprised of a large region of resting chondrocytes above a narrow region composed of clusters of disorganized proliferative and hypertrophic chondrocytes. Chondrocytes in all zones show massive intracellular retention of COMP and the surrounding extracellular matrix is deficient in COMP. Moreover, the 511Y COMP mutation selectively affects type IX collagen as little is found in the growth plate matrix whereas type II collagen and aggrecan are abundant in the matrix. Chondrocyte remnants are observed in the chondrocyte clusters and dead cells are found throughout the growth plate. Apoptosis studies demonstrate an unusual pattern of TUNEL staining in the PSACH chondrocytes compared to the control growth plate. These in vivo findings support our previous observation that retention of COMP leads to chondrocyte death. These results also add to the increasing evidence that PSACH and EDM1 are rER storage diseases and that impaired linear growth and joint erosion are caused by the disruptive effect of massive amounts of COMP within the chondrocytes.

The C677T and A1298C mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are each associated with reduced MTHFR activity. The C677T mutation in the heterozygous and homozygous state correlates with increased enzyme thermolability, with homozygous mutant genotypes showing significantly elevated plasma homocysteine levels and decreased plasma folate levels. The A1298C mutation results in decreased MTHFR activity, but changes in neither homocysteine nor folate levels are associated with A1298C variant genotypes. Our study determined the frequencies of the C677T and A1298C MTHFR mutations for spina bifida (SB) cases, mothers and fathers of SB cases, and controls in Hispanics of Mexican-American descent. In addition, our subject population was further categorized as to whether the spina bifida lesion occurred as an upper or lower level defect, according to the Van Allen "multi-site closure" model. Hispanic SB cases with upper level defects and their mothers were homozygous for the C677T variant allele at a higher rate than their respective controls (OR = 1.5 [95% CI 0.8-2.9], P = 0.30; OR = 2.3 [1.1-4.8], P = 0.04, respectively), with statistically significant results seen only for the maternal homozygous genotype. Homozygosity for the A1298C mutation was seen at a higher rate only in Hispanic mothers of both upper and lower level SB cases when compared to controls, but these results were not statistically significant. Our study provides evidence that the maternal C677T MTHFR homozygous mutant genotype is a risk factor for upper level spina bifida defects in Hispanics.