James Rice

Motor function in 5-year-old children with cerebral palsy in the South Australian population.

The aim of this study was to describe the motor function of a population of children at age 5 years enrolled on the South Australian Cerebral Palsy Register. Among children born between 1993 and 1998, there were 333 with confirmed cerebral palsy (prevalence rate 2.2 per 1000 live births), in whom 247 assessments (56.7% males, 43.3% females) were completed. The distribution by Gross Motor Function Classification System (GMFCS) level was: level I, 50.6%; level II, 18.2%; level III, 9.3%; level IV, 9.7%; level V, 12.1%. The most common topographical classification was spastic diplegia (38.5%), followed by spastic hemiplegia (34.8%) and spastic quadriplegia (14.6%). Abnormal movements occurred at rest or with intention in 19.4% of children. A high proportion of the population with relatively mild gross motor impairments have difficulty with everyday bimanual tasks, reinforcing the need to assess upper limb function independently of gross motor function. The use of ankle–foot orthoses was common, particularly across GMFCS levels II to IV. Further refinement is indicated for this population’s motor dataset, to include more recently described classification measures as well as future novel measures to better describe the presence of both spasticity and dystonia.

Functional outcome following paediatric stroke

Background: Paediatric stroke has a significant impact on functional ability; however, few studies describe outcomes using valid and reliable measures. Aim: To describe functional abilities of children following ischemic stroke using a validated outcome measure. Methods: Eighteen children who had sustained an ischemic stroke were recruited from the stroke service of a tertiary childrens hospital. The Pediatric Evaluation of Disability Inventory (PEDI) was used to describe functional abilities in domains of self-care, mobility and social function. Results: All children demonstrated lower functional skills and required more caregiver assistance than would be expected for their age. These findings were seen across all functional areas; however, self-care was more affected than mobility and social functions. Conclusion: The PEDI provides a useful measure of functional outcomes following paediatric stroke. Children in this study demonstrated reduced abilities across all domains. Further research to investigate the relationship between location of injury and functional outcome would assist understanding of paediatric stroke outcomes.

Family-centred outcome measurement following paediatric stroke.

BACKGROUND/AIM Therapy programmes aim to provide services that are family-centred and address the specific needs of children. The Canadian Occupational Performance Measure (COPM) and the Perceived Efficacy and Goal Setting system (PEGS) are two measures that are available to assist in determining therapy priorities for children and their parents; however, the use of these measures has not been documented for children who have sustained a stroke. This project aimed to describe the functional concerns identified by children and their parents following paediatric stroke. METHODOLOGY A cross-sectional design was used. A total of 26 children were recruited from a paediatric stroke outpatient clinic, and functional concerns were identified using either the COPM or the PEGS. RESULTS Children and their parents identified similar issues. Of the 26 participants, 23 (88.5%) reported ongoing functional concerns at three months or more following stroke, whereas three participants did not identify any ongoing functional concerns. Functional concerns were grouped into categories of self-care, productivity and leisure as outlined in the Canadian Model of Occupational Performance. Concerns were identified across all functional domains by both children and their parents. CONCLUSIONS The COPM and PEGS provided useful information about functional issues that are important to children and their parents following paediatric stroke. Use of these client-centred measures provides an opportunity to better understand the impact of paediatric stroke on childrens functional abilities, and allows greater scope for service provision and planning for this group of children.

Pharmacological and neurosurgical interventions for managing dystonia in cerebral palsy: a systematic review

To systematically review evidence for pharmacological/neurosurgical interventions for managing dystonia in individuals with cerebral palsy (CP) to inform a care pathway.

Identification and measurement of dystonia in cerebral palsy

To establish the prevalence and severity of dystonia in a population of children with cerebral palsy (CP) with hypertonia assessment and measurement tools.

Minimal and mild paediatric brain injury: A 3-year cohort of consecutive presentations

Objective: To determine the number of children with minimal and mild traumatic brain injury (TBI) and their demographic factors, causes, associated signs/symptoms and management. Methods: A cross-sectional analysis of consecutive presentations to a tertiary paediatric centre. Results: There were 2043 presentations of minimal and mild TBI over 3 years (minimal TBI = 79.7% [n = 1628]; mild TBI = 20.3% [n = 415]). Mean age was 5.12 years (SD = 5.14) with children ≤3 years comprising 53.2% (n = 1086). There was a bimodal distribution in mild TBI with peaks at 0–2 and 13–15 years. The male-to-female ratio was 1.6:1. Only 34.6% of GCS scores were documented. Falls caused most injury. Overall, 6.3% (n = 129) required hospital admission and 29.1% (n = 594) were reviewed clinically. Conclusion: Minimal and mild TBI is common, representing a significant burden on individuals, families and healthcare providers. High rates of follow-up impact on the healthcare system and warrant further investigation.

Abstract LB-311: Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor

The protein-protein interaction (PPI) between the tumor suppressor antizyme (AZ) and its endogenous regulator antizyme inhibitor (AZIN) has recently been demonstrated to be important in several human cancers. AZIN siRNA treatment reduces AZIN expression and slows prostate cancer cell growth in vitro and in vivo but is not currently a viable therapeutic strategy. To further probe the AZ/AZIN PPI and to screen for potential small molecule inhibitors, we have developed a FRET assay (Z score >0.7) utilizing the Clover (donor) and mRuby2 (acceptor) fluorescent proteins linked to AZIN and AZ, respectively. An alanine mutant screen of 43 amino acid positions in the AZIN protein revealed 2 hotspots that dramatically affect the affinity for the AZ protein, thereby identifying key regions for disruption by potential therapeutics. Furthermore, mutating the N327 and Y331 positions in ornithine decarboxylase (ODC) to equivalent residues in the homologous AZIN protein, increased the affinity of ODC for AZ, providing evidence for key residues that contribute to AZ/AZIN PPI. In addition, the S367G AZIN mutation, which is associated with an mRNA editing event in hepatocellular carcinoma, further increases the affinity of AZIN for AZ and supports a mechanism of AZ sequestration as an important driver in cancer cell growth. Taken together, this data expands our current understanding of the contribution of different amino acid residues to the AZ/AZIN binding interaction. The development of small molecule inhibitors to target these regions of the AZIN protein would rescue the tumor suppressive activity of AZ and present a novel therapeutic opportunity for the treatment of prostate cancer and hepatocellular carcinoma. Note: This abstract was not presented at the meeting. Citation Format: James M. Rice, Michael S. Rogers, Bruce R. Zetter. Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-311. doi:10.1158/1538-7445.AM2017-LB-311

Abstract 4565: Antizyme inhibitor regulates the expression of proteins involved in mitosis and affects prostate cancer cell growth

Upregulation of polyamine biosynthesis is a requirement for cell growth and proliferation. Increases in polyamine levels are mediated by the enzyme ornithine decarboxylase (ODC), which is inhibited by antizyme (AZ). Rescue of ODC activity is accomplished by expression of antizyme inhibitor (AZI), which prevents binding of AZ to ODC. Increases in AZI gene copy number, mRNA transcripts, protein expression and AZI nuclear localization are all associated with prostate cancer. Furthermore, knockdown of AZI expression prevents prostate cancer cell growth in vitro and in vivo. To determine if AZI regulation affects prostate cancer cell growth via mechanisms that are independent of polyamide levels, we conducted a proteomic analysis of the AZI interactome by co-IP and MS/MS. This resulted in the identification of 29 high-confidence interacting proteins (HCIPs), 10 of which are associated with microtubules or with the mitotic spindle including TPX2 and KIFC1. Constitutive overexpression of AZI in PC3M-LN4 prostate cancer cells leads to a decrease in expression of the microtubule associated protein KIFC1, further supporting an interaction between AZI and KIFC1. Silencing of AZI gene expression using siRNA nanoparticles results in a decrease in prostate cancer cell proliferation and altered expression of proteins involved in mitosis. Taken together, this data suggests that AZI may influence prostate cancer cell proliferation via mechanisms that are independent of polyamine regulation. Citation Format: James M. Rice, Amanda Kusztos, Bruce R. Zetter. Antizyme inhibitor regulates the expression of proteins involved in mitosis and affects prostate cancer cell growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4565.

Benign hereditary chorea: more than meets the eye

Benign hereditary chorea (BHC) is an autosomal dominant disorder that has remained relatively poorly understood, owing, at least in part, to its rare prevalence. At the root cause of this condition is a mutation in the NKX2.1 gene, responsible for the production of thyroid transcription factor 1, which in turn regulates the activity of genes in the formation of brain, lung and thyroid tissue. First described in 1966, BHC usually presents with hypotonia in infancy and gross motor delay, with onset of chorea in early childhood and later improvement in adolescence. Neuroimaging is normal. Because of its non-progressive nature, this condition has generally been considered benign particularly in comparison to the distinctly different profile of chorea seen in Huntington disease. Despite this, a relatively small number of cases have been described with persistent motor impairments and features of additional movement disorders such as ataxia, dystonia, myoclonus, and spasticity. The phenotype of BHC has since been expanded with the identification of coexistent hypothyroidism and respiratory disease under the alternative name ‘brain-lung-thyroid’ syndrome, reflecting the implications on broader organogenesis. Peall et al. have continued this work in further describing the BHC picture in a larger cohort. They identified ten cases consistent with BHC and/or NKX2.1 mutations in paediatric movement disorder clinics which were further evaluated by clinical examination, relevant medical history, and exon gene sequencing. Beyond chorea, hypothyroidism and respiratory disease were encountered, as were other physical and behavioural features. A range of oral medication was used in treating chorea. From the findings of this study and that of Gras et al. it appears in BHC that chorea tends to remain relatively mild and resolves in most cases; however, for the majority in the current study it was associated with myoclonus and/or dystonia, both of which have been described to persist into adulthood with ongoing disability. The label ‘benign’ may therefore be a misnomer: whilst the chorea waxes and wanes, other more ominous movement disorders may take its place. Because of the relatively young age range of this patient group and the absence of prospective follow-up, we do not know whether such movement disorders inevitably cause ongoing functional impairment. A range of medications were used to treat chorea, most commonly levodopa, without significant benefit. In contrast, Gras et al. described consistent improvement from the use of low-dose tetrabenazine. The pharmacological treatment of chorea in childhood disorders has limited description; a finding of tetrabenazine efficacy is encouraging and warrants further evaluation, particularly with regard to any impact that early onset of treatment may have on disease process. The relatively frequent observation of coexistent lung and thyroid disease adds to the argument that the full phenotype can look far from benign. Furthermore, description of learning disorders and attention-deficit–hyperactivity disorder in BHC perhaps links the impact of NKX2.1 mutations on both the basal ganglia and associative striatum: this mechanism is also not understood. What are the implications of this study for clinical practice and future research? The nature of this rare, heterogeneous, and evolving condition ensures the need for collaborative research between institutions. Enrolling young children with BHC into a clinical register could