Nanoformulated cell-penetrating survivin mutant and its dual actions

In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A) against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH) cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells), and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic-co-glycolic acid) nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome.

Feasibility of trialling cord blood stem cell treatments for cerebral palsy in Australia

Umbilical cord blood may have therapeutic benefit in children with cerebral palsy (CP), but further studies are required. On first appearance it seems that Australia is well placed for such a trial because we have excellence in CP research backed by extensive CP registers, and both public and private cord blood banks. We aimed to examine the possibilities of conducting a trial of autologous umbilical cord blood cells (UCBCs) as a treatment for children with CP in Australia.

Development of a condition-specific measure of quality of life for children with cerebral palsy: empirical thematic data reported by parents and children

Background: Although there is increasing recognition that quality of life (QOL) and health-related quality of life (HRQOL) are important outcome variables in clinical trials for children with cerebral palsy, there are substantial limitations in existing measures of QOL. This study identify themes of QOL for children with cerebral palsy and their parents to guide the development of a new condition-specific QOL scale. Methods: A qualitative study of parent and child views on QOL composition was conducted, using a grounded theory framework. Families participated in semistructured interviews on QOL until thematic saturation was reached (n = 28 families). Results: Overall, 13 themes emerged from the interviews: physical health, body pain and discomfort, daily living tasks, participation in regular physical and social activities, emotional well-being and self-esteem, interaction with the community, communication, family health, supportive physical environment, future QOL, provision of, and access to services, financial stability, and social well-being. Conclusions: Research with parents and children with cerebral palsy, representative of severity across the disease spectrum and socio-economic status, reinforced and expanded on the traditional themes that have underpinned QOL measurement development. This has implications not only for the development of a new QOL scale for children with cerebral palsy, but also for clinical interventions and community care management.

Tanshinone IIB, a primary active constituent from Salvia miltiorrhza, exhibits neuro-protective activity in experimentally stroked rats

Tanshinone IIB (TSB) is a major active constituent of the root of Salvia miltiorrhiza (Danshen) used in the treatment of acute stroke. Danshen extracts and TSB have shown marked neuron-protective effects in mouse studies but there is a lack of clinical evidence for the neuron-protective effects of Danshen and its active ingredients. This study investigated the neuron-protective effects of TSB in experimentally stroked rats. TSB at 5 and 25 mg/kg by intraperitoneal injection significantly reduced the focal infarct volume, cerebral histological damage and apoptosis in rats subjected to middle cerebral artery occlusion (MCAO) compared to MCAO rats receiving vehicle. This study demonstrated that TSB was effective in reducing stroke-induced brain damage and may represent a novel drug candidate for further development. Further mechanistic studies are needed for the neuron-protective activity of TSB.

A comparison study of cerebral protection using Ginkgo biloba extract and Losartan on stroked rats

It has been well documented that oxidative stress is involved in stroke. Currently, many neuroprotective strategies have been targeted at molecules that are able to act as an oxidant to intervene with free-radical mediated apoptosis in the ischemic penumbra. In particular, natural products which contain antioxidant properties have undoubtedly efficacious for stroke treatment. In the current study, therapeutic effects of Ginkgo biloba extract (EGb) against cerebral protection in Wistar rats underwent middle cerebral artery occlusion (MCAO) was evaluated. A comparison study was conducted by using Losartan, an antihypertensive drug. Gene expression levels of pro-apoptotic genes (AT2 receptor, Fas, Bax and Bcl-xS) have shown to have significant reduction by EGb- and Losartan-treated groups as compared to vehicle group. Significant reduction of immunoreactivity of protein production of these genes, together with least nuclear green fluorescence observed in TUNEL, EGb, as an antioxidant drug, is concluded to have potent and promising therapeutic effect for stroke treatment.

Efficacy of neuromuscular electrical stimulation in improving ankle kinetics during walking in children with cerebral palsy

Neuromuscular electrical stimulation (NMES) applied to the triceps surae muscle is claimed to be effective in improving gait in children with cerebral palsy. The main aim of this study was to determine the effect of NMES on the triceps surae muscle in improving the gait and function of children with cerebral palsy. Twelve children with spastic diplegia or hemiplegia were recruited and randomly assigned to the two experimental groups. The period of the study was 8 weeks (2-4-2 week design). The initial 2 weeks was the control period, in which usual treatment was given to both groups of patients with a pre- and post-treatment assessment. The middle 4 weeks was the experimental period, in which the Treadmill+NMES group received NMES plus treadmill walking training and the Treadmill group underwent treadmill walking training only. Assessment was performed at 2-week intervals. The final 2 weeks was the carryover period, in which treatment to be tested was stopped and reassessment performed again at the end of week 8. An additional treatment and post-treatment assessment were given at weeks 2, 4 and 6 to test for the immediate effect of treatment. Altogether, eight repeated measures with three-dimensional gait analysis and five clinical measurements using the gross motor function measure (GMFM) were performed. Kinetic changes in ankle moment quotient (AMQ) and ankle power quotient (APQ) were not significant either immediately or cumulatively in both groups. Improvement in trend was observed in both groups immediately but not cumulatively. Using the GMFM, functional changes were detected in standing (GMST, p < 0.001) and in walking (GMWK, p = 0.003) using a 'time' comparison. Significant interaction was also detected in GMWK using 'treatment by time' (p = 0.035). The difference between the two groups was not significant on 'treatment' comparison of both GMST and GMWK. Both groups showed improvement in GMST and GMWK cumulatively but there was no difference between the two groups. The effects in both groups could be carried over to 2 weeks after interventions stopped. Both the Treadmill+NMES and Treadmill groups showed improvement in functional outcomes. The trend in the changes of the GMFM score suggested that improvements were greater in the Treadmill+NMES group. There was also a trend showing some immediate improvement in AMQ and APQ.

The tri-focal model of care : Advancing the teaching-nursing home concept

Providing residential aged care is challenging because of the complexity of residents' health status, difficulties recruiting and retaining skilled staff, and financial and regulatory constraints. This paper discusses some of these challenges and describes an innovative model of care, termed 'The Tri-focal model of care'. This model was developed based on the concepts of 'partnership-centred care', 'positive work environment' and the need for evidence-based practice to underpin all aspects of care. It is envisaged that the implementation of this model will provide a rich learning environment that advances the teaching-nursing home concept and the quality of residential aged care.

To do or not to do (exercise) : physical activity in the lives of people with cerebral palsy

We examined the lives of adults with cerebral palsy who had minimal involvement in physical activity (Judy, aged 60; Alana, aged 29), who were involved in physical activity (Amy, aged 25; Ben, aged, 30), or who had minimal involvement in physical activity and who then participated in physical activity (David, aged 27; Tim, aged, 24). After receiving ethical approval, a life-history research approach (Denzin, 1989: Interpretive biography. Newbury Park, CA: Sage) was used, with the participants’ stories being interpreted using primarily psychodynamic theory (Freud, Erikson, Adler, Basch) to gain insight into their meaning and experiences of physical activity.

Judy and Alana had similar childhood experiences, which included: performing difficult, and sometimes painful, physiotherapy; wearing callipers to assist their walking; lacking competence at physical activity; and being socially isolated from their classmates. These aspects of their life histories seemed to contribute to their subsequent avoidance of physical activity and early onset of functional decline.

Amy and Ben had negative experiences with physical activity as children (similar to Judy and Alana), but were involved in, and valued, physical activity as adults. Physical activity was a means of displaying competence, delaying further functional loss, and becoming socially connected.

David and Tim lost the ability to walk in early adolescence. The minimal physical activity in which they engaged during their adult lives was directed towards trying to walk again. Walking seemed to be intimately connected with psychosocial growth. David’s weight-training programme seemed to provide him with another avenue for self-improvement towards his goal of attracting a life partner. Tim’s warm-water aerobic programme provided him with an opportunity to develop competence at swimming and at walking, and to enhance his self-esteem for these activities.

Involvement in physical activity may be important for people with cerebral palsy in their endeavours to successfully face the various psychosocial challenges throughout life. Implications of this research include: parents and teachers of children with cerebral palsy should provide support for their involvement in physical activity; physiotherapists should try to reduce the pain and increase the perceived relevancy of the treatments they deliver to young people with cerebral palsy; and psychologists should be aware of some of the difficulties people with cerebral palsy face and how they may manifest in adults with the condition.

A pseudosymmetric cell adhesion regulatory domain in the β7 tail of the integrin α4β7 that interacts with focal adhesion kinase and src

The β7 integrins α4β7 and Eβ7 play key roles in forming the gut-associated lymphoid tissue, and contribute to chronic inflammation. The α4β7 integrin-mediated adhesion of activated lymphocytes is largely due to a transient increase in avidity from ligand-induced clustering of α4β7 at the cell-surface. Here, we report that L and D enantiomers of a cell-permeable peptide YDRREY encompassing residues 735-740 of the cytoplasmic tail of the β7 subunit inhibit the adhesion of T cells to β7 integrin ligands. The YDRREY peptide abrogated mucosal addressin cell adhesion molecule-1-induced clustering of α4β7 on the surface of activated T cells. A mutated form of the YDRREY peptide carrying either single or double conservative mutations at Tyr⁷³⁵Phe and Tyr⁷⁴⁰Phe was unable to inhibit T cell adhesion, suggesting that both tandem tyrosines are critical for activity. The YDRREY peptide was bound and phosphorylated by focal adhesion kinase and src, which may serve to sequester cytoskeletal proteins to the cytoplasmic domain of 4β7. The quasi-palindromic sequence YDRREY within the β7 cytoplasmic tail constitutes a cell adhesion regulatory domain that modulates the interaction of β7-expressing leukocytes with their endothelial and epithelial ligands. Cell-permeable peptidomimetics based on this motif have utility as anti-inflammatory reagents for the treatment of chronic inflammatory disease.

Adults with cerebral palsy benefit from participating in a strength training programme at a community gymnasium

Purpose : This study examined whether a community-based progressive resistance strength training programme could improve muscle strength and functional activity in a group of adults with cerebral palsy with high support needs.

Method : Using a single group pre-post clinical design, 10 adults (7 males, 3 females; mean age 47.8 SD 5.7 years) with cerebral palsy and high support needs completed 4 weeks of introduction and familiarization, followed by a 10-week progressive resistance strength training programme in a community gymnasium. Participants were measured for muscle strength, locomotion speed and timed sit-to-stand.

Results : After establishment of a stable baseline from weeks 2 to 5 with no systematic change and a high degree of association ( r  > 0.86), participants increased leg strength by 22.0% ( p  = 0.02), arm strength by 17.2% ( p  = 0.01) and improved performance of sit-to-stand ( p  = 0.02) during the 10-week strength training intervention.

Conclusions : This study adds to the accumulating evidence that strength training can be beneficial for people with cerebral palsy by demonstrating benefits for adults with cerebral palsy and high support needs who are subject to decline in physical function associated with the ageing process.

Strength training can be enjoyable and beneficial for adults with cerebral palsy

Purpose: To explore the positive and negative perceptions of participating in a strength- training programme for adults with cerebral palsy.

Method: Ten adults aged over 40 years with cerebral palsy participated in a group-based 10-week progressive resistance strength-training programme in a community gymnasium. After the programme, each participant was interviewed using an in-depth semi-structured format and the results coded thematically.

Results: Participants perceived that their strength, and ability to perform everyday activities had improved. However, the main benefit for participants was enjoyment and social interaction. The only negative perceptions related to fatigue, short-term muscle soreness and a feeling that they had not improved as much as they had expected.

Conclusions: Enjoyment, a factor that can promote adherence and sustainability, was a key benefit of this strength-training programme for adults with cerebral palsy that led to perceptions of increased strength and physical functioning. These findings suggest that exercise programmes for adults with cerebral palsy should be conducted in a group in the community, thereby promoting community inclusion. In addition, it is important to provide education to participants about the normal responses and expectations of an exercise programme.