Open-label use of placebos in the treatment of ADHD: a pilot study.

BACKGROUND: This study examined short-term efficacy, side effects and acceptability of a placebo treatment procedure designed to maintain children with attention deficit hyperactivity disorder (ADHD) on 50% of their usual stimulant dose. METHODS: An open-label prospective crossover trial was conducted in 26 children with ADHD, ages 7-15 years, stable on stimulant therapy, followed at a community-based developmental paediatrics ADHD clinic. Subjects were randomly assigned to one of two orders of experimental conditions: (1) baseline (100%) dose (1 week), then 50% dose (1 week), then 50% dose + placebo (1 week), or (2) baseline (100%), then 50% dose + placebo, then 50% dose. The inert nature of the placebo was fully disclosed to parent and child. Treatment was open-label for child, parents and physician, but single blind for teachers. Main outcome measures included weekly IOWA Conners parent and teacher rating scales, the Pittsburgh side effects rating scale (PSERS) and the Clinical Global Impressions (CGI) scale. RESULTS: Parent IOWA showed ADHD behaviour tended to remain the same when the dose of stimulant medication was reduced with placebo but to deteriorate when the dose was reduced without placebo. There were no significant differences between conditions on the Teacher IOWA. PSERS scores were higher at baseline than on 50% dose. On the CGI, there was a significant difference (P = 0.004) between the 50% dose and the 50% + placebo conditions. Individual subject analysis showed that eight subjects met criteria for responder. CONCLUSIONS: Results indicate that the open-label placebo treatment was acceptable and efficacious in the short term for some children.

Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma.

Caspase 8 is a key apoptotic factor in the receptor/ligand apoptosis-signaling cascade. Absent caspase 8 expression is shown to correlate with poor prognosis in neuroblastoma. Paradoxically, the caspase 8 gene can produce as plice variant and novel inhibitor of itself-caspase 8l. The presence of caspase 8 alone in tumors may not necessarily portend a good prognosis. We sought to determine whether caspase 8l is present in neuroblastoma and whether over-expression of this protein could inhibit caspase 8-dependent apoptosis. Six of 6 histologically undifferentiated and 2 of 5 differentiated neuroblastoma tumors expressed the caspase 8l isoform, whereas caspase 8l was absent in 3 of 3 ganglioneuromas. Seven human neuroblastoma cell lines were surveyed. Two of the 5 cell lines that expressed caspase 8 also expressed the caspase 8l isoform and both were of a less differentiated neuronal phenotype. Over-expression of caspase 8l in cell lines afforded protection against TRAIL, but not against etoposide induced apoptosis. Conversely, blockade of Caspase 8l in cells that express this splice variant made them more sensitive to apoptosis induced cell death. We demonstrate the caspase 8l isoform is present in neuroblastoma and appears to be associated with undifferentiated cell lines and tumors. Furthermore, it suppresses caspase 8-dependent apoptosis.

Response of the cricothyroid and thyroarytenoid muscles to stereotactic injection of substance P into the region of the nucleus tractus solitarius in developing dogs.

Substance P (SP), a putative sensory neurotransmitter, mediates reflex laryngeal adductor activity in developing dogs. Such reflex activity includes life-threatening laryngospasm induced by stimulation of distal esophageal afferent nerves. The site of SP's activity is unknown. This research was undertaken to determine whether injection of SP into the nucleus tractus solitarius (NTS) of developing beagles alters laryngeal adductor motor activity. Six animals, 57 to 78 days of age, underwent stereotactic injection of 5 to 10 microL of SP into the region of the NTS, identified by electrical stimulation of the ipsilateral superior laryngeal nerve. In 8 additional studies, SP was injected into the cerebellum (2) or brain stem (6) distant from the NTS. Cardiovascular and electromyographic (EMG) responses of the diaphragm and the cricothyroid (CT) and/or thyroarytenoid (TA) muscles were recorded in all 6 animals. Injection of SP into the region of the NTS induced a decrease in blood pressure in all animals and an increase in either ipsilateral CT or TA activity. Three of these animals experienced mixed apnea characterized by sustained EMG activity (spasm) of the ipsilateral CT or TA muscles and an absence of diaphragm EMG activity. The apnea event was fatal in 1 of these animals. In the 6 animals who underwent injections in the brain stem but outside the region of the NTS, diaphragm and laryngeal EMG activity generally did not change after injection of SP, with the exception of 1 animal who experienced a mild, short-lived increase in ipsilateral CT activity. A brief phasic increase in ipsilateral CT activity was seen in both animals who underwent injection of SP into the cerebellum. A putative sensory neurotransmitter, SP evokes ipsilateral CT and/or TA EMG activity when injected into the region of the NTS in developing beagle dogs. This research suggests that SP in the NTS may play a role in mediating life-threatening laryngeal adductor reflexes in developing mammals and may provide important information regarding therapeutic intervention.

Value of pH probe testing in pediatric patients with extraesophageal manifestations of gastroesophageal reflux disease: a retrospective review.

Extended pH probe testing is often performed in patients believed to have extraesophageal symptoms of gastroesophageal reflux disease (GERD), although for this indication its diagnostic value is not well established. A retrospective review of all patients who underwent pH probe testing between 1994 and 1998 was conducted to determine the outcome of antireflux therapy in the subgroup with probable extraesophageal symptoms of GERD. Sixty-eight patients underwent antireflux therapy and had adequate follow-up after pH probe testing to be included in the study. Fifty-eight patients (85%) responded to antireflux therapy (improved, 44%; cured, 41%). The positive predictive value of distal pH probe testing was greater than 90%, but the negative predictive value was less than 50%. The reproducibility of pH probe testing on different study days was poor, but pH probe testing was helpful in assessing the adequacy of antireflux therapy. The presence of gastrointestinal symptoms did not correlate with the response of extraesophageal symptoms to antireflux therapy. Thirteen patients underwent double-probe pH studies. The mean percent time the pH was less than 4 in the upper esophagus was 2.6% (range, 1% to 9.6%). Twelve of these patients were improved or cured with antireflux therapy. Distal pH probe testing is of limited benefit in predicting whether patients with extraesophageal symptoms of GERD will respond to antireflux therapy. If extraesophageal symptoms of GERD are suspected, patients should undergo an empiric trial of antireflux therapy. Distal pH probe testing should be reserved for assessing the adequacy of antireflux therapy if symptoms persist. A prospective, randomized, controlled study will aid in determining the predictive value of double-probe pH studies in pediatric patients with probable extraesophageal symptoms of GERD.

Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder.

BACKGROUND: Secretin is a peptide hormone that stimulates pancreatic secretion. After recent publicity about a child with autism whose condition markedly improved after a single dose of secretin, thousands of children with autistic disorders may have received secretin injections. METHODS: We conducted a double-blind, placebo-controlled trial of a single intravenous dose of synthetic human secretin in 60 children (age, 3 to 14 years) with autism or pervasive developmental disorder. The children were randomly assigned to treatment with an intravenous infusion of synthetic human secretin (0.4 microg per kilogram of body weight) or saline placebo. We used standardized behavioral measures of the primary and secondary features of autism, including the Autism Behavior Checklist, to assess the degree of impairment at base line and over the course of a four-week period after treatment. RESULTS: Of the 60 children, 4 could not be evaluated - 2 received secretin outside the study, and 2 did not return for follow-up. Thus, 56 children (28 in each group) completed the study. As compared with placebo, secretin treatment was not associated with significant improvements in any of the outcome measures. Among the children in the secretin group, the mean total score on the Autism Behavior Checklist at base line was 59.0 (range of possible values, 0 to 158, with a larger value corresponding to greater impairment), and among those in the placebo group it was 63.2. The mean decreases in scores over the four-week period were 8.9 in the secretin group and 17.8 in the placebo group (mean difference, -8.9; 95 percent confidence interval, -19.4 to 1.6; P=0.11). None of the children had treatment-limiting adverse effects. After they were told the results, 69 percent of the parents of the children in this study said they remained interested in secretin as a treatment for their children. CONCLUSIONS: A single dose of synthetic human secretin is not an effective treatment for autism or pervasive developmental disorder.

American Academy of Pediatrics. Committee on Children with Disabilities. The treatment of neurologically impaired children using patterning.

This statement reviews patterning as a treatment for children with neurologic impairments. This treatment is based on an outmoded and oversimplified theory of brain development. Current information does not support the claims of proponents that this treatment is efficacious, and its use continues to be unwarranted.

American Academy of Pediatrics. Committee on Children With Disabilities. Care coordination: integrating health and related systems of care for children with special health care needs.

Care coordination is a process that links children with special health care needs and their families to services and resources in a coordinated effort to maximize the potential of the children and provide them with optimal health care. Care coordination often is complicated because there is no single entry point to multiple systems of care, and complex criteria determine the availability of funding and services among public and private payers. Economic and sociocultural barriers to coordination of care exist and affect families and health care professionals. In their important role of providing a medical home for all children, primary care pediatricians have a vital role in the process of care coordination, in concert with the family.

Effect of intravenous calcitonin gene-related peptide antagonist on the laryngeal chemoreflex in piglets.

The laryngeal chemoreflex (LCR) is characterized by mixed apnea and cardiovascular instability and is elicited by applying water to the laryngeal mucosa of developing animals. The LCR may be fatal in very young animals, and the reflex has been postulated as a possible mechanism of sudden infant death syndrome. Several antagonists have been found to alter the severity of the LCR, but the primary neurotransmitters involved in mediating the reflex response are not yet well understood. This study investigates the effect, on the LCR, of the pharmacologic antagonism of calcitonin gene-related peptide (alphaCGRP), a neurochemical found in abundance in the mammalian laryngeal mucosa and its innervating system. The LCR was elicited in 10 mixed breed piglets, 17.7 days of age (12 to 22 days), before and during infusion of alphaCGRP 8-37, a pharmacologic inhibitor of alphaCGRP, and cardiorespiratory and laryngeal responses were compared. The duration of obstructive apnea decreased from 17.9 to 9. 8 seconds (P < 0.03) in the presence of alphaCGRP 8-37. Mean central apnea did not change for the group (P > 0.05), although it was completely inhibited in 2 animals. Cardiovascular changes were not significantly altered by the alphaCGRP inhibitor. alphaCGRP appears to play a regulatory role in the apneic response of the LCR, particularly its obstructive component, but not the cardiovascular response.

Assessment of an itinerant medical evaluation program for school dysfunction.

This paper describes an itinerant medical evaluation (IME) project and reports on the outcome of 108 consecutive referrals made in the first year. Subjects were of ages 5 to 17 years. Most students had been evaluated by the schools but were not receiving special education or related services. IME led to clinical diagnosis of ADHD in 70% of the sample, and specific learning disabilities were diagnosed in 26%. Several other clinically significant and educationally relevant diagnoses were made. As a result of the IME, many students were placed in special education and/or began to receive related services. At three-month follow-up, classroom accommodations were being made for 97% of the students. Teachers reported they felt more capable of teaching challenging students as a result of the IME. Significant improvements occurred in hyperactivity, conduct problems, and inattention, and grades improved in 31% of the sample. Reasons for the project's success are discussed.

Unsuccessful air-enema reduction of intussusception: is a second attempt worthwhile?

Pneumatic reduction of idiopathic intussusception is successful in about 80% of cases, while 60% of the failures are reduced at surgery without resection. To determine whether delayed, repeated attempts at enema reduction of failures would reduce the need for operation in selected cases, over a 2-year period (1994-1996 inclusive), 17 infants with idiopathic intussusception underwent delayed repeat enemas 2-19 h following the first failed attempt at reduction. Clinical parameters and radiologic findings were evaluated with respect to outcome. Ten intussusceptions were successfully reduced after the second attempt in 9 and after the fourth attempt in 1. Seven children underwent a laparotomy, 5 because of failure of progressive reduction at air enema (AE). Two were taken to surgery early in the series, 1 because of perforation during a second attempt and 1 while awaiting a third reduction attempt. The 10 successful reductions all showed progressive movement of the intussusceptum on each AE; the 2 who perforated failed to show progressive reduction on their second AE. Because of these cases, the remaining 5 were referred to surgery because of failure of progressive reduction of the intussusceptum on the second attempt. At laparotomy, of the 7 unsuccessful reductions, 4 required resection and 3 had difficult manual reduction. The presence of vomiting, a mass, and/or bloody stools were not predictors of outcome. Failures had higher body temperatures (38.1 +/- 0.3 vs 37.4 +/- 0.1 degrees C, P = 0.07), heart rates (153.7 +/- 8 vs 136.9 +/- 2.1 min, P = 0.03), and longer duration of symptoms (36.8 +/- 4 vs 21.3 +/- 3.6 h; P = 0.01) than successes. Delayed repeat AEs may be safe and effective in selected cases of idiopathic intussusception, but should be considered only if significant movement of the intussusceptum is noted at each attempt. The ideal time for repeat AE reduction prior to surgery is not established, but 2-4 h appears appropriate. Pyrexia, tachycardia, and duration of symptoms greater than 36 h are relative contraindications to this course of management.

Effect of intravenous substance P on laryngeal adductor activity in young dogs.

Reflex laryngeal adduction is a component of both the laryngeal chemoreflex and the esophagolaryngeal adductor reflex, two life-threatening reflexes that occur in immature animals. These two reflex responses are also thought to exist in infants and may play a role in causing life-threatening laryngospastic events and perhaps sudden infant death syndrome. Identifying neurotransmitters that mediate laryngeal adduction is important to understanding the mechanism of reflex laryngeal responses and to identifying potential means of pharmacologic prevention. Substance P (SP), a tachykinin, putatively functions as a sensory neurotransmitter and may play a role in mediating laryngeal reflexes. Substance P-immunoreactive-like fibers and receptors are present in the subepithelial tissues of the larynx, the vagus nerves, the nodose and jugular ganglia, and the vagal brain stem nuclei. In this investigation, the effect of SP infusion on laryngeal motor activity in an in vivo model is reported. Substance P was infused intravenously into 8 puppies (20 to 133 days of age, mean 81.2), on a mean of 3.0 occasions (range 1 to 6). Cardiovascular, respiratory, arterial blood gas, and cricothyroid (CT), thyroarytenoid (TA), and genioglossus electromyographic (EMG) responses to infusion of the tachykinin were recorded and subsequently analyzed. The SP infusion induced a marked increase in CT or TA EMG activity in 23 of 24 studies, and the increase was typically apparent within 60 seconds of the infusion. An increase in genioglossus EMG activity did not occur. An immediate, profound decrease in mean arterial pressure and an increase in respiratory rate and depth of chest wall excursion accompanied the laryngeal response. Arterial blood gas values remained unchanged (p > .05). The laryngeal adductor response to SP infusion was blocked when animals were pretreated with a systemic SP antagonist (Pfizer CP-96,345). This study demonstrates that peripheral infusion of the tachykinin SP induces a marked increase in laryngeal adductor activity. The response may be blocked by pretreatment of animals with a systemic SP antagonist. Because SP is thought to act primarily as a sensory neurotransmitter, these findings may be important in understanding the mechanism of reflex laryngeal adductor responses.

Role of substance P in the laryngeal chemoreflex.

The laryngeal chemoreflex (LCR) is a potentially life-threatening reflex that is elicited in immature animals by the topical application of water to the laryngeal mucosa. The reflex response is characterized by immediate apnea and laryngeal adduction and delayed cardiovascular instability. The cardiorespiratory changes of the LCR may be life-threatening, particularly in very immature animals such as piglets under 2 weeks of age. The afferent and efferent limbs of the LCR are mediated through the vagus nerve, but the neuromediators responsible for the reflex changes have not yet been clearly elucidated. Previous agonist and antagonist studies in immature dogs demonstrated that substance P, a sensory tachykinin, mediates the life-threatening esophagolaryngeal adductor reflex elicited by distal esophageal sensory nerve stimulation. This study was conducted to determine if substance P also plays a role in mediating the LCR. The LCR response was compared before and after treatment with intravenous substance P antagonist (Pfizer CP-96,345-1) in eight piglets (mean 27.7 days of age). The laryngeal and cardiovascular responses of the animals following intravenous administration of the tachykinins substance P, neurokinin A, and neurokinin B were also assessed. Pretreatment with substance P antagonist did not alter the LCR's duration of apnea (p > .10), laryngeal adductor response, or early change in mean arterial pressure (p > .10), although the early maximal heart rate response was significantly altered (p < .01). Intravenous substance P, neurokinin A, and neurokinin B did not reproduce the laryngeal respiratory response of the LCR. We conclude that substance P, neurokinin A, and neurokinin B are not key neurotransmitters of the LCR.

To tube or not to tube: do infants and children need post-laparotomy gastric decompression?

The purpose of this study was to evaluate the role of nasogastric (NG) decompression after laparotomy in pediatric surgical practice: 94 children who underwent abdominal surgery by a single surgeon were consecutively prospectively managed without postoperative NG tubes. Patients with either bowel obstruction or intra-abdominal infection were excluded from the study. These children were compared with 94 retrospective, matched controls who were routinely managed with postoperative NG decompression by the same surgeon. Data were analyzed with regard to patient, operative, and outcome variables. There was no difference in gender, age (3.8 +/- 0.5 vs 3.5 +/- 0.4 years, P > 0.7), or postoperative complications (P > 0.8) between the two groups. However, there was a higher incidence of postoperative vomiting (22% vs 11%, P > 0.05) in the children who did not have postoperative NG decompression. Nevertheless, a significant decrease in time to first feed, first stool, and discharge was noted in the group of patients managed without NG tubes (P < 0.05). NG decompression thus need not be routinely used in the pediatric patient undergoing abdominal surgery, as there is no difference in postoperative complications and the hospital stay is shortened.

Neurodevelopmental dysfunction among nonreferred children with idiopathic megalencephaly.

PURPOSE: To determine whether nonreferred children with idiopathic megalencephaly show evidence of specific neurodevelopmental dysfunction compared with sibling control subjects and age-matched control subjects. DESIGN: Cross-sectional, case-control study in a large, suburban pediatric practice. Subjects included 20 children between the ages of 6 and 15 years with a head circumference at greater than the 98th percentile, 19 siblings of these children with normalsize heads, and 16 age-matched control subjects. Standardized tests of language, academic achievement, visuomotor integration, motor function, and neurodevelopmental function were administered. RESULTS: Multivariate analysis, with control for age, showed a main effect for the presence of megalencephaly (F = 3.2; p < 0.05). Follow-up univariate analyses, with control for age, showed that children with megalencephaly had poorer performance on tasks of upper limb speed, visuomotor control, running speed, bilateral coordination, visuomotor integration, naming fluency, and minor neurologic indicators. CONCLUSION: The relationship between idiopathic megalencephaly and external hydrocephalus in infants is discussed. Results show that so-called "benign" idiopathic megalencephaly in nonreferred school-age children appears to be a clinical entity associated with subtle motor problems and neurodevelopmental dysfunction.

The impact of a previous Kasai procedure on liver transplantation for biliary atresia.

The usual treatment for biliary atresia is a Kasai procedure followed by liver transplantation when indicated. Although primary transplantation for biliary atresia without a previous Kasai procedure is occasionally advocated, it is rarely performed. This review was undertaken to evaluate the impact of a Kasai procedure on the morbidity and mortality of patients who went on to need a liver transplant. Sixty-three patients with biliary atresia were included in this review. Fifty seven patients underwent transplantation: eight patients had a liver transplant only (group 1), and 49 patients underwent a Kasai procedure before transplantation (group 2). Six patients died before receiving a transplant. Time spent on the waiting list for liver transplant was longer in group 2 than in group 1 (170.3 +/- 24.6 days versus 63.3 +/- 7.1 days, P < .05). The patients in group 1 were younger (0.7 +/- 0.2 versus 2.3 +/- 0.4 years) and smaller (6.9 +/- 0.4 kg versus 11.6 +/- 1.2 kg) than the patients in group 2 (P = .07). There was no difference in pretransplant urgency status between the two groups. The mean duration of the transplant operation was shorter in group 1 patients (476.8 +/- 53.3 minutes) compared with group 2 (593.9 +/- 29.3 minutes, P = .06). Group 1 patients received 199.8 +/- 46.2 mL/kg blood transfusion intraoperatively, and group 2 patients had twice that amount, 466 +/- 122.5 mL/kg. No patients in group 1 experienced postoperative bowel perforations or required reoperation for bleeding. In group 2 however, 11 of 49 (22.4%) experienced bowel perforations and 7 of 49 (14.2%) required reoperation for bleeding. There was no difference in nonsurgical complications between the two groups. Long-term survival was equal in the 2 groups: six of eight patients (75%) in group 1 and 36 of 49 (74%) in group 2. The marked increase in complications noted in group 2 patients did not reach statistical significance because of the much smaller number of patients in group 1. These results suggest that patients with biliary atresia have fewer complications after transplantation if a Kasai procedure is not performed before the transplant, and that a more careful selection of surgical options available in treating patients with biliary atresia is required.

Biliary atresia: should all patients undergo a portoenterostomy?

PURPOSE: The management of noncorrectable extra hepatic biliary atresia includes portoenterostomy, although the results of the surgery are variable. This study was done to develop criteria that could successfully predict the outcome of surgery based on preoperative data, including percutaneous liver biopsy, allowing a more selective approach to the care of these babies. METHODS: The charts and biopsy results of 31 patients who underwent a Kasai procedure for biliary atresia between 1984 and 1994 were reviewed. Values for preoperative albumin, bilirubin, age of patient at Kasai, and lowest postoperative bilirubin were recorded. Surgical success was defined as postoperative bilirubin that returned to normal. A pathologist blinded to the child's eventual outcome graded the pre-Kasai needle liver biopsy results according to duct proliferation, ductal plate lesion, bile in ducts, lobular inflammation, giant cells, syncitial giant cells, focal necrosis, bridging necrosis, hepatocyte ballooning, bile in zone 1, 2, and 3, cholangitis, and end-stage cirrhosis. Clinical outcome was then predicted. RESULTS: Success after portoenterostomy could not reliably be predicted based on gender, age at Kasai, preoperative bilirubin or albumin levels. Histological criteria, however, predicted outcome in 27 of 31 patients (P < .01). Fifteen of 17 clinical successes were correctly predicted; as were 12 of 14 clinical failures (sensitivity, 86%; specificity, 88%). Individually, the presence of syncitial giant cells, lobular inflammation, focal necrosis, bridging necrosis, and cholangitis, were each associated with failure of the portoenterostomy (P < .05). Bile in zone 1 was associated with clinical success of the procedure (P < .05). CONCLUSIONS: Based on the predictive information available in a liver biopsy, we conclude that those patients who will not benefit from a Kasai procedure can be identified preoperatively, and channeled immediately to transplantation.

Sexual function and erection capability among young men with spina bifida.

In a study of sexual function and erection capability, 15 young men with spina bifida were interviewed, underwent physical examination, and completed two consecutive night recordings of penile tumescence and rigidity with the Rigi-Scan (Dacomed Inc.). Eleven reported erections with stimulation. Rigi-Scan data showed that two subjects (both with lesions at the sacral level) had normal numbers and durations of erections, that seven others had abnormally brief and infrequent nocturnal erections, and that six had none. Ten subjects had at least 'some' glans sensation on physical examination. Self-reported erection capability was related to motor level and glans sensation. The number of nocturnal erections was related to sensory level. The study suggests that lower motor and sensory levels are associated with greater potential sexual function in males with spina bifida.

Respiratory manifestations of gastroesophageal reflux disease in pediatric patients.

Respiratory manifestations of gastroesophageal reflux disease (GERD) are being recognized with increasing frequency. We present the evaluation and management of four infants and children with unusual respiratory symptoms attributed to GERD. The advantages and disadvantages of diagnostic studies of GERD are discussed, and an evaluation and treatment protocol is presented. Treatment must be tailored to the nature and severity of the patient's presenting symptoms and includes conservative, pharmacologic, and/or surgical management.