Topiramate for intractable childhood epilepsy.

To better define the efficacy and tolerability of the new anticonvulsant topiramate in pediatric patients, the clinical courses of 49 children with intractable seizures were monitored during topiramate therapy. The 80% of children who had complex partial seizures experienced better seizure control with topiramate than the 20% who had generalized seizures. Efficacy was greatest with doses between 2.5 and 7.5 mg/kg/day. More than half the children on topiramate experienced adverse effects which could interfere with learning at school, but 20% demonstrated increased alertness or improved behavior. Topiramate is effective and may be considered as part of the treatment pathway for complex partial seizures in children, although careful monitoring of cognitive function is required.

The effect of GH therapy on the immunoreactive forms and distribution of IGFBP-3, IGF-I, the acid-labile subunit, and growth rate in GH-deficient children.

We have previously shown that the major correlates of growth following growth hormone (GH) therapy in growth hormone-deficient (GHD) children are changes in circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3), suggesting a synergistic interaction between IGF-I and IGFBP-3 (1). The first aim of this project was to examine the molecular forms of IGFBP-3 and the acid-labile subunit (ALS), and to assess the changes in these molecular forms during GH administration to GHD children. Plasma samples from prepubertal GHD patients, prior to therapy and during the first year of GH treatment, were subjected to Western ligand and immunoblot analysis. Densitometric analysis of Western ligand blotting (WLB) showed a 76% increase in IGFBP-3 (p = 0.02), but a 56% decrease in 36-kDa IGFBP-2 (p = 0.03) during GH therapy. Western immunoblot (WIB) analysis of IGFBP-3 revealed the presence of intact (40- to 45-kDa doublet) as well as a proteolyzed (28-kDa) form of IGFBP-3 in the serum of GHD and healthy children. Both immunoreactive forms of IGFBP-3 increased by 64% during GH therapy (intact p = 0.003; proteolyzed p = 0.0001). WIB analysis of the ALS showed an 84-to 86-kDa doublet, which increased by 41% with GH therapy (p = 0.01). The response to GH therapy, as measured by the height velocity standard deviation score (SDS) adjusted for bone age, correlated with the percent change in total IGFBP-3 (r = 0.772, p = 0.002 by WIB), intact IGFBP-3 (r = 0.845, p = 0.0005 by WLB; r = 0.541, p = 0.05 by WIB), and proteolyzed IGFBP-3 (r = 0.703, p = 0.007), as well as with the percent change in ALS (r = 0.813, p = 0.014). The second aim of this project was to assess the changes in distribution of the immunoreactive forms of IGFBP-3 and IGF-I among the ternary (ALS/IGFBP-3/IGF) complex, the binary (IGFBP-3/IGF) complex, and uncomplexed IGF during the first year of GH therapy, and to explore further the correlation with growth response to GH. Plasma samples, prior to therapy and after the first year of GH treatment, were separated by neutral size-exclusion chromatography and then subjected to IGFBP-3 immunoradiometric assay (IRMA), IGFBP-3 WIB, and IGF-I IRMA analysis. IGFBP-3 increased in both the ternary (p < 0.0001) and binary (p = 0.01) complexes, but there was a shift in the percentage of IGFBP-3 from the binary to the ternary complex during GH therapy. Both intact and proteolyzed forms of IGFBP-3 were found in both the ternary and binary complexes, but the shift occurred primarily for the proteolyzed (28-kDa) form (p = 0.001). There was a significant increase in IGF-I in the ternary (p = 0.001) and binary (p = 0.005) complexes, but not in uncomplexed IGF-I. The percentage of IGF-I in the ternary complex increased (p = 0.006), whereas the percentage of uncomplexed IGF-I decreased (p = 0.02), during GH therapy. Growth rate, assessed by the height velocity SDS for bone age, correlated best with the changes in ternary complex IGFBP-3 (r = 0.72, p = 0.01) and ternary complex IGF-I (r = 0.56, p = 0.10). In conclusion, GH treatment of GHD children results in significant increases of intact, proteolyzed, and total IGFBP-3, as well as an increase in ALS, which all correlate with the growth response to GH therapy. In addition, GH treatment results in increases in ternary complex IGFBP-3 and IGF-I, which also correlate with the response to therapy. We suggest that the formation of the ternary complex may be a determining factor in the somatic growth response.

Collection of blood in heparinized tubes does not alter the molecular distribution or forms of IGFBP-3 and IGF.

The major serum carrier of the insulin-like growth factors (IGFs) is IGF-binding protein-3 (IGFBP-3) that exists in the circulation associated with IGF and an acid labile subunit to form a ternary (158-kDa) complex. It has been reported that heparin disrupts the IGF carrying capacity of the ternary complex and is a potent inhibitor of ternary complex reformation (Clemmons et al., 1983; Baxter, 1990). Thus, the aim of this study was to determine if, in a clinical setting where blood may be collected in both nonheparinized and heparinized tubes, heparin alters the molecular distribution or immunoreactive measurement of IGFBP-3 and IGF-I. Two different collection modalities were examined: protocol 1, blood was drawn and immediately centrifuged and aliquotted; and protocol 2, blood was drawn, left at room temperature for 2 h and then at 4°C overnight prior to centrifugation. Samples were drawn from a normal adult and from a growth hormone-deficient (GHD) child and subjected to neutral size-exclusion chromatography to separate the ternary 158-kDa complex from the binary IGFBP-3-IGF (approx 50 kDa) complex. Fractions were then subjected to Western ligand blot (WLB), western immunoblot (WIB), and measurement of IGFBP-3 by immunoradiometric assay (IRMA), while the IGF distribution was measured by radioimmunoassay (RIA) following acidic size-exclusion chromatography. In both serum and plasma of a normal adult, WLB detected a 45-40-kDa IGFBP-3 doublet eluting primarily within the 158-kDa IGFBP region (i.e., ternary complex). Similarly, assessment of immunoreactive IGFBP-3 by WIB showed a 45-40-kDa IGFBP-3 doublet, as well as a 29 kDa immunoreactive form primarily eluting in the 158-kDa IGFBP region of the chromatography. Measurement of IGFBP-3 by IRMA confirmed these findings. No difference between serum and plasma was detected in either collection protocol. RIA of IGF-I revealed that the ternary complex carried the majority of the circulating IGF-I and that there was no difference between serum and plasma. Assessment of serum and plasma of a GHD child showed reduced serum concentrations of IGFBP-3 but no difference in the IGFBP profiles between serum and plasma. These data demonstrate that the collection of blood in heparinized tubes does not alter the molecular distribution or forms of IGFBP-3 and IGF-I.

Changes in insulin-like growth factor-I (IGF-I), IGF-binding protein-3, growth hormone (GH)-binding protein, erythrocyte IGF-I receptors, and growth rate during GH treatment.

To assess the relative determinants of growth rate, we measured serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and GH-binding protein (GHBP) as well as IGF-I erythrocyte receptor specific binding (SB) in 14 prepubertal GH-deficient children before and during the first year of treatment with 0.043 mg/kg.day GH. Serum IGF-I and IGFBP-3 levels, measured by RIA, were significantly increased by 2 weeks and showed progressive increases throughout the year of GH therapy. Growth rate (height velocity SD score adjusted for bone age) correlated best with the 12 month changes in IGFBP-3 (r = 0.81; P < 0.001) and IGF-I (r = 0.72; P = 0.005), and to a lesser extent with the 12 month absolute IGFBP-3 (r = 0.58; P = 0.04) and the 6 month change in IGFBP-3 (r = 0.55; P = 0.05). The baseline IGF-I correlated inversely with the growth rate during GH therapy (r = -0.55; P = 0.05) and was the best pretreatment predictor of growth response. GHBP, as measured by ligand-mediated immunofunctional assay, showed no significant change during GH therapy and did not correlate with growth response. The baseline GHBP, however, did correlate with both the 12 month IGFBP-3 (r = 0.72; P = 0.006) as well as the 2 week change in IGFBP-3 (r = 0.63; P = 0.05). Erythrocyte IGF-I SB showed a significant decrease by 6 months secondary to a decrease in IGF-I receptor number, with no change in affinity. The 6 month IGF-I receptor binding correlated inversely with the increase in IGF-I (r = -0.88; P < 0.001). Erythrocyte IGF-I SB at baseline did not correlate with the growth response, although there was an inverse trend between the 6 month IGF-I receptor level and the growth rate. IGF-I and IGFBP-3 show progressive increases, whereas the erythrocyte IGF-I receptor-binding capacity decreases by 6 months, and GHBP shows little change during the first year of GH treatment. Data from this study suggest that changes in IGFBP-3 and, to a lesser extent, IGF-I are the major correlates of growth rate, and that down-regulation of the IGF-I receptor may have relatively little influence on growth rate compared with changes in IGFBP-3 and IGF-I.

Nonresponse bias to mail survey questionnaires within a professional population.

Mail survey questionnaires are often used in dental research. In most instances, results depend on a single mailing and an incomplete return rate. The possible bias resulting from excluding nonresponders in tabuling data from mail survey questionnaires in a dentist population was investigated. Two different questionnaires, one soliciting attitudes, the other knowledge, were sent to randomly selected dentists. The differences between the responders and the nonresponders were analyzed with respect to the dentists' demographic data, attitudes, and knowledge. It was concluded that: (1) subject matter does affect dentist response rates to mailed survey questionnaires, (2) there are no differences in demographic data between dentist responders and nonresponders, and (3) nonresponse bias does not affect the results of dental surveys on a typical dentist response rate.