171 Ashley Ave.
Charleston, SC 29425
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June 2007
2007 PAS Meeting Abstracts
Distance-Based QI for Immunization Delivery: Feasible? Effective?
Eric J. Slora, Jennifer M. Steffes, Donna L. Harris, Herbert W. Clegg II, David Norton, Paul M. Darden II, Susan A. Sullivan, Richard C. Wasserman. PROS, Dept of Research, AAP, Elk Grove Village, IL; Eastover Pediatrics, Charlotte, NC; Holyoke Pediatric Associates, Holyoke, MA; Pediatrics, Medical Univ of South Carolina, Charleston, SC; Pediatrics, Univ of Vermont College of Medicine, Burlington, VT.
BACKGROUND: US immunization rates (IR) have failed to achieve the Healthy People 2000 objectives. Quality improvement (QI) approaches based on systems theory have been effective in improving preventive care when delivered locally, but it is unclear whether they are feasible and effective when delivered at a distance.
OBJECTIVE: To assess the feasibility and effectiveness of a distance-based QI intervention as compared with traditional education in improving immunization delivery in practice.
DESIGN/METHODS: From an original group of 82 Pediatric Research in Office Settings (PROS) practices, 29 with baseline IR at or below the median (88%) were block randomized into one of two year-long interventions: distance-based QI (including monthly conference calls, QI Listserv, and a QI website) or paper-based traditional education. Key outcomes were 1) usage and helpfulness of the QI modalities; 2) pre-post changes in practice IR; and 3) behavioral changes assessed on a practitioner survey.
RESULTS: In terms of feasibility, QI practices attended 8.8 of 11 conference calls on average, as compared with usage of the QI Listserv (mean of 1.09 uses) and website (mean of .92 uses). Helpfulness ratings of the QI modalities mirrored usage. Conference calls averaged 1.38 on a three-point scale (1 = very helpful; 2 = somewhat helpful; 3 = not helpful at all) , as compared with 1.86 for the website and 2.00 for the Listserv. In terms of comparative effectiveness, within-group analyses revealed a 4.9 percentage point (PP) pre-post increase in IR for the QI group (p=.061), as opposed to a 0.8 PP increase for the traditional group (p=.752). The 4.1 PP between-group difference in favor of the QI group was not significant; however the study s power to detect a difference was only .24. Survey analyses indicated that a significantly higher proportion of QI practices introduced a system identifying children behind in immunizations.
CONCLUSIONS: A distance-based QI model appears to be a feasible, and possibly effective means for improving immunization delivery in practice.
Prevalence of Headache in the South Carolina Pediatric Practice-Based Research Network (SCPPRN)
Shannon A. Kennedy, Kristina K. Gustafson, J. Routt Reigart, Bernard L. Maria, Paul M. Darden. Academic Generalist Fellowship Program; South Carolina Pediatric Practice Research Network; Darby Children s Hospital Research Institute; Dept of Pediatrics, Med Univ of SC, Charleston, SC.
BACKGROUND: Headaches reportedly affect 12.8% of school age children and are a leading cause of school absenteeism and decreased quality of life. Based on reported surveys using the International Classification of Headache Disorders II (ICHD II), migraines occur in 10.6% of children.
OBJECTIVE: To examine the rate of headache diagnoses in children ages 4 through 18 years old in primary care pediatric offices.
DESIGN/METHODS: All visits in 2005 by children 4-18 years old to three practices in SCPPRN were examined for headache diagnoses. Using ICD9 codes, headaches were classified as common (784.0), tension (307.81), or migraine (346). These headache types were summed for all headaches. Age was categorized into three 5 year intervals 4-8, 9-13 and 14-18. Insurance was categorized as private, Medicaid or self-pay.
RESULTS: Eligible children made 8,572 visits (practice range 1,605 to 5,134) with 169 (1.97%) for headache. Headache types diagnosed were common (1.81%), followed by migraine (0.14%) and tension headaches (0.02%). The diagnosis rates of all headache differed by practice site: 1.25%, 1.91% and 2.22% (P<.05). Age and headache were associated with older children more likely to be diagnosed, 4.5% (14-18 years), 3.2% (9-13) and 0.74 (4-8) (P<.01). Neither insurance status nor race was associated with headache diagnosis. In a multivariable logistic model predicting headache and including age, sex, insurance, and practice site, only age was a significant predictor of headache diagnosis. Older children were much more likely to be diagnosed with headache when compared to 4-8 year olds: 9-13 years OR 4.6 (CI 3.0-6.8) and 14-18 years OR 6.5 (4.2-10.17).
CONCLUSIONS: Headaches, including migraine, are infrequently diagnosed by general pediatricians in SCPPRN practices. Although the mean age of onset of migraine is typically 5 to 7 years of age, relatively few children are diagnosed at that age. It remains to be seen if systematic use of ICHD II criteria for headache can increase ascertainment of children with migraine. Improving early recognition of migraine headache could improve quality of life and decrease school absences.
Measuring Practice Immunization Rates Quickly, Accurately and Confidentially: A Study from South Carolina Pediatric Practice Research Network (SCPPRN)
Henry M. Lemon, Paul M. Darden. MUSC Children s Care; South Carolina Pediatric Practice Research Network; Dept. of Pediatrics, Med Univ of SC, Charleston, SC.
BACKGROUND: Measuring practice-specific immunization rates have become more complicated with HIPAA and related privacy concerns. In a previous study on high immunization-rate practices, the quickcount method performed well: kappa 0.84.
OBJECTIVE: To continue validation of a HIPAA- compliant method for measuring immunization rates in office practices.
DESIGN/METHODS: Seven practices in the SC Pediatric Practice Research Network (SCPPRN) collected immunization data on 50-60 consecutive patients aged 8-35 months using two methods. The reference standard method used two trained examiners (a physician and a nurse) independently examining photocopied patient Vaccine Administration Records with resolution of any disagreement. In the quick-count (QC) method, office staff recorded counts of the number of patient vaccine doses without submitting patient identifiable information. Up-to-date immunizations (UTD) at 8 months of age was assessed for each patient. UTD was defined as 3 DTaP, 2 Hib, 2 Hep B and 2 Polio vaccines. Measures examined included kappa, sensitivity, specificity, positive predictive value, and negative predictive value.
RESULTS: Both methods were used to assess 368 patients. The mean percentage of patients UTD by 8 months of age using the reference standard method was 80%, (practice range 69%-94%). The mean percentage of patients UTD by the QC method was 85% (practice range 82%-96%). Of concern, the lowest performing practice by the reference standard (69% UTD) had the highest misclassification rate (13%), except for this practice rank order by QC was preserved. The quick count method was more likely to classify a patient as UTD compared to the reference standard (McNemar s test P<0.01). Agreement with the reference standard was excellent (Kappa = 0.80). QC was highly sensitive in determining UTD immunizations (94%) and had a specificity of 96%. QC had a positive predictive value for UTD immunizations of (99%) and negative predictive value of (74%). A debriefing survey demonstrated that all practices found the QC data collection form easy to follow.
CONCLUSIONS: The QC method is a valid and HIPAA-compliant tool for assessing practice immunization rates. This method must incorporate controls to insure that misclassification of patients in low performing practices is minimized.
Nutritional Status at Discharge (NSD), a Marker for Moderate Neurodevelopmental Delays (MND) in Extreme Low Birth Weight Infants (ELBWI) without Neuropathology (NP)
Lakshmi Katikaneni, Michelle Macias, Angela LaRosa, Myla Ebeling, Thomas Hulsey. Pediatrics, MUSC, Charleston, SC.
BACKGROUND: Risk for MND is significant in the presence of NP (IVH III/IV/PVL or Stage III+ ROP in ELBWI. Neurodevelopment depends on nutrition.
OBJECTIVE: To assess the impact of nutritional status at discharge on growth and neurodevelopment of ELBWI without known neuropathology.
DESIGN/METHODS: 216 ELBWI qualified over 9 yr period ; two groups identified based on NSD (Babson and Brenda 2003): A) Appropriate weight for Gestational Age infants (AGAI, N=53), and B) Small for Gestational Age Infants (SGAI, N=163),101 of these wereAGA at birth. NICUvariables impacting development were noted. Follow up growth and developmental assessement (Language and Cognitive/fine motor by Capute scales and Grossmotor by modified Peabody tests). MND were defined as ADQ <80 in >1 area vs. those with ADQ> 80 in > 1area (Normal). Groups were compared using Mantel-Haenszel chi-square and Kruskal-Wallis Test for non-parametric analysis and significance accepted as p<0.05.
RESULTS: The SGAI % increased at dischrge (29 to 75). with lower median Ponderal Index (PI), NICU weight gain, Head circumference (HC) at follow up (Table). SGAI had increased MND (28%) compared to AGAI (17%) and those with PI <11 had increasedMND risk (60%, p<0.002.,Fig).
| VARIABLE |
AGA |
SGA |
P VALUE |
| BIRTH |
71 |
29 |
|
| DISCH |
25 |
75 |
|
| PONDERAL INDX |
11.93 |
11.2 |
0.0003 |
| NICU WG G/D |
20 |
16 |
0.007 |
| FU HC |
45.1 |
44.1 |
0.002 |
CONCLUSIONS: Significant % of ELBW AGA infants without NP become SGA at discharge with an increased risk for MND at 12 months (28%), with the highest risk being those with low PI (60%). Identification of variables improving nutritional status at discharge are vital for preventing MND in extreme ELBWI.
Predictors of Child Maltreatment: A Population Based Study
Eve G. Spratt, Michelle M. Macias, Thomas Hulsey, Keith Rodgers. Pediatrics, Psychiatry and Epidemiology, Medical University of South Carolina, Charleston, SC.
BACKGROUND: Rates of poverty, low birth weight, infant mortality and child maltreatment (CM) are markers of community health. If public health prevention programs are to improve child health outcomes then they must understand the relative risks involved with co-existing factors in their community.
OBJECTIVE: The hypothesis was that counties with the highest rates of poverty would be predictive of counties with the highest rates of infant mortality, low birth weight and founded cases of CM.
DESIGN/METHODS: The state Child Protection Service (CPS) office provided 2004 data on ages and subtypes of founded CM in the 46 S.C. counties (N= 8134). Correlations were examined with rates of poverty, rural living, infant mortality (IM), very low birth weight (VLBW), maternal age, alcohol and tobacco use during pregnancy. Data was divided by the median and correlations between variables were examined.
RESULTS: Correlates with poverty included infant mortality (p =. 0026), VLBW (p=. 0082) and pregnancy rates for ages 10-14 (p=. 047), but not total number of CM cases or CM subtypes except for emotional neglect (p= 0.015). Infant mortality rate was significantly associated with CPS cases for ages 1-3 (Odds ratio (OR) = 2.15; Confidence Interval (CI) = .44-10.6), medical neglect (OR=2.17; CI= .76-6.2), total CM (OR=2.07; CI=. 54-7.9) and rural home (OR=2.61; CI= .18-38.3). Predictors of physical neglect included rates of pregnancies in mothers ages 10-14 (OR=2.15; CI=.94-4.9). A direct relationship existed with counties with highest and lowest rates of infant mortality and with highest and lowest rates of poverty. Population density was examined as a predictor of CM and 1 to 3 year olds with CM history were much more likely to live in urban than rural areas (p= .000002).
CONCLUSIONS: Poverty is identified risk factor for infant mortality, VLBW, and early pregnancy (ages 10-14). However, it is surprising that children living in counties with greatest poverty rates do not appear to be at proportionate increased risk of CM. It is unclear if CM findings represent true differences in prevalence or differences in reporting to CPS in poorer and less urban counties. The findings support that rates of CM occur across all socioeconomic groups and that health care providers need to improve efforts with young women living in poverty if they are to improve rates of infant morbidity and mortality.
Predictive Factors Associated with Combined ADHD Medication Treatment
Scott W. Stuart, Natalia Davila, Conway F. Saylor, Michelle M. Macias, Brandon S. Jordan. Developmental Pediatrics, Medical University of South Carolina, Charleston, SC; Psychology, The Citadel, Charleston, SC.
BACKGROUND: Evidence based medicine clearly supports pharmacological therapy as a cornerstone in the treatment for Attention Deficit Hyperactivity Disorder (ADHD). Published literature does not illustrate patient characteristics that may be linked with the use of combined pharmacotherapy.
OBJECTIVE: The purpose of this study was to identify predictive factors associated with combined pharmacotherapy strictly for ADHD treatment.
DESIGN/METHODS: IRB approval was obtained to conduct this retrospective chart review study. Billing data were screened for the diagnosis of ADHD. Entry criteria included; 6-12 years of age, diagnosis of ADHD, current medication treatment, medical management by the divisions of General Pediatrics or Developmental Pediatrics and at least three clinic visits. Out of 488 subjects that met study criteria, 25 of each gender and clinic were randomly selected for study (n=100). Information from all clinical and medication encounters over the past two years for ADHD care were assessed. Combination pharmacotherapy was identified as either poly-pharmacy or poly-stimulant treatment use. Poly-pharmacy was defined as the daily utilization of a stimulant and non-stimulant medication while poly-stimulant use was defined as the daily utilization of two or more stimulant medications to treat ADHD.
RESULTS: Of the patient sample, 70% were black and 81% had public health insurance. Ten percent (n=10) met poly-pharmacy criteria, 15% (n=15) met poly-stimulant criteria and 3% (n=3) met both criteria. Pearson chi-square analyses were completed. Factors positively associated with poly-pharmacy use included being white (p<.004), male gender (p<008), cared by Developmental Pediatrician (p<.008), psychiatric co-morbidity (p<.03) and diagnosis <7 y.o. (p<.005). Factors positively associated with poly-stimulant use included having psychiatric co-morbidity (p<.005), sleep disorders (p<.001), enuresis (p<0.19) and diagnosis < 7 years of age (p<.03).
CONCLUSIONS: In these data, 22% of a randomly selected school aged cohort met study criteria for combined ADHD medication treatment. The identified predictive factors should be considered carefully in the management of ADHD. Future research should be directed to assessing this combined treatment trend in adolescents.
First author is a fellow in training.
What Parent Concerns are Predictive for Failed Critical Items on the Modified Checklist for Autism in Toddlers?
Kimberly A. Twyman, MD, Michelle M. Macias, MD and Frances Page Glascoe, PhD. (Sponsored by Kimberly A. Twyman, M.D.) Developmental and Behavioral Pediatrics, Medical University of South Carolina, Charleston, SC and Pediatrics, Vanderbilt University, Nashville, TN.
BACKGROUND: Early detection of autism spectrum disorders (ASD) is crucial for best outcomes; therefore it is essential to identify the specific characteristics on developmental-behavioral (DB) screening that call for further ASD screening.
OBJECTIVE: This study determines what DB concerns on the Parents Evaluation of Developmental Status (PEDS), a parent competed DB screening tool, were associated with critical (2/6 items most sensitive to ASD diagnosis) failures on an ASD specific screening tool, the Modified Checklist for Autism in Toddlers (M-CHAT), and if specific concerns are predictive for certain failed M-CHAT critical items.
DESIGN/METHODS: By retrospective chart review, demographic data and scores for M-CHAT and PEDS were abstracted from the website www.forepath.org. Subjects who failed the M-CHAT were divided into two groups: Critical vs. Non-Critical Failure. One or more predictive concerns on PEDS constituted a failed screen. Concerns in each PEDS developmental domain were analyzed for prediction of critical M-CHAT failures, and if particular concerns were associated with certain failed items.
RESULTS: Of the 361 subjects, 59% failed on the basis of critical items. With respect to demographic factors, the 2 groups differed only on residential location. The Critical Fail group was more likely to have a PEDS score that would lead to referral for further testing (OR 4.3 CI 1.34-13.77). The predictive items on PEDS for M-CHAT critical failure included expressive language (OR 2.1 CI 1.01-4.55), receptive language (OR 2.3 CI 1.33-3.91), and self-help (OR 2.2 CI 1.30-3.69), while behavior concerns were less predictive (OR .46 CI .21-.99). Each of these domains was associated with failed responses for 3 M-CHAT items-imitation, sharing, and joint attention; receptive language was also associated with response to name (p<0.05).
CONCLUSIONS: Concerns within language domains are expected, as these are prominent ASD features. The association between the self-help domain and M-CHAT critical items reinforces the importance of joint attention in detecting a possible ASD. Particular attention to the language and self-help domains in DB screening tools such as PEDS may elicit concerns for behaviors most sensitive to ASD which require further screening.
Exposures related to pesticide residues in children
James R. Roberts, John R. Reigart, Thomas C. Hulsey. Pediatrics, Medical University of South Carolina, Charleston, SC.
BACKGROUND: The 2000-2001 National Health and Nutrition Examination Survey (NHANES), a nationally representative data set on childrenÕs health, included measurement of urinary pesticide residues in children. Understanding these data and mechanisms of exposure is the first step to identifying methods to reduce body burden.
OBJECTIVE: To evaluate the association between pesticide metabolite levels and indicators of exposure.
METHODS: NHANES data were used to evaluate exposure of US children to pesticides. Questions including treatment by a professional or non professional and frequency of use were examined. Lab data consisted of 7 urinary metabolites of organophosphate (OP) and pyrethroid insecticides. Data were analyzed using SAS callable SUDAAN to create a representative US sample. Age for all variables was limited to 6-18 years. Frequencies were determined and continuous variables were compared with t-tests and ANOVA.
RESULTS: The 3073 surveys comprise a representative sample of 50,704,925 US children ages 6-18 years. Of the 18% that reported a pesticide treatment in the home in the last month, 74% were by non professionals and 32% by professionals. (some had both). Of respondents with 2 or more treatments in the last month, 44% were by nonprofessionals v. 7% by professionals. Metabolites of pyrethroids and all OPs except chlorpyrifos were higher in children whose homes were treated in the past month versus untreated homes. All metabolites except parathion were higher in children whose home was treated by non-professionals v. homes treated by professionals, (pyrethroids highest (3.4 x)). 61% of children had total OP metabolites exceeding the 50%ile or higher if the home was treated by non professional, compared to 45% of children of professionally treated homes. This equates to 1.4 million more US children whose total OP urinary levels exceed the 50%ile when treated by a non-professional. 20% reported having the yard treated in the last month. All metabolite levels were higher when a non-professional treated the yard v. a professional; especially pyrethroids (2x) and total OP levels (3x).
CONCLUSIONS: Home treatment with pesticides occurred more often by non professionals and non professionals were more likely to treat the home ³ 2 times. Treatment by non professionals was associated with 1.4 million excess US children with OP residues exceeding the 50%ile. Clinical relevance is unclear without evaluating tolerances.
PEDS Developmental Milestones: A New Tool for Screening and Surveillance in Primary Care
Frances P. Glascoe, Nicholas S. Robertshaw, Michelle M. Macias, Lynn M. Wegner, Kyle B. Brothers. Pediatrics, Vanderbilt University, Nashville, TN; Director, Forepath.org, Washington, DC; Pediatrics, Medical University of South Carolina, Charleston, SC.
BACKGROUND: Most primary care providers use informal checklists in their efforts to detect children with delays and disabilities. Because fewer than 30% are identified with this method, there is need for a brief milestones measure that has high levels of sensitivity/specificity and thus clear referral criteria.
OBJECTIVE: To identify skills most predictive of developmental status in each domain of development across the birth to 8 year age range.
DESIGN/METHODS: Data were drawn from the standardization/validation studies of the Brigance Inventory of Early Development-II (IED-II) and the Brigance Comprehensive Inventory of Basic Skills-Revised (CIBS-R): diagnostic developmental measures of more than 700 items each. Subjects were 1619 children from 22 states, 0 to 8 years of age, whose sociodemographic characteristics conformed to US population parameters. Spanish administrations were given to 6%. Pediatric offices/public health clinics, day care/preschool/Head Start programs served as sites. Performance on each domain of the IED-II/CIBS-R was grouped into quotients at/below the 16th percentile versus above. Binary logistic regression analyses were run at each age level using items within each domain to predict overall performance in that same domain. Each potential item was viewed for sensitivity/specificity to performance above vs. below the 16th percentile. Final item selection included minimal need for stimulus materials (such as scissors). Inter-rater, test-retest, and readability statistics were computed.
RESULTS: A total of 112 items (6 - 8 per age level) met selection criteria. Sensitivity to performance at/below versus above the 16th percentile in each domain and by age level ranged from 70% to 93% and specificity from 77% to 93%. Test-retest and inter-rater reliability were high (.81 - .99). Readability clustered at the high first grade level (range 1.1 to 2.6).
CONCLUSIONS: This study shows that the PEDS:DM is a reliable, valid, and accurate, milestones-type screening tool. The measure is best viewed as setting lower limits on typical development and best used within a surveillance model (e.g., capturing and addressing parental concerns, resilience and risk factors, etc.).
Involvement of the Dihydroceramide Desaturase in Cell Cycle Progression in Human Neuroblastoma Cells
Jacqueline M. Kraveka, Li Li, Mehrdad Rahmaniyan, Zdzislaw M. Szulc, Jacek Bielawski, Besim Ogretmen, Yusuf A. Hannun, Lina M. Obeid, Alicja Bielawska. Division of Pediatric Hematology/Oncology, Medical University of South Carolina, Charleston, SC; Department of Biochemistry and Molecular Biology; Department of Medicine, Medical University of South Carolina.
BACKGROUND: The sphingolipid ceramide has been shown to be involved in neuroblastoma cell growth arrest and differentiation. In addition, ceramide has emerged as an important regulator of apoptosis in response to multiple stress inducers such as chemotherapeutic agents, TNF- and UV radiation. The role of dihydroceramide desaturase as a key enzyme in the de-novo pathway of ceramide generation was investigated in human neuroblastoma cells (SMS-KCNR). A novel assay using water-soluble analogs of dihydroceramide, dihydroceramidoids (D-e-dhCCPS analogs) was used to measure desaturase activity in-situ. Conversion of D-e-C12-dhCCPS (C12-dhCCPS) to its 4,5-desaturated counterpart: D-e-C12-CCPS (C12-CCPS) was determined by LC/MS analysis. The validity of the assay was confirmed by C8-cyclopropenylceramide, a competitive inhibitor of dihydroceramide desaturase. A human homologue (DEGS-1) of the Drosophila melanogaster degenerative-spermatocyte-gene-1 (des-1) was recently identified, and reported to have desaturase activity. Transfection of SMS-KCNR cells with siRNA to DEGS-1 significantly blocked the conversion of C12-dhCCPS to C12-CCPS. The associated accumulation of endogenous dihydroceramides confirmed DEGS-1 as the main active dihydroceramide desaturase in these cells. The partial loss of DEGS-1 inhibited cell growth with cell cycle arrest at G0/G1. This was accompanied by a significant decrease in phosphorylation of the retinoblastoma protein. This effect was inhibited by tautomycin, (an inhibitor of protein phosphatase-1, PP-1) suggesting the activation of PP-1 by dihydroceramides. Additionally, we found that treatment of SMS-KCNR cells with fenretinide inhibited desaturase activity in a dose dependent manner. Increase of dihydroceramides, but not ceramides, (as has been previously reported) paralled this process as measured by LC/MS. There were no effects on the mRNA or protein levels of DEGS-1. Results suggest that fenretinide acts at the post-translational level as an inhibitor of this enzyme. DEGS-1 is a novel target for neuroblastoma therapy.
Prevention of Subsequent Births to Teens with a School-Based Intervention
Janice Key, Linda Marsh, Mulugeta Gebregziabher, Kathleen O'Rourke. Pediatrics, Medical University of South Carolina, Charleston, SC; Biometry, Medical University of South Carolina, Charleston, SC; University of South Florida, Tampa, FL.
BACKGROUND: The rate of subsequent births to teen mothers remains a significant problem with few successful prevention programs.
OBJECTIVE: To evaluate the effectiveness of a school-based program in reducing subsequent births to teen mothers.
DESIGN/METHODS: A prospective cohort study compared subjects to two groups (students at another school and matched state data) over 24 months, with births measured by mother s name reappearing in state data. Eligible students were pregnant/already parenting girls. Analysis was based on intent to treat and included Fisher s Exact Test, Wilcox s log rank test for survival times, and Cox regression for relative risk.
RESULTS: Subjects (n=63 (100% eligible; 99% AA; mean age 16; 52% pregnant, 47% parenting)) did not differ from comparison groups (local n=31, state n=252). Participation in program components included: (1) group meetings: 76%, mean # meetings=5.6; (2) case management: 95%, mean # sessions=6.4; (3) medical care: 63%, mean # visits=5.0. Subsequent births were more common in the state comparison group (33%) than subjects (17%) or local comparison group (16%) (p =0.001, RR=2.6) with difference in survival curve (p=0.007).
Among subjects, there was a trend toward association of fewer births with participation in coordinated medical care (p=0.08) and case management (p=0.08).
CONCLUSIONS: The intervention was effective in reducing subsequent births to teens compared to state data, with increased effectiveness trending toward association with dosage for some program components. However this outcome cannot exclude the effect of inherent selection bias of a school-based program. Limitations of the local comparison group included difficult recruitment and contamination by another program.
Alendronate Increased Bone Density, Cortical Thickness and Reduced Fracture Frequency
Lester L. Key, Prema Madyastha, William L. Ries, Bruce Hollis, Frederick Reed. Pediatrics, Medical University of South Carolina, Charleston, SC.
BACKGROUND: A phase I/IIa study of efficacy and safety demonstrated that alendronate improved bone density, increased the cortical bone thickness (mm), and reduced fracture frequency (#/yr).
OBJECTIVE: Ten children (age 6-13 years) with two or more fractures, associated with minimal or no trauma, were identified to have a Z-score of <-2.0 SD based upon dual energy x-ray analysis.
DESIGN/METHODS: Ten children were treated with alendronate (35mg if patients <40kg, and 70mg if >40kg). Calcium supplementation (500mg or 1000mg daily, using the same weight cutoffs) was administered for 12 months. Lumbar spine and hip BMD were the primary outcomes of efficacy. Analysis of iliac crest biopsies before and upon completion of 12 months of alendronate was the major endpoint for safety.
RESULTS: The mineral apposition rate (MAR, m/d) using iliac crest specimens demonstrated that the MAR (n=9) decreased significantly (p<0.005) from greater than a normal rate (1.63 0.4) prior to therapy to the expected normal rate (1.03 0.3) for age [normal values for 7 to 10.9 years: 0.81-1.09] by the end of treatment. This reduction in MAR could signify a reduction in bone formation leading to excessive density if alendronate is used for prolonged periods of time. The micro architecture was normal with no areas of osteosclerotic bone. The average height increased normally at the rate of 6.4+0.7 cm/yr. Secondary safety outcomes were determined by monthly phone calls to assess the clinical status of each patient. No serious adverse events occurred. During the Alendronate therapy, the BMD improved the score from 0.57+0.017g/cm2(se) to 0.65+0.02 g/cm2 (n=20, p<0.00001). In conjunction with the increase in BMD, the cortical thickness of the iliac crest bone increased from 0.59+0.09 mm to 0.89+0.11 mm (p<0.01). There was one fracture (0.11+0.04(se) fractures/year/patient) in 9 patients (one patient with genetically-proven OI was excluded) during the treatment period as compared to 27 fractures (0.33+0.1(se) fractures/year/patient) in the same 9 patients, P<0.05) prior to the study.
CONCLUSIONS: In conclusion, alendronate therapy resulted in an increased bone density, a reduced fracture rate, and an increased cortical bone thickness with no reduction in the rate of height growth.
ACT1 Peptide Modulates Glioma Cell Invasiveness
Ching Zhu, Jane Jourdan, Anne G. Gilg, Robert G. Gourdie, Bernard L. Maria. Harvard University, Boston, MA; Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC; Department of Pediatrics, Medical University of South Carolina, Charleston, SC.
BACKGROUND: The infiltration of glioma cells within the central nervous system (CNS) accounts for high rates of mortality and morbidity. This infiltration requires cellular attachment, cytoskeletal-dependent motility, and protease-dependent invasiveness. Recent research has revealed that a hallmark of many glioma cell lines is the aberrant expression of gap junctions, intercellular membrane channels that allow direct cell-to-cell communication. Gap junction channels are composed of protein subunits called connexins, which are maintained and organized by many scaffolding proteins and cytoskeletal components. One such scaffolding protein is zonula occludens-1 (ZO-1), which binds to the carboxyl terminus of connexin43 (Cx43), a major gap junction protein subtype. The ACT-1 (Alpha Connexin carboxy Terminal) peptide was designed as a competitive inhibitor of Cx43 and ZO-1 interaction. ACT-1 peptide alters gap junction dynamics in fibroblasts, and accelerates wound healing.
OBJECTIVE: In this study, we examined the effects of ACT-1 on cell morphology, attachment, and invasiveness of glioma cells.
RESULTS: Human U87 MG glioblastoma cells (which express Cx43) treated with the ACT-1 peptide displayed a higher degree of aggregation (Bonferroni t-test, p<0.003), reflecting higher degrees of cellular attachment. In contrast, the adhesive properties of the Cx43-deficient rat C6 glioma cell line did not change in response to ACT-1 peptide treatment. ACT-1 treated C6 cells displayed a more rounded morphology and less cellular polarity, suggesting decreased motility in culture. Boyden chamber migration assays showed that ACT-1 significantly decreased both U87 MG (p<0.003) and C6 (p<0.015) motility across a porous membrane (Bonferroni t-test).
CONCLUSIONS: These results provide insights into the role of the Cx43 C-terminus in the malignant behavior of glioma cells. Small molecules such as ACT-1 peptide that target gap junction organization and promote wound healing may also modulate invasiveness or metastasis of malignant cells.
Attendance Roster
| Sarah Taylor |
Heather Will |
Sarah Mennito |
| James McElligott |
Lisa Johnson |
Jacqueline Kraveka |
| Lester Key |
Kristina Gustafson |
Paul Darden |
| Michelle Macias |
John Reigart |
Andrea Summer |
| James Roberts |
William Basco |
Jonathan Slaughter |
| Colleen Thomas |
Becky Hasegawa |
George Johnson |
| Jan Key |
Lakshmi Katikaneni |
Debra Bowlby |
| Carol Wagner |
Doe Jenkins |
Bernard Maria |
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