Allospecific CD154+ T cells associate with rejection risk after pediatric liver transplantation.

Antigen-specific T cells, which express CD154 rapidly, but remain untested in alloimmunity, were measured with flow cytometry in 16-h MLR of 58 identically-immunosuppressed children with liver transplantation (LTx), to identify Rejectors (who had experienced biopsy-proven rejection within 60 days posttransplantation). Thirty-one children were sampled once, cross-sectionally. Twenty-seven children were sampled longitudinally, pre-LTx, and at 1-60 and 61-200 days after LTx. Results were correlated with proliferative alloresponses measured by CFSE-dye dilution (n = 23), and CTLA4, a negative T-cell costimulator, which antagonizes CD154-mediated effects (n = 31). In cross-sectional observations, logistic regression and leave-one-out cross-validation identified donor-specific, CD154 + T-cytotoxic (Tc)-memory cells as best associated with rejection outcomes. In the longitudinal cohort, (1) the association between CD154 + Tc-memory cells and rejection outcomes was replicated with sensitivity/specificity 92.3%/84.6% for observations at 1-60 days, and (2) elevated pre-LTx CD154 + Tc-memory cell responses were associated with significantly increased incidence (p = 0.02) and hazard (HR = 7.355) of rejection in survival/proportional hazard analysis. CD154 expression correlated with proliferative alloresponses (r = 0.835, p = 7.1e-07), and inversely with CTLA4 expression of allospecific CD154 + Tc-memory cells (r =-0.706, p = 3.0e-05). Allospecific CD154 + T-helper-memory cells, not CD154 + Tc-memory, were inhibited by increasing Tacrolimus concentrations (p = 0.026). Collectively, allospecific CD154 + T cells provide an estimate of rejection risk in children with LTx.

Pyruvate inhibits growth of mammary adenocarcinoma 13762 in rats.

The growth of implanted mammary adenocarcinoma 13762 was measured in rats consuming a liquid diet (35% fat, 18% protein, 47% carbohydrate) supplemented with pyruvate (37.3 g/liter; n = 13) or maltose-dextrin (placebo; n = 13) for 21 days. Mean tumor diameter, measured on day 11, 14, 18, and 21 subsequent to tumor implantation, was 41, 32, 21, and 19% smaller in the pyruvate group (P < 0.05). When euthanized, tumor weight was also smaller in the pyruvate group: pyruvate = 15.0 +/- 2.3 (SEM) g; placebo = 24.9 +/- 3.2 g, P < 0.05. Visual inspection of organs suggested decreased lung metastases with pyruvate feeding (P < 0.05). Upon microscopic evaluation of organs, hepatic tumor was found only in the placebo group. We conclude that pyruvate inhibits implanted tumor growth in rats.

Use of the single subject design for practice based primary care research.

The use of a single subject research design is proposed for practice based primary care research. An overview of the rationale of the design, an introduction to the methodology, strengths, limitations, a sample of recent literature citations, a working example, and possible clinical applications are presented.

Medical comorbidity of major depressive disorder in a primary medical practice.

Despite much speculation about the relationship between depression and medical comorbidity in primary care settings, few investigators have examined this issue empirically. Using a two-stage screening procedure, we assessed 618 patients aged 18 to 64 years in an academic general medicine clinic. Forty-one patients (6.6%) suffered from a current episode of major depressive disorder (MDD). We compared this group with a 20% random sample of nondepressed patients. While patients with MDD were younger (mean age, 41.1 vs 47.2 years), they were assessed by the Duke University Severity of Illness Scale as having more severe medical illness. Patients with MDD were more likely to have malignant tumors and "ill-defined conditions" than nondepressed patients. The 18 patients with MDD (44%) who were correctly diagnosed by their physicians had less severe medical illness than those whose depression was clinically undetected. A logistic regression model predicting MDD group membership included female gender, younger age, higher Duke University Severity of Illness Scale score, and more frequent inactive ill-defined diagnoses. These findings are consistent with assertions: (1) patients with MDD have more physical illness than nondepressed patients and/or (2) somatic symptoms and disability caused by MDD add to the burden of physical illness.

The relationship of physical fitness to lipid and lipoprotein(a) levels in adolescents with IDDM.

OBJECTIVE--Increased physical activity and physical fitness are recommended therapeutic modalities in addition to insulin and diet in the management of children with IDDM. The aim of this study was to assess the fitness levels of adolescents with IDDM compared with healthy control subjects and to evaluate the relationship between physical fitness and metabolic control. RESEARCH DESIGN AND METHODS--We studied 59 patients with IDDM, 28 boys and 31 girls, age 15.6 +/- 2.5 yr, duration of diabetes 7.6 +/- 3.5 yr, HbA1 10.6 +/- 2.1% (mean +/- SD), and compared them with 18 healthy, nondiabetic control subjects, 9 boys and 9 girls, matched for age, BMI, and Tanner stage. Physical fitness was measured by VO2max during progressive bicycle ergometry. HbA1 was used to determine glycemic control. Lipid profile included fasting total cholesterol, HDL, LDL, Lp(a), and TG levels. RESULTS--Patients with IDDM had lower VO2max levels than control subjects (33.7 +/- 7.0 vs. 41.0 +/- 10.4 ml.kg-1.min-1, P = 0.001). Males with IDDM had lower VO2max than male control subjects, but diabetic and control females showed no difference. In IDDM patients, VO2max correlated inversely with HbA1, insulin dose, cholesterol, LDL, TGs, and Lp(a), but did not correlate with HDL, which correlated inversely with BMI. CONCLUSIONS--We conclude that the state of physical fitness is an important correlate of lipid levels and Lp(a) in adolescents with IDDM. We speculate that higher physical fitness levels in adolescents with IDDM may decrease the risk of CVD through modulating lipid levels.

Insulin secretion and sensitivity in black versus white prepubertal healthy children.

We had previously demonstrated greater insulin secretion and lower insulin sensitivity in black pubertal adolescents compared with whites. This study aimed to investigate whether similar black/white differences are present in the prepubertal period or are characteristics of the pubertal period. Twelve black and 11 white healthy prepubertal children, matched for age, body mass index, and Tanner I pubertal development, underwent a 2-h hyperglycemic clamp (225 mg/dL). Physical fitness was assessed by maximal oxygen consumption (VO2max) measurement during graded bicycle ergometry, and resting energy expenditure was measured by indirect calorimetry after overnight fast. Fasting and first phase insulin concentrations were higher in blacks than in whites [14.7 +/- 1.3 vs. 10.4 +/- 1.2 (P = 0.02) and 76.9 +/- 6.8 vs. 52.1 +/- 6.4 microU/mL (P = 0.016)]. There were no differences in second phase insulin levels and insulin sensitivity index. Both maximal oxygen consumption (VO2max) and resting energy expenditure were lower in black children, whereas insulin-like growth factor I was higher. After controlling for these differences, race contributed significantly to basal insulin, but not to first phase insulin. In summary, previously reported black/white differences in insulin secretion and sensitivity during adolescence may have their origin in early childhood manifested as hyperinsulinemia. However, genetic (race) vs. environmental factors (physical activity/fitness and energy balance) should be carefully scrutinized as potential factors responsible for such differences.

Lipolysis in African-American children: is it a metabolic risk factor predisposing to obesity?

Rates of obesity and type 2 diabetes are higher in African-American (AA), compared with American white (AW), adults and children. It is not known whether biologic and/or environmental differences are responsible for this racial disparity. We and others have demonstrated that AA children are hyperinsulinemic, compared with their AW peers. This investigation tested the hypothesis that hyperinsulinemia in AA children is associated with lower rates of lipolysis, which could be a risk factor for future obesity. Forty prepubertal children (20 AA and 20 AW) with comparable body composition (assessed by dual-energy x-ray absorptiometry) and visceral adiposity (evaluated with computed tomography scan) were studied. Total body lipolysis was measured with [(2)H(5)]glycerol after overnight fasting. Basal lipolysis was approximately 40% lower in AA vs. AW children, whether the data were expressed for total body (85.7 +/- 8.9 vs. 130.3 +/- 14.1 micromol/min, P = 0.011) or per-kilogram BW (2.4 +/- 0.2 vs. 3.8 +/- 0.4 micromol/min.kg, P = 0.002) or per kilogram fat free mass (FFM) (3.3 +/- 0.3 vs. 5.2 +/- 0.5 micromol/min.kg FFM, P = 0.004), or per kg fat mass (FM) (13.7 +/- 1.6 vs. 21.3 +/- 3.3 micromol/min.kg FM, P = 0.046). Fasting insulin levels were higher in AA children (99.6 +/- 7.8 vs. 77.4 +/- 5.9 pmol/L, P = 0.032). Lipolysis correlated positively with fat mass, percent body fat, and abdominal fat mass. However, in multiple-regression analysis models after controlling for insulin and body composition, race remained a significant contributor to the variance in lipolysis. In summary, the present study demonstrates that rates of lipolysis are significantly lower in AA children, compared with their white peers. This may constitute an early metabolic phenotype that may mediate fat trapping and susceptibility to obesity in a specific environmental context of energy excess conducive to fat accretion.

Validity of bioelectrical-impedance analysis in measuring changes in lean body mass during weight reduction.

The aim of this study was to investigate the validity of bioelectrical-impedance analysis (BIA) in measuring changes in lean body mass (LBM) that occur in the treatment of obesity with very-low-calorie diets (VLCDs). Resistance (R), reactance (Xc), and nitrogen balance (BN) were measured for 28 consecutive days in 16 obese women consuming isocaloric and isonitrogenous ketogenic and nonketogenic liquid VLCDs while housed in a metabolic ward. Changes in LBM were calculated by using eight BIA-predictive equations and from cumulative BN. Changes in LBM calculated by BN were larger in the ketogenic than in the nonketogenic diet (1.5 +/- 0.1 vs 0.6 +/- 0.2 kg/28 d, P less than 0.05). Neither R nor Xc changed significantly during treatment with either diet but each equation showed losses of LBM with time. All the equations overestimated the losses in LBM calculated by BN. BIA does not appear to be a valid method for measuring the small losses in LBM that occur during treatment of obesity with VLCDs.

Skeletal muscle density: effects of obesity and non-insulin-dependent diabetes mellitus.

Obesity is associated with increased lean mass but its effects on lean-tissue density are less clear. To examine the effects of obesity and non-insulin-dependent diabetes mellitus (NIDDM) on lean-tissue composition and density, cross-sectional computed tomography (CT) scans of the midthigh were obtained in 20 men of various weights. Obesity was associated with increases in thigh-adipose (r = 0.75) and lean-tissue volumes (r = 0.52) and with reduced density of lean tissue (r = -0.73). The increased lean tissue in obesity was due to a nonadipose tissue component with a density below the normal range of muscle, an effect compounded by NIDDM, whereas normal-density muscle volume was unchanged.

Pyruvate supplementation of a low-cholesterol, low-fat diet: effects on plasma lipid concentrations and body composition in hyperlipidemic patients.

The effects of the three-carbon compound pyruvate on plasma lipid concentrations and body composition were evaluated in hyperlipidemic patients consuming a low-cholesterol (165-180 mg), low-fat (22-24% of energy; 18-20% of energy as saturated fatty acid) diet (0.091-0.099 MJ.kg body wt-1 x d-1). After consuming the above diet for 4 wk, during which time plasma lipid concentrations decreased, 34 subjects were randomly assigned to receive either 22-44 g pyruvate (n = 17) or 18-35 g polyglucose (placebo, Polycose, n = 17), iso-energetically substituted for a portion of carbohydrate energy for 6 wk. Despite greater weight and fat losses with pyruvate (P < 0.05), plasma concentrations of cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride were not different between the two groups of subjects. We conclude that subsequent to diet-induced reduction in plasma lipid concentrations, pyruvate supplementation of a low-cholesterol, low-fat diet providing 6.7-7.6 MJ/d for 6 wk has no effect on plasma lipid concentrations but enhances body weight and fat losses.

Cyclosporine nephrotoxicity in cardiac allograft patients--a seven-year follow-up.

Renal function was observed retrospectively in a population of 228 adults who underwent a cardiac allograft at the University of Pittsburgh from June 1980 through June 1987, survived a minimum of one year, and received cyclosporine. Renal function was determined by serial measurement of serum creatinine concentration. Serum creatinine rose from 1.2 +/- 0.0 mg/dl at time of hospital discharge to 2.0 +/- 0.0 mg/dl at two and four years and 3.3 +/- 0.1 mg/dl at seven years. The fall in renal function was biphasic, with a rapid decline (reciprocal creatinine slope -0.018 dl/mg-mo) through 24 months and a slower decline thereafter -0.0036 dl/mg/month). This occurred despite a progressive decrease in cyclosporine levels from 668 +/- 23 ng/ml (whole blood RIA) to 380 +/- 12 ng/ml at seven years. Three of 222 patients (1.6%) developed end-stage renal disease within 18 months of initiation of cyclosporine therapy. Only one additional patient of 26 followed through 54 months (3.8%) developed end-stage disease thereafter. The decline in renal function seen with cyclosporine is rapid in the first 18 months, with a slower but continuing decline seen with later follow up. At least in heart transplantation, the risk of end-stage renal disease is significant, but not prohibitive.

Epstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression.

In children undergoing renal transplantation, Epstein-Barr virus- (EBV) related disorders, including posttransplant lymphoproliferative disorder, constitute a major complication associated with tacrolimus-based immunosuppression. In this study, we reviewed the EBV complications in 81 children, all of whom had EBV serological studies before renal transplantation. We also highlight the data in a subgroup of 30 children transplanted more recently who were monitored sequentially for EBV symptoms and signs and with immunological studies, and in whom the donor EBV serology was also determined. During a mean follow-up time of 3.9+/-2.3 years, 19 children developed symptomatic Epstein-Barr virus (EBV*) infection. This consisted of the clinical syndrome of infectious mononucleosis in 7 children; in addition, 10 children developed posttransplant lymphoproliferative disorder (PTLD), which was histologically confirmed in 8, and 2 others developed malignant lymphoma. Recipient seronegativity (EBV-) and donor EBV seropositivity (EBV+) predicted a high probability for seroconversion (P=0.0072) and for developing PTLD or malignancy (P<0.01). In the subgroup of 30 children studied prospectively, seroconversion occurred in 15 of 19 seronegative recipients of EBV seropositive grafts at 6.6+/-2.6 months (mean+/-SD) after transplantation. Seven children developed symptomatic EBV infection (including three with PTLD) in association with seroconversion and a rise in EBV viral load in the peripheral blood, demonstrated by an EBV-specific polymerase chain reaction (EBV-PCR). Of 15 seroconverters, 7 who developed symptomatic infection had received EBV+ grafts; 8 others with EBV+ grafts seroconverted but did not become symptomatic. These two subgroups did not differ in age, rejection rate, antiviral prophylaxis, or level of immunosuppression. In the overall group of 81 children, only the two with malignant lymphoma who were managed with chemotherapy had substantial morbidity. The 10 individuals with PTLD received a regimen combining i.v. ganciclovir and CytoGam, and stopping or reducing the tacrolimus. Four children with associated marked tonsilar growth underwent tonsillectomy. All 19 individuals with EBV disorders resolved their symptoms and signs, and all have maintained good allograft function during a follow-up time of 3.0+/-2.5 years (mean+/-SD) after the development of symptomatic EBV infection, PTLD, or malignancy. We conclude that seronegative recipients of EBV+ grafts are at high risk for developing EBV-related disorders after renal transplantation under tacrolimus-based immunosuppression, although the ultimate clinical outcomes have been remarkably good. These data form the basis for formulating strategies for early identification of children at risk for EBV complications, and for instituting preventive and treatment strategies that permit these children to realize the substantial benefits offered by tacrolimus-based immunosuppression.

Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects committing suicide.

A variety of postmortem brain studies and clinical investigations have provided evidence that reduced serotonin neurotransmission is associated with suicidal behavior and depression, and several serotonergic parameters have been found to be altered in the prefrontal cortex of suicide victims. However, the integrity of the serotonin innervation of the prefrontal cortex in mood disorders has not been directly investigated. The present study used immunocytochemical methods and an antibody against the serotonin transporter to examine the relative density of serotonin axons in the dorsolateral prefrontal cortex of suicide victims with a diagnosis of major depression. The mean total length of serotonin transporter-immunoreactive axons per unit area was unchanged in layers 2 and 4 of area 46 in the depressed suicide subjects compared to controls, but was significantly (P < 0.01) decreased by 24% in layer 6 in the depressed suicide group. The total length of serotonin transporter-positive axons in layer 6 was reduced in eight of the 12 depressed suicide subjects compared to their matched control subjects. These findings reveal that depressed subjects who have committed suicide exhibit a lamina-specific reduction in a marker of serotonin axons in the dorsolateral prefrontal cortex that may reflect an alteration in cortical serotonin neurotransmission.

Oral versus initial intravenous therapy for urinary tract infections in young febrile children.

BACKGROUND: The standard recommendation for treatment of young, febrile children with urinary tract infection has been hospitalization for intravenous antimicrobials. The availability of potent, oral, third-generation cephalosporins as well as interest in cost containment and avoidance of nosocomial risks prompted evaluation of the safety and efficacy of outpatient therapy. METHODS: In a multicenter, randomized clinical trial, we evaluated the efficacy of oral versus initial intravenous therapy in 306 children 1 to 24 months old with fever and urinary tract infection, in terms of short-term clinical outcomes (sterilization of the urine and defervescence) and long-term morbidity (incidence of reinfection and incidence and extent of renal scarring documented at 6 months by 99mTc-dimercaptosuccinic acid renal scans). Children received either oral cefixime for 14 days (double dose on day 1) or initial intravenous cefotaxime for 3 days followed by oral cefixime for 11 days. RESULTS: Treatment groups were comparable regarding demographic, clinical, and laboratory characteristics. Bacteremia was present in 3.4% of children treated orally and 5.3% of children treated intravenously. Of the short-term outcomes, 1) repeat urine cultures were sterile within 24 hours in all children, and 2) mean time to defervescence was 25 and 24 hours for children treated orally and intravenously, respectively. Of the long-term outcomes, 1) symptomatic reinfections occurred in 4.6% of children treated orally and 7.2% of children treated intravenously, 2) renal scarring at 6 months was noted in 9.8% children treated orally versus 7.2% of children treated intravenously, and 3) mean extent of scarring was approximately 8% in both treatment groups. Mean costs were at least twofold higher for children treated intravenously ($3577 vs $1473) compared with those treated orally. CONCLUSIONS: Oral cefixime can be recommended as a safe and effective treatment for children with fever and urinary tract infection. Use of cefixime will result in substantial reductions of health care expenditures.

The compensatory anti-inflammatory cytokine interleukin 10 response in pediatric sepsis-induced multiple organ failure.

STUDY OBJECTIVES: To determine the circulating anti-inflammatory cytokine interleukin 10 (IL-10) response during the development of sepsis-induced multiple organ failure in children. DESIGN: Prospective study. SETTING: University pediatric ICU. PATIENTS: Fifty-three consecutive children with sepsis and 15 critically ill children without sepsis. INTERVENTIONS: Plasma IL-10, interleukin 6 (IL-6), and nitrite+nitrate (stable end products of nitric oxide) levels and an organ failure index (OFI indicating the number of failing organ systems) were determined in 53 children on days 1 to 3 of sepsis and in control children on day 1. The effect of exogenous human IL-10 or neutralizing IL-10 antibody on supernatant IL-6 levels in ex vivo whole blood culture from 17 children on day 1 of sepsis. MEASUREMENTS AND RESULTS: Children with three or more organ failures had higher plasma IL-10 levels than children with less than 3 organ failures (days 1 and 3; p<0.05). Children who developed sequential pulmonary/hepatic/renal failure had higher IL-10 levels (days 1 to 3; p<0.05). Nonsurvivors had higher IL-10 levels (day 3; p<0.05). IL-10 levels correlated with IL-6 levels (days 1 and 2) and nitrite+nitrate levels (days 1 and 3; p<0.05). Whole blood samples incubated ex vivo with exogenous recombinant human IL-10 had decreased supernatant IL-6 levels (p<0.05) and neutralizing IL-10 antibody showed no significant effect. CONCLUSION: A persistent compensatory anti-inflammatory cytokine response characterizes sepsis-induced multiple organ failure. Administration of exogenous IL-10 may inhibit the early proinflammatory response; however, identification of individual immune responsiveness and possibility of persistent infection could be important to rational use in the later stages of pediatric sepsis.

Plasma leptin in children: relationship to puberty, gender, body composition, insulin sensitivity, and energy expenditure.

Leptin has been demonstrated to reflect body fat mass (FM) in humans, but the regulation of leptin levels during childhood growth and development is poorly understood. We studied the relation between plasma leptin, fasting insulin, insulin sensitivity, and resting energy expenditure in 22 healthy prepubertal children and 27 adolescents. Body composition was assessed by the H2(18)O-dilution principle, insulin sensitivity by a hyperinsulinemic (40 mU/m2/min)-euglycemic clamp, and energy expenditure by indirect calorimetry. Plasma leptin in prepubertal children (9.3 +/- 2.0 ng/mL) was not different from that in pubertal adolescents (10.9 +/- 2.2 ng/mL). Plasma leptin correlated with FM (r = .77, P < .001). There were no gender differences in leptin after controlling for FM differences. In prepubertal and pubertal subjects, plasma leptin correlated with fasting insulin independently of FM (r = .60, P < .001), but did not correlate with insulin sensitivity independently of body fat content. Leptin showed no relationship to resting energy expenditure after adjusting for body composition. The present cross-sectional evaluation of normal children shows that (1) plasma leptin reflects body fat content, (2) leptin concentrations are similar between prepubertal children and pubertal adolescents, (3) there are no gender differences in leptin independent of adiposity, and (4) leptin correlates with fasting insulin but not with insulin sensitivity. Contrary to animal data, our cross-sectional results in healthy children do not suggest a role for leptin in puberty or a female-related leptin resistance as reported in adults. It remains to be determined at which stage of human development the sexual dimorphism in leptin becomes evident.

Influence of family functioning and income on vaccination in inner-city health centers.

OBJECTIVES: To assess family functioning and consumer decision-making about vaccinations and to compare the results with age at vaccination. DESIGN: Self-administered survey that was mailed to parents with comparison to vaccination records from chart audits. SETTINGS: Two inner-city health centers in Pittsburgh, Pa, that receive free vaccine supplies. PARTICIPANTS: Systematic sample from the billing computer records of parents whose children were aged 2 to 4 years as of July 2, 1993. INTERVENTIONS: The survey used simplified versions of the Family Profile and the Triandis model of consumer decision-making that includes perceived consequences of vaccinations, attitude about vaccinations, social influences, and facilitating conditions (eg, ease of obtaining an appointment). MAIN OUTCOME MEASURES: Variables associated with age at vaccination for third diphtheria and tetanus toxoids and pertussis vaccine immunization and first measles-mumps-rubella immunization. RESULTS: Of 395 families, 167 responded. Higher family dysfunction scores and lower family concordance scores each were associated with receiving first measles-mumps-rubella vaccination (P < or = .02) and third diphtheria and tetanus toxoids and pertussis vaccination (P < = .02) at later ages. Many (30%-54%) of the respondents reported that they knew little about the risks and benefits of vaccination. However, knowledge about vaccines was not associated with vaccination status. Those respondents with an annual income of less than $10000 received the first measles-mumps-rubella vaccination later than those with an annual income $10000 or greater (P < .02) when the data were analyzed by age at vaccination but not when the data were analyzed as on-time vs late vaccinations. CONCLUSIONS: To increase vaccination rates in innercity clinics, strategies need to consider family dysfunction and income and not merely focus on education. The use of age at vaccination as a continuous variable offers advantages over the dichotomy of immunized vs not immunized.

Naltrexone in young autistic children: a double-blind, placebo-controlled crossover study.

OBJECTIVE: This study evaluated the efficacy and safety of naltrexone, an opiate blocker, in the treatment of autism. METHOD: Thirteen children with autistic disorder, aged 3.4 to 8.3 years (mean 5.4), were studied in home, school, and outpatient laboratory. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, placebo-controlled crossover design. Dependent measures included parent and teacher Clinical Global Impressions (CGI), Conners Rating Scales, and Naltrexone Side-Effects (SE) Rating Scale; laboratory CGI, movement actometer readings, and a 10-second interval recording system analysis of on-task, communication initiations, disruptive behavior, and self-stimulation. RESULTS: Eight of 13 subjects improved in two or more settings. Changes in parent measures (CGI, Conners Impulsivity-Hyperactivity Factor, and SE-Restlessness) and Teacher CGI achieved statistical significance. Teacher SE-Restlessness and initiation of communication in the clinic showed a trend toward improvement. Actometer readings improved in two children who were very active at baseline. Adverse side effects were behavioral, mild, and transient. Administering the bitter tablet was a challenge. CONCLUSIONS: Naltrexone offers promise as an agent for modest improvement of behavior and social communication in young children with autism. Parent and teacher measures can be useful in outpatient trials to evaluate change.

Naltrexone in young autistic children: replication study and learning measures.

OBJECTIVE: This study expanded upon previous work on naltrexone efficacy and safety in young autistic children and assessed performance on learning measures. METHOD: Eleven children with autistic disorder, aged 3.0 to 8.3 years, were studied in home, school, and outpatient laboratory, bringing to 24 the combined study sample. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, crossover design. Dependent measures were parent and teacher Clinical Global Impressions (CGI) and Naltrexone Side Effects Rating Scale (SE), Conners Parent Impulsivity/Hyperactivity Factor, Teacher Hyperactivity Factor, laboratory CGI, and analysis of videotaped behavior. Learning measures were the Early Intervention Developmental Profile-Language and paired-associate learning. RESULTS: Comparisons between naltrexone and baseline, but not naltrexone and placebo, on parent and teacher ratings showed statistical significance. Three of 11 subjects improved in two or more settings. Side effects were mild. Administering naltrexone was a challenge. The combined study sample showed improvement on all parent measures and on Teacher CGI and SE-Restlessness compared with baseline and placebo. Eleven of the 24 children improved in two or more settings. Scores on learning measures did not change across conditions. CONCLUSIONS: Naltrexone was associated with modest improvement of behavior in 11 of 24 children, but learning did not improve.

Prediction of response to methylphenidate among children with ADHD and mental retardation.

OBJECTIVE: The primary purpose of this study was to predict stimulant medication response among children with attention-deficit hyperactivity disorder (ADHD) and mental retardation (MR). METHOD: Forty-seven children with ADHD and MR (IQs of 48 to 77) served as subjects; ages ranged from 6.1 to 12.5 years. Subjects participated in a double-blind, placebo-controlled study of two doses of methylphenidate (0.3 and 0.6 mg/kg per dose) and a placebo. Data were collected in each child's weekday classroom and a Saturday laboratory classroom. Stepwise multiple regression analyses were used to predict drug responses in both settings. RESULTS: Higher parent ratings of impulsivity and activity level at baseline were associated with greater gains in weekday classroom dependent measures. Similarly, higher weekday teacher measures of activity level, impulsivity, inattention, and conduct problems at baseline were related to improvement on Saturday laboratory classroom dependent measures. Finally, gender, race, and socioeconomic status (SES) were found to be important predictors, with males, Caucasian subjects, and subjects from families of higher SES more likely to evidence clinical gains on a number of variables than other subjects. CONCLUSION: These results were generally consistent with research conducted among children with ADHD but without MR. However, factors such as race and conduct problems appear to have predictive utility specific to children with MR.