Effect of secretin on children with autism: a randomized controlled trial.

To determine the effect of intravenous porcine secretin on autistic behaviours in children aged 2 to 7 years, the effects of secretin on (1) performance on a standardized language measure, and (2) autistic behaviours, as rated by parents and child development professionals was examined. Employing a randomized, double-blind, placebo-controlled design, 95 participants were assigned to one of two groups and administered a single dose of either secretin or placebo. A follow-up assessment was conducted 3 weeks after the injection. No significant differences in language or autistic behaviour measures were observed at the 3-week follow-up between the groups. Also, there was no significant difference in the proportion of individuals who improved by > or = 6 points on the language measure at follow-up. This study showed no significant effects of secretin on children with autism. Our results are consistent with a systematic review of randomized controlled trials evaluating the effect of secretin in children with autism.

Performance of the ImmunoCard STAT! E. coli O157:H7 test for detection of Escherichia coli O157:H7 in stools.

ImmunoCard STAT! E. coli O157:H7 (Meridian Diagnostics, Inc., Cincinnati, Ohio) is a novel rapid (10-min) test for the presence of Escherichia coli O157:H7 in stools. The test may be performed either directly on stool specimens or on an overnight broth culture of stool. In a multicenter prospective study, 14 of 14 specimens positive by culture for E. coli O157:H7 were positive by the ImmunoCard STAT! O157:H7 test, and there were no false positives from 263 culture-negative specimens. In a retrospective study, the test was positive in 339 (81%) of 417 stored culture-positive specimens and the specificity was 95% (98 of 103 specimens). No false positives were associated with alternate stool pathogens. The ImmunoCard STAT! O157:H7 test has high sensitivity and specificity.

Circulating inflammatory cytokine levels in hemolytic uremic syndrome.

Experimental data suggest that the host's inflammatory response is involved in the pathophysiology of verotoxin-producing Escherichia coli (VTEC)-associated hemolytic uremic syndrome (HUS). We compared the circulating levels of pro- [interleukin (IL)-6, IL-8] and anti-inflammatory [IL-10 and IL-1 receptor antagonist (Ra)] mediators on enrollment among children with HUS due to E. coli O157:H7, according to the severity of renal dysfunction. The latter was evaluated by the occurrence of oligoanuria, the requirement for dialysis, and a glomerular filtration rate (GFR)

Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation.

Infantile nephropathic cystinosis, an autosomal recessive disease characterized by a lysosomal accumulation of cystine, presents as failure to thrive, rickets and proximal renal tubular acidosis. The cystinosis gene, CTNS, which maps to chromosome 17p13, encodes a predicted 55 kDa protein with characteristics of a lysosomal membrane protein. We have conducted extensive linkage analysis in a French Canadian cystinosis cohort identifying a founding haplotype present in approximately half (21/40) of the chromosomes studied. Subsequent mutational analysis, in addition to identifying two novel mutations, has unexpectedly revealed a mutation which has been previously found in Irish (but not French) cystinotic families on these 21 French Canadian chromosomes. Haplotype analysis of two Irish families with this mutation supports the hypothesis that Celtic chromosomes represent an extensive portion of cystinosis chromosomes in French Canada. Our analysis underlines the genetic heterogeneity of the French Canadian population, reflecting a frequently unrecognized contribution from non-Gallic sources including the Irish.

Neuropsychological sequelae of haemolytic uraemic syndrome. Investigators of the HUS Cognitive Study.

BACKGROUND: Severe haemolytic uraemic syndrome (HUS) in childhood can cause stroke, hemiplegia, cortical blindness, and psychomotor retardation. These outcomes are evident at the time of discharge immediately after the acute illness. Less is known about the neuropsychological outcomes of less severely affected children who recover from acute HUS. AIMS: This multicentre case control study investigated the hypothesis that children who survive an acute episode of HUS without recognizable neurological injuries have greater impairment of cognitive, academic, and behavioural functions than controls. DESIGN: Children with HUS were eligible if they had no evidence of severe neurological dysfunction when discharged from one of six Canadian hospitals. Controls had been admitted to hospital for a non-HUS illness and were matched by age, sex, first language, and socioeconomic status. All subjects underwent evaluation of behaviour, academic achievement, cognitive function, and verbal abilities using standardised tests administered by a psychometrist blinded to the case or control status. RESULTS: Ninety-one case control pairs were enrolled. No important differences between patients with HUS and paired controls were evident on tests of IQ, behaviour, verbal abilities, or academic achievement. There was no increased risk of attention deficit disorder among patients with HUS. There was no correlation between the severity of acute renal failure and neuropsychological measures, although scores on some verbal ability tests were lower in those with the highest serum creatinine concentrations during illness. CONCLUSIONS: Children discharged from hospital without apparent neurological injury after an episode of acute HUS do not have an increased risk of subclinical problems with learning, behaviour, or attention.

Renal function in Inuit survivors of epidemic hemolytic-uremic syndrome.

We undertook a case-control study to evaluate the renal health of survivors of hemolytic-uremic syndrome (HUS) from the 1991 Arctic epidemic of Escherichia coli O157:H7 gastroenteritis 4 years after the epidemic. Eighteen children who developed HUS during the 1991 epidemic and 18 age- and sex-matched controls from the same community who had uncomplicated gastroenteritis were compared in 1995 for height, weight, blood pressure, urinalysis, and glomerular filtration rate (GFR), measured using continuous subcutaneous infusion of non-radioactive iothalamate. HUS survivors did not differ from controls in height, weight, systolic (HUS 118 mmHg, control 117 mmHg) or diastolic (HUS 64 mmHg, control 62 mmHg) blood pressures. Hematuria was detected more frequently in HUS survivors (11/18 vs. 4/18, P<0.05), but no child had proteinuria. Mean GFR did not differ between the two groups (HUS 159 ml/min per 1.73 m2, control 147 ml/min per 1.73 m2). Survivors of post-enteritic HUS from the 1991 Arctic E. coli 0157:H7 outbreak have excellent renal function 4 years after the epidemic.

Sensitivities and specificities of premier E. coli O157 and premier EHEC enzyme immunoassays for diagnosis of infection with verotxin (Shiga-like toxin)-producing Escherichia coli. The SYNSORB Pk Study investigators.

This study describes the performance of two rapid enzyme immunoassays, Premier E. coli O157 and Premier EHEC (Meridian Diagnostics Inc., Cincinnati, Ohio) for the detection in stools of Escherichia coli O157 and verotoxins (Shiga-like toxins), respectively. Both tests were performed on stools from 876 children presenting to eight emergency departments with diarrhea. Standard culture, including E. coli O157:H7 isolation, was performed, and paired sera were taken for anti-O157-lipopolysaccharide antibody determination. Stools from patients enrolled in the study, and those yielding discordant results, were sent to a reference laboratory for repeat testing and further investigation, including cytotoxicity and non-O157 verotoxin-producing E. coli culture. Results were classified as field results (obtained in the eight site laboratories) and resolved results (obtained after repeat testing in the central laboratory). The "gold standard" for sensitivity of both tests and for specificity of Premier E. coli O157 was isolation of E. coli O157:H7 or a fourfold anti-O157 antibody rise. Specimens positive by the Premier EHEC test and negative for E. coli O157 culture were examined for non-O157 verotoxin-producing E. coli. The field sensitivity of Premier E. coli O157 was 86%, that of Premier EHEC was 89%, and the specificity of Premier E. coli O157 was 98%. Ten of 13 discordant Premier E. coli O157 results were reassigned as true results after repeat testing. Ten non-O157 verotoxin-producing E. coli isolates were recovered from Premier EHEC-positive, E. coli O157 culture-negative stools. Only one specimen gave an unequivocally false-positive Premier EHEC result. Both tests are highly sensitive and are specific if correctly performed. The Premier EHEC test will be particularly valuable as a practical routine test for the detection of non-O157 verotoxin-producing E. coli.

Risk of hemolytic uremic syndrome after sporadic Escherichia coli O157:H7 infection: results of a Canadian collaborative study. Investigators of the Canadian Pediatric Kidney Disease Research Center.

OBJECTIVES: The objectives of this study were to better estimate the age-specific risks of hemolytic uremic syndrome (HUS) and hemolytic anemia after Escherichia coli O157:H7 infection among a representative cohort of both referred and nonreferred children with documented illness from the province of Alberta and to compare this with the rates in children evaluated at referral centers in the rest of Canada. STUDY DESIGN: Children with HUS or E. coli O157:H7 gastroenteritis were eligible if they were < 15 years of age. Hemoglobin, blood smear, urinalysis, and serum creatinine were obtained 8 to 10 days after the onset of diarrhea to ascertain for hemolysis, anemia, thrombocytopenia, and renal injury. Subjects were monitored for 1 month. RESULTS: From June 1991 to March 1994, HUS was diagnosed in 205 children. Of these 77% had evidence of E. coli O157:H7 infection. A further 582 children had E. coli O157:H7 gastroenteritis, of whom 18 had hemolytic anemia. The risk of HUS after E. coli O157:H7 infection in Alberta was 8.1% (95% confidence interval, 5.3 to 11.6) compared with 31.4% in referral centers in the rest of Canada. In Alberta the highest age-specific risk of HUS/hemolytic anemia was 12.9% in those < 5 years of age. CONCLUSIONS: These data will help guide clinical care and provide a basis for estimating the sample sizes required in future treatment trials for the secondary prevention of HUS.

A phase I study of chemically synthesized verotoxin (Shiga-like toxin) Pk-trisaccharide receptors attached to chromosorb for preventing hemolytic-uremic syndrome.

A double-blind, placebo-controlled study was conducted to document possible side effects associated with oral consumption of synthetic verotoxin (VT, shiga-like toxin) Pk-trisaccharide receptor sequences attached to Chromosorb (Synsorb-Pk) by healthy adult volunteers. Synsorb-Pk reclaimed from volunteer stool samples was also analyzed to determine if its VT-binding activity was affected by exposure to the pH extremes and digestive processes of the human gastrointestinal tract. No participant reported any Synsorb-Pk-related adverse reactions, and no clinically important trends in laboratory data were evident. Synsorb-Pk recovered from stools retained its ability to absorb VT in polymyxin extracts of VT-producing Escherichia coli and also neutralized VT when mixed in vitro with VT-positive stools from children with hemorrhagic colitis or hemolytic-uremic syndrome (HUS). These results suggest a potential use for Synsorb-Pk in preventing HUS in patients infected with VT-producing E. coli.

Epidemic Escherichia coli O157:H7 gastroenteritis and hemolytic-uremic syndrome in a Canadian inuit community: intestinal illness in family members as a risk factor.

OBJECTIVE: To evaluate risk factors for childhood hemolytic-uremic syndrome (HUS) and gastroenteritis during an epidemic of Escherichia coli O157:H7 infection. DESIGN: Case-control study. SETTING: Remote Inuit community of Arviat in northern Canada. PARTICIPANTS: Of the 565 Arviat residents less than 15 years of age, 19 had HUS and 65 more had E. coli O157:H7 gastroenteritis. The 19 children with HUS were compared with 19 age- and gender-matched children with uncomplicated E. coli O157:H7 gastroenteritis, and both HUS and gastroenteritis patients were compared with 19 healthy control subjects. INTERVENTIONS: Questionnaire administered face-to-face to parents of participants in the home. MAIN OUTCOME MEASURES: Rates of exposure to foods, travel, sources of water, and gastrointestinal illness in family members. RESULTS: Patients with HUS and those with uncomplicated E. coli O157:H7 gastroenteritis differed only on measures of clinical severity. In the 7 days before the onset of gastrointestinal symptoms, children with HUS and those with uncomplicated gastroenteritis were more likely to have been exposed to a family member with diarrhea than were the healthy control subjects (odds ratio = 9 for HUS vs healthy control subjects; 95% confidence interval 2 to 43; p < 0.01). Undercooked ground meat and foods traditionally consumed by the Inuit were not implicated as risk factors in E. coli O157:H7 infection. CONCLUSIONS: These findings emphasize the potential for extensive intrafamilial transmission of verotoxin-producing E. coli once infection is introduced into certain communities.

A prospective study of exposure to verotoxin-producing Escherichia coli among Canadian children with haemolytic uraemic syndrome. The CPKDRC co-investigators.

Haemolytic uraemic syndrome (HUS) is a leading cause of acute renal failure in childhood. Although infection with Escherichia coli O 157. H7 has been associated with HUS in North America and Europe, only a limited number of studies have examined the role of other verotoxin-producing E. coli (VTEC) serotypes in this condition. To address this issue, we conducted a comprehensive, prospective microbiological study of patients treated for HUS at eight Canadian hospitals in the summer of 1990. Of the 34 consecutive patients with HUS enrolled over 4 months, E. coli O 157. H7 was isolated from the stools of 26, and other E. coli serotypes were isolated from four patients. In four subjects no pathogenic E. coli serotypes were identified on stool culture. Using oligonucleotide probes specific for VT-1 and VT-2, verotoxin genes were detected in the stool isolates of all patients with E. coli O 157. H7, and from two with other E. coli serotypes. Two other patients had at least a fourfold rise in anti-verotoxin antibodies. Strong evidence of exposure to a verotoxin was present in 30/34 (88%). Patients with E. coli O 157. H7 infection were more likely to develop an antibody response to VT-2 than to VT-1 (22/22 vs 12/22; P = 0.002). These results further strengthen the association of HUS with verotoxin-producing E. coli in North America, and confirm that E. coli serotypes other than O 157.H7 are isolated in a small proportion of summertime HUS episodes.

Diarrhoea in close contacts as a risk factor for childhood haemolytic uraemic syndrome. The CPKDRC co-investigators.

To determine whether the risk factors for childhood haemolytic uraemic syndrome (HUS) are similar to risk factors previously reported for Escherichia coli O 157. H7 gastroenteritis, we conducted a case-control study at eight paediatric hospitals in the summer of 1990. Thirty-four consecutive children with HUS were prospectively enrolled; all had diarrhoea and 88% had laboratory evidence of exposure to verotoxin-producing E. coli (VTEC). The 102 controls were otherwise healthy children with minor acute injuries. Parents of all subjects responded to a questionnaire about each child's exposure to various foods, methods of food preparation, sources of water, travel, and individuals with diarrhoea. Children with HUS were significantly more likely than controls to have had close contact with an individual with diarrhoea in the 2 weeks before the onset of illness (74 v. 29%, P < 0.00001; odds ratio 7.0, 95% CI 2.7-18.5). The onset of diarrhoea in the contacts occurred a median of 6 days (range, 1- > 14 days) before the onset of diarrhoea in the HUS patients. Exposure to undercooked ground meat was not significantly more common in the patients with HUS (15 v. 8%; P = 0.05). These data provide evidence consistent with person-to-person transmission of VTEC in a substantial proportion of episodes of childhood HUS.

Sequelae of haemolytic uraemic syndrome.

Twenty two patients with previous episodes of haemolytic uraemic syndrome (HUS) were investigated for evidence of deficits in cognitive, behavioural, and academic function. Patients were pair matched with 22 controls for age (+/- 1 year), gender, and socioeconomic status. HUS patients had numerically lower cognitive and achievement scores and higher behavioural problem ratings than their controls on every measure. None of the group differences was significant at the 0.01 level. Significance values between 0.10 and 0.01 were obtained for the Wechsler full scale and verbal intelligence quotient scores and for several of the achievement measures and behaviour ratings. These results were conservatively interpreted as trends and are considered to provide preliminary indications of a post-HUS deficit in behaviour, verbal intelligence, and the verbally based skills of reading comprehension and vocabulary. The findings provide interim guidelines for follow up care but require confirmation and elaboration in a larger study.

Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988. The Canadian Pediatric Kidney Disease Reference Centre.

OBJECTIVE: To define the epidemiologic features of childhood hemolytic-uremic syndrome (HUS) on a national level in Canada, to determine the proportion of patients in whom Escherichia coli O157:H7 was isolated from stools, and to examine risk factors for more severe HUS. DESIGN: From January 1986 to December 1988, patients with HUS were reported prospectively to the Canadian Pediatric Kidney Disease Reference Centre, a national registry for pediatric renal disorders, or were identified retrospectively through a medical records search at participating institutions. SETTING: All children's hospitals in Canada and the children's wards of general hospitals in Canadian cities with populations greater than 350,000. PATIENTS: Two hundred twenty-six children, including 126 girls. MEASUREMENTS AND MAIN RESULTS: The average annual incidence of HUS in children younger than 15 years was 1.44 per 100,000; the peak age-specific incidence was 3.11 per 100,000 younger than 5 years. The incidence of HUS varied by region; the risk of HUS in Alberta was 2.9 times that in Ontario (p less than 0.0001). Of the 169 patients whose stools were screened, E. coli O157:H7 was isolated in 87 (51%). Risk factors for prolonged dialysis or death included young age, seizures, elevated white blood cell count at admission to hospital, and shorter, more severe prodromal illness. The rate of dialysis was higher in female patients (55% vs 39%; p = 0.02). CONCLUSIONS: HUS is relatively common in Canadian children younger than 5 years, and is strongly associated with E. coli O157:H7 infection. Reasons for the striking regional variation in the incidence of HUS and for the increased rate of dialysis in female patients are unexplained and deserve further investigation.