Autism in context 2: Assessment,intervention and services in Australia

Continuing from part 1, part 2 of the autism spectrum disorders review explores clinical practice and service delivery aspects of autism spectrum disorders including current assessment approaches in Australia, family‐centred models of care, and key service structure and delivery issues. Treatments including behavioural interventions, established and emergent medication, and complementary and alternative therapies are discussed. The key role of paediatricians as both individual child and family care providers and advocates, as well as agents of service reform in Australia, is evident. Much still needs to be done.     

Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Purpose

Endosialin/tumor endothelial marker-1 (TEM1) is an attractive theranostic target expressed by the microenvironment of a wide range of tumors, as well as by sarcoma and neuroblastoma cells. We report on the radiolabeling and preclinical evaluation of the scFv78-Fc, a fully human TEM1-targeting antibody fragment cross-reactive with mouse TEM1.

Procedures

The scFv78-Fc was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with indium-111. The number of chelators per molecule was estimated by mass spectrometry. A conventional saturation assay, extrapolated to infinite antigen concentration, was used to determine the immunoreactive fraction of the radioimmunoconjugate. The radiopharmaceutical biodistribution was assessed in immunodeficient mice grafted with Ewing’s sarcoma RD-ES and neuroblastoma SK-N-AS human TEM1-positive tumors. The full biodistribution studies were preceded by a dose-escalation experiment based on the simultaneous administration of the radiopharmaceutical with increasing amounts of unlabeled scFv78-Fc. Radiation dosimetry extrapolations to human adults were obtained from mouse biodistribution data according to established methodologies and additional assumptions concerning the impact of the tumor antigenic sink in the cross-species translation.

Results

[¹¹¹In]CHX-DTPA-scFv78-Fc was obtained with a radiochemical purity >?98 % after 1 h incubation at 42 °C and ultrafiltration. It showed good stability in human serum and >?70 % immunoreactive fraction. Biodistribution data acquired in tumor-bearing mice confirmed fast blood clearance and specific tumor targeting in both xenograft models. The radiopharmaceutical off-target uptake was predominantly abdominal. After a theoretical injection of [¹¹¹In]CHX-DTPA-scFv78-Fc to the reference person, the organs receiving the highest absorbed dose would be the spleen (0.876 mGy/MBq), the liver (0.570 mGy/MBq) and the kidneys (0.298 mGy/MBq). The total body dose and the effective dose would be 0.058 mGy/MBq and 0.116 mSv/MBq, respectively.

Conclusions

[¹¹¹In]CHX-DTPA-scFv78-Fc binds specifically to endosialin/TEM1 in vitro and in vivo. Dosimetry estimates are in the range of other monoclonal antibodies radiolabeled with indium-111. [¹¹¹In]CHX-DTPA-scFv78-Fc could be potentially translated into clinic.

     

Social Phobia Among Depressed Individuals Entering Residential Rehabilitation Programmes: Prevalence and Correlates

Social phobia commonly co-occurs with substance use disorders and depression; however, the prevalence and correlates of social phobia among individuals with both of these disorders remain unknown. Interviews were conducted with 120 individuals entering residential rehabilitation for substance use treatment, who endorsed criteria for major depression and were recruited to a randomised controlled trial. Nearly three quarters (72.5%) of the sample met diagnostic criteria for social phobia. These individuals were more likely to report problematic drinking, more severe anxiety and depressive rumination, and lower distress tolerance, compared to individuals without social phobia. When examining the impact of applying diagnostic exclusion rules for social phobia among this cohort, results indicate that one third (32.2%) of those with social phobia specified their fear was related to a co-occurring mental health and/or substance use disorder. This group—who would not have met diagnostic criteria for social phobia if exclusion rules were strictly followed—experienced more severe depression, anxiety, depressive rumination, and repetitive negative thinking than those who did not make such attributions. The high prevalence and burden associated with social phobia among depressed substance users highlight the importance of screening for, assessing, and treating the disorder upon entry to treatment, irrespective of whether symptoms are related to other conditions.

     

24-h catecholamine excretion: relationships with age and weight

24-hour urines were obtained from groups of volunteer subjects recruited from populations in the UK, USA, Nigeria and the South Pacific. Urines were collected during the course of normal daily activities. HPLC/electrochemical detection was used to measure concentrations of adrenaline and noradrenaline in each urine. Calculated 24-h output of catecholamines was tested for significant linear regression relationships with age, weight and 24-h urine volume in each population. Noradrenaline excretion tended to be positively related to age and to body wt. Adrenaline excretion tended to show little or no relationship with either age or body wt. Relationships based on catecholamine excretion/U creatinine were notably different to those based on absolute catecholamine excretion. Differences were observed in the nature and strength of the relationships in the different populations, indicating the likely importance of interactions with other factors.     

Processing of timbre and rhythm in musicians and non-musicians

Expert musicians and non-musicians of similar educational and social class background were compared in two experiments involving perception of timbre and rhythm. In Experiment 1 where dichotic monitoring for the sound of the violin was required, there was a practice effect but no ear or group differences. The rhythm monitoring experiment produced a group by ear interaction with musicians faster on the right ear than the left and faster than non-musicians on the right ear only. Analysis of strategies reported by subjects showed that verbal labelling did not apparently influence laterality. Lack of evidence for individual laterality effects reinforces the claim that with stringent experimental and subject controls there is minimal evidence for musicians non-musician laterality effects.     

Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: A transesophageal echocardiographic study

BACKGROUND: Transesophageal echocardiography (TEE) is the gold standard for evaluation of the left atrium and the left atrial appendage (LAA) for the presence of thrombi. Anticoagulation is conventionally used for patients with atrial fibrillation to prevent embolization of atrial thrombi. The mechanism of benefit and effectiveness of thrombi resolution with anticoagulation is not well defined. METHODS AND RESULTS: We used a TEE database of 9058 consecutive studies performed between January 1996 and November 1998 to identify all patients with thrombi reported in the left atrium and/or LAA. One hundred seventy-four patients with thrombi in the left atrial cavity (LAC) and LAA were identified (1.9% of transesophageal studies performed). The incidence of LAA thrombi was 6.6 times higher than LAC thrombi (151 vs 23, respectively). Almost all LAC thrombi were visualized on transthoracic echocardiography (90.5%). Mitral valve pathology was associated with LAC location of thrombi (P <.0001), whereas atrial fibrillation or flutter was present in most patients with LAA location of thrombi. Anticoagulation of 47 +/- 18 days was associated with thrombus resolution in 80.1% of the patients on follow-up TEE. Further anticoagulation resulted in limited additional benefit. CONCLUSIONS: LAC thrombi are rare and are usually associated with mitral valve pathology. Transthoracic echocardiography is effective in identifying these thrombi. LAA thrombi occur predominantly in patients with atrial fibrillation or flutter. Short-term anticoagulation achieves a high rate of resolution of LAA and LAC thrombi but does not obviate the need for follow-up TEE.     

Risk Indicators: Assessment of Infancy Predictors of Pre-School Behavioural Maladjustment

The prediction of later outcome from factors present in infancy has been an ongoing concern, with difficult temperament frequently being posited as one important risk factor. Using data from a longitudinal study of a large representative sample of children, and a categorical approach to analysis, a set of infancy risk factors covering within-child, environmental and relationship variables was related to behavioural and emotional adjustment at 4-5 years. Single risk factors, including difficult temperament, resulted in only modest increases in the prevalence of later maladjustment. However, certain combinations of risk factors were associated with markedly increased prevalence rates. The results indicate the cumulative effects of risk factors, and the need to consider temperament within a contextual framework.     

Temperament and behavior of preterm infants: a six-year follow-up

To test the commonly held premise that prematurity is a risk factor for problems of behavior and social interaction, as well as cognitive and physical development, temperament and behavior of children born preterm and full-term control subjects were compared at five separate time periods from infancy through early school age. All the preterm infants (n = 126) of a representative group of infants enrolled in a longitudinal study (n = 2443) were surveyed at 4 to 8 months corrected age. Subsamples of the group were studied further in successive years as young toddlers (n = 65), older toddlers (n = 60), preschoolers (n = 84), and at early school age (n = 81). At each period there were no differences between those studied and those not studied on socioeconomic status, gestational age, sex, or birth order. Parental ratings of temperament and behavior were used at appropriate ages: the Revised Infant Temperament Questionnaire, the Toddler Temperament Scale, the Childhood Temperament Questionnaire, Behaviour Checklist, Preschool Behaviour Questionnaire, and Rutter's Childhood Behaviour Questionnaire (CBQ), as well as mother's overall rating of temperament. In infancy there were no significant differences on temperament dimensions, clinical temperament categories, or parental ratings of individual or composite behaviors between the preterm and full-term groups. For toddlers, temperament scores were similar for the two groups but preterm subjects were significantly more likely (P less than .01) to have an easy temperament and less likely to have a difficult temperament. There were no differences on any of the other temperament or behavior ratings.(ABSTRACT TRUNCATED AT 250 WORDS)