Genetic and phenotypic characterization of complex hereditary spastic paraplegia

The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease- causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15. Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.

Switching curve control of functional electrical stimulation assisted rowing exercise in paraplegia

An indoor rowing machine has been modified for functional electrical stimulation (FES) assisted rowing exercise in paraplegia. To perform the rowing manoeuvre successfully, however, the voluntarily controlled upper body movements must be co-ordinated with the movements of the electrically stimulated paralysed legs. To achieve such co-ordination, an automatic FES controller was developed that employs two levels of hierarchy. At the upper level, a finite state controller identifies the state or phase of the rowing cycle and activates the appropriate lower-level controller, in which electrical stimulation to the paralysed leg muscles is applied with reference to switching curves representing the desired seat velocity as a function of the seat position. In a pilot study, the hierarchical control of FES rowing was shown to be intuitive, reliable and easy to use. Compared with open-loop control of stimulation, all three variants of the closed-loop switching curve controllers used less muscle stimulation per rowing cycle (73% of the open-loop control on average). Further, the closed-loop controller that used switching curves derived from normal rowing kinematics used the lowest muscle stimulation (65% of the open-loop control) and was the most convenient to use for the client.

Development and experimental identification of a biomechanical model of the trunk for functional electrical stimulation control in paraplegia

Objectives. Theoretic modeling and experimental studies suggest that functional electrical stimulation (FES) can improve trunk balance in spinal cord injured subjects. This can have a positive impact on daily life, increasing the volume of bimanual workspace, improving sitting posture, and wheelchair propulsion. A closed loop controller for the stimulation is desirable, as it can potentially decrease muscle fatigue and offer better rejection to disturbances. This paper proposes a biomechanical model of the human trunk, and a procedure for its identification, to be used for the future development of FES controllers. The advantage over previous models resides in the simplicity of the solution proposed, which makes it possible to identify the model just before a stimulation session ( taking into account the variability of the muscle response to the FES). Materials and Methods. The structure of the model is based on previous research on FES and muscle physiology. Some details could not be inferred from previous studies, and were determined from experimental data. Experiments with a paraplegic volunteer were conducted in order to measure the moments exerted by the trunk-passive tissues and artificially stimulated muscles. Data for model identification and validation also were collected. Results. Using the proposed structure and identification procedure, the model could adequately reproduce the moments exerted during the experiments. The study reveals that the stimulated trunk extensors can exert maximal moment when the trunk is in the upright position. In contrast, previous studies show that able-bodied subjects can exert maximal trunk extension when flexed forward. Conclusions. The proposed model and identification procedure are a successful first step toward the development of a model-based controller for trunk FES. The model also gives information on the trunk in unique conditions, normally not observable in able-bodied subjects (ie, subject only to extensor muscles contraction).

Activation of lower back muscles via FES for pressure sores prevention in paraplegia: a case study

The aim of this paper is to show the feasibility of the use of functional electrical stimulation (FES) applied to the lower back muscles for pressure sores prevention in paraplegia. The hypothesis under study is that FES induces a change in the pressure distribution on the contact area during sitting. Tests were conducted on a paraplegic subject (T5), sitting on a standard wheelchair and cushion. Trunk extensors (mainly the erector spinae) were stimulated using surface electrodes placed on the skin. A pressure mapping system was used to measure the pressure on the sitting surface in four situations: (a) no stimulation; (b) stimulation on one side of the spine only; (c) stimulation on both sides, at different levels; and (d) stimulation at the same level on both sides, during pressure-relief manoeuvres. A session of prolonged stimulation was also conducted. The experimental results show that the stimulation of the erector spinae on one side of the spine can induce a trunk rotation on the sagittal plane, which causes a change in the pressure distribution. A decrease of pressure on the side opposite to the stimulation was recorded. The phenomenon is intensified when different levels of stimulation are applied to the two sides, and such change can be sustained for a considerable time (around 5 minutes). The stimulation did not induce changes during pressure-relief manoeuvres. Finally, from this research we can conclude that the stimulation of the trunk extensors can be a useful tool for pressure sores prevention, and can potentially be used in a routine for pressure sores prevention based on periodical weight shifts.

Electrical stimulation for trunk control in paraplegia:A feasibility study

Paraplegic subjects lack trunk stability due to the loss of voluntary muscle control.This leads to a restriction of the volume of bi-manual workspace available,and hence has a detrimental impact on activities of daily living. Electrical Stimulation of paralysed muscles can be used to stabilize the trunk, but has never been applied in closed loop for this purpose. This paper describes the development of two closed loop controllers(PID and LQR),and their experimental evaluation on a human subject. Advantages and disadvantages of the two are discussed,considering a potential use of this technology during daily activities.

Method of plant tissue culture and regeneration

Plants may be regenerated from stomatal cells or protoplasts of such cells. Prior to regeneration the cells or protoplasts may be genetically transformed by the introduction of hereditary material most preferably by a DNA construct which is free of genes which specify resistance to antibiotics. The regeneration step may include callus formation on a hormone-free medium. The method is particularly suitable for sugar beet.

Understanding the resurgence of traditional authorities in post-apartheid South Africa

Drawing their power not from the ballot box but from a supposedly ancient wellspring of power, hereditary traditional authorities in postcolonial Africa have frequently posed challenges for incoming ‘democratic’ governments. The situation in post-apartheid South Africa is no different. However contentious their role under the colonial and apartheid systems of government was, the Constitution of the new South Africa (1996) recognised traditional authorities and afforded them opportunities for a political resurgence. This paper reviews the changing status of traditional authorities in the Eastern Cape Province over the twenty years since 1994. It explores the resurgence of the chiefs in relation to the consolidation of both democratic processes and of emergent, neo-patrimonial modes of government. It briefly considers the role of traditional authorities in three key and closely related spheres, namely the institution of the Eastern Cape House of Traditional Leaders, the question of how gender is handled by and within traditional institutions, and the continuing challenges of land administration and development in rural areas. In all these spheres, and in the face of real opposition, the voice and influence traditional authorities have emerged stronger than ever. We conclude by suggesting that as they are drawn deeper into governance and have to play a formal role in addressing the myriad institutional challenges, new questions will and should be asked about the status and influence of traditional authorities, and their substantive contribution to democracy in South Africa.