Short-term foetal immobility temporally and progressively affects chick spinal curvature and anatomy and rib development.

Congenital spine deformities may be influenced by movements in utero, but the effects of foetal immobility on spine and rib development remain unclear. The purpose of the present study was to determine (1) critical time-periods when rigid paralysis caused the most severe disruption in spine and rib development and (2) how the effects of an early, short-term immobilisation were propagated to the different features of spine and rib development. Chick embryos were immobilised once per single embryonic day (E) between E3 and E6 and harvested at E9. To assess the ontogenetic effects following single-day immobilisation, other embryos were immobilised at E4 and harvested daily between E5 and E9. Spinal curvature, vertebral shape and segmentation and rib development were analysed by optical projection tomography and histology. The results demonstrated that periods critical for movement varied for different aspects of spine and rib development. Single-day immobilisation at E3 or E4 resulted in the most pronounced spinal curvature abnormalities, multiple wedged vertebrae and segmentation defects, while single-day immobilisation at E5 led to the most severe rib abnormalities. Assessment of ontogenetic effects following single-day immobilisation at E4 revealed that vertebral segmentation defects were subsequent to earlier vertebral body shape and spinal curvature abnormalities, while rib formation (although delayed) was independent from thoracic vertebral shape or curvature changes. A day-long immobilisation in chicks severely affected spine and rib development, highlighting the importance of abnormal foetal movements at specific time-points and motivating targeted prenatal monitoring for early diagnosis of congenital scoliosis.

The importance of foetal movement for co-ordinated cartilage and bone development in utero : clinical consequences and potential for therapy.

Construction of a functional skeleton is accomplished through co-ordination of the developmental processes of chondrogenesis, osteogenesis, and synovial joint formation. Infants whose movement in utero is reduced or restricted and who subsequently suffer from joint dysplasia (including joint contractures) and thin hypo-mineralised bones, demonstrate that embryonic movement is crucial for appropriate skeletogenesis. This has been confirmed in mouse, chick, and zebrafish animal models, where reduced or eliminated movement consistently yields similar malformations and which provide the possibility of experimentation to uncover the precise disturbances and the mechanisms by which movement impacts molecular regulation. Molecular genetic studies have shown the important roles played by cell communication signalling pathways, namely Wnt, Hedgehog, and transforming growth factor-beta/bone morphogenetic protein. These pathways regulate cell behaviours such as proliferation and differentiation to control maturation of the skeletal elements, and are affected when movement is altered. Cell contacts to the extra-cellular matrix as well as the cytoskeleton offer a means of mechanotransduction which could integrate mechanical cues with genetic regulation. Indeed, expression of cytoskeletal genes has been shown to be affected by immobilisation. In addition to furthering our understanding of a fundamental aspect of cell control and differentiation during development, research in this area is applicable to the engineering of stable skeletal tissues from stem cells, which relies on an understanding of developmental mechanisms including genetic and physical criteria. A deeper understanding of how movement affects skeletogenesis therefore has broader implications for regenerative therapeutics for injury or disease, as well as for optimisation of physical therapy regimes for individuals affected by skeletal abnormalities. Cite this article: Bone Joint Res 2015;4:105-116.

Vaccination against cestode parasites: anti-helminth vaccines that work and why.

Highly effective recombinant vaccines have been developed against the helminth parasites Taenia ovis, Taenia saginata and Echinococcus granulosus. These vaccines indicate that it is possible to achieve a reliable, high level of protection against a complex metazoan parasite using defined recombinant antigens. However, the effectiveness of the vaccines against the taeniid cestodes stands in contrast to the more limited successes which characterise attempts to develop vaccines against other platyhelminth or nematode parasites. This review examines the features of the host-parasite relationships among the taeniid cestodes which have formed the basis for vaccine development. Particular consideration is given to the methodologies that have been used in making the cestode vaccines that might be of interest to researchers working on vaccination against other helminths. In developing the cestode vaccines, antigens from the parasites' infective larval stage contained within the egg (oncosphere) were identified as having the potential to induce high levels of protection in vaccinated hosts. A series of vaccination trials with antigen fractions, and associated immunological analyses, identified individual protective antigens or fractions. These were cloned from cDNA and the recombinant proteins expressed in Escherichia coli. This strategy was independently successful in developing vaccines against T. ovis and E. granulosus. Identification of protective antigens for these species enabled rapid identification, cloning and expression of their homologues in related species and thereby the development of effective vaccines against T. saginata, E. multilocularis and, more recently, T. solium. The T. saginata vaccine provides an excellent example of the use of two antigen components, each of which were not protective when used individually, but when combined they induce a reliable, high level of protection. One important contributing factor to the success of vaccine development for the taeniid cestodes was the concentration on studies seeking to identify native host-protective antigens, before the adoption of recombinant methodologies. The cestode vaccines are being developed towards practical (commercial) application. The high level of efficacy of the vaccines against T. solium cysticercosis and hydatid disease suggests that they would be effective also if used directly in humans.