Phenobarbital is widely used in the treatment of children with febrile seizures, although there is concern about possible behavioral and cognitive side effects. In 217 children between 8 and 36 months of age who had had at least one febrile seizure and were at heightened risk of further seizures, we compared the intelligence quotients (IQs) of a group randomly assigned to daily doses of phenobarbital (4 to 5 mg per kilogram of body weight per day) with the IQs of a group randomly assigned to placebo. After two years, the mean IQ was 7.03 [corrected] points lower in the group assigned to phenobarbital than in the placebo group (95 percent confidence interval, -11.52 to -2.5, P = 0.0068 [corrected]). Six months later, after the medication had been tapered and discontinued, the mean IQ was 5.2 points lower in the group assigned to phenobarbital (95 percent confidence interval, -10.5 to 0.04, P = 0.052). The proportion of children remaining free of subsequent seizures did not differ significantly between the treatment groups. We conclude that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage, which may outlast the administration of the drug by several months, is not offset by the benefit of seizure prevention.

The primary analysis of a randomized clinical trial should compare patients in their randomly assigned treatment groups (intention to treat analysis). When a substantial number of subjects fail to take a prescribed medication or are switched to a different study medication, it is tempting to consider treatment comparisons using only those subjects with treatment as actually received rather than as prescribed. There are several arguments against this approach: the prognostic balance brought about by randomization is likely to be disturbed; sample size will be reduced; and the validity of the statistical test procedures will be undermined. Further, results of analysis by treatment actually received may suffer from a bias introduced by using compliance, a factor often related to outcome independently of the treatment received, to determine the groups for comparison. The extent and nature of this bias will be related to the definition of compliance in an as treated analysis, a definition which could be unintentionally self-serving. We have investigated the problem of the definition of actual treatment in the context of a recent clinical trial. We used several definitions to classify patients as having received or not received treatment as prescribed. These definitions, when used in as treated analyses, provided results that were at times inconsistent or counter-intuitive, and which neither helped to confirm nor further explain the intention to treat analysis.

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.

We studied the frequency of oligoclonal immunoglobulin G bands in the cerebrospinal fluid (CSF) of patients with various neurological diseases. We used a micromethod employing sodium dodecyl sulfate polyacrylamide gel electrophoresis that required only 50 microliters of unconcentrated CSF. Oligoclonal bands were detected in the CSF of 95% of the patients with multiple sclerosis, 90% with subacute sclerosing panencephalitis, and 100% with herpes simplex encephalitis, but less frequently in other central nervous system infections. No oligoclonal bands were detected in the CSF of patients with Parkinson, Huntington, Creutzfeldt-Jakob, or herniated disc diseases. Bands were detected in some patients with Alzheimer disease, cerebrovascular accident, idiopathic vertigo, idiopathic seizures, amyotrophic lateral sclerosis, polyneuropathy, and central nervous system glioma. Patients with other conditions infrequently had positive bands. The determination of oligoclonal bands is a useful aid in the diagnosis of multiple sclerosis, subacute sclerosing panencephalitis, and herpes simplex encephalitis. The presence of oligoclonal bands indicates an immunological response but is not diagnostic for a particular condition.

OBJECTIVE -Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal losses at the extremes of glycemia in diabetic and nondiabetic pregnancy. To test this hypothesis, we examined relationships of proximate measures of prior glycemia, glycated protein and fructosamine, to pregnancy loss. RESEARCH DESIGN AND METHODS-A total of 389 diabetic and 429 nondiabetic pregnant subjects participated in the Diabetes In Early Pregnancy study. Glycated protein and fructosamine measurements were standardized as multiples of control values for each center (Z score). The logarithm of odds of pregnancy loss were plotted against Z scores and tested by logistic models.RESULTS -Mean pregnancy loss rates were 12% in diabetic and 13% in normal pregnancies. However, over six intervals of glycated protein in diabetic pregnancy, fetal loss rates at the upper and lower extremes (24 and 33%, respectively) were approximately threefold higher than the four intervening rates (8 -14%). The odds ratio of pregnancy loss for these extreme intervals to the intervening intervals is 3.0 (P ϭ 0.01). Nondiabetic losses showed a similar pattern. In confirmation, logit pregnancy losses were increased in a J-shaped curve at the glycemic extremes in normal (P Ͻ 0.019) and diabetic (P Ͻ 0.015) pregnancy. The upper glycemic extreme in diabetic pregnancy was two-to fivefold higher than in control pregnancy.CONCLUSIONS -Pregnancy losses are increased at the extremes of glycemia in both normal and diabetic pregnancy but at higher levels in diabetic pregnancy. The data suggest defensive adaptations against hyperglycemia in diabetic pregnancy.

We consider several covariance models for analysing repeated measures data from a study of ovarian steroid secretion in reproductive-aged women. Urinary oestradiol and serum oestrogen were repeatedly observed over three or four menstrual periods, each period separated by one year. For each menstrual period, daily first morning urine specimens were collected 8 to 18 times, and serum specimens 2 to 5 times. Thus, measurements were repeatedly observed over menstrual cycle days within menstrual periods. Owing to missing observations, the number of observations differed from subject to subject. In this study, there were two repeat factors: menstrual cycle day and menstrual period. The first repeat factor, cycle day, is nested within the second repeat factor, menstrual period. In analysing these nested repeated measures data, the correlation structure should be modelled that will account for both repeat factors. We present several covariance models for defining appropriate covariance structures for these data.

In 42 patients with African Burkitt's lymphoma, we have studied biochemical and clinical correlations with prognosis. Clinical stage and anti-EA titer were the best predictive factors, but lactic dehydrogenase (LDH) and uric acid (UA) concentrations also correlated with stage and prognosis, whereas lactic acid (LA), which was significantly elevated in Stage D, did not significantly correlated with prognosis or with LDH and UA levels. All of these factors with the possible exception of LA reflect the total body burden of tumor. We conclude that the tumor burden is the single most important prognostic factor in Burkitt's lymphoma, and that this is reflected directly by LDH and UA concentrations, and probably indirectly by anti-EA titer.

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.