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Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in half-somites. Repulsion is reduced bothin vivoandin vitroby a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.

An ethically problematic clinical case is used to illustrate the potential importance of understanding clinical ethics in an interdisciplinary context. Whilst much has been written on ethics education for multidisciplinary and interdisciplinary teams, we argue that it is important that both healthcare professions and healthcare teams are able to look outside their own disciplinary ethos and sometimes outside their formal teams when considering the ramifications of an ethical issue. A complex (fictional but based on the authors’ pooled experiences) case involving the delivery of a new-born from a mother with HIV is used to illustrate this, because multiple clinical teams will be involved at different times and in parallel with one another.

Nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent Ca(2+) mobilizing second messenger discovered to date, has been implicated in Ca(2+) signaling in some lymphomas and T cell clones. In contrast, the role of NAADP in Ca(2+) signaling or the identity of the Ca(2+) stores targeted by NAADP in conventional naive T cells is less clear. In the current study, we demonstrate the importance of NAADP in the generation of Ca(2+) signals in murine naive T cells. Combining live-cell imaging methods and a pharmacological approach using the NAADP antagonist Ned-19, we addressed the involvement of NAADP in the generation of Ca(2+) signals evoked by TCR stimulation and the role of this signal in downstream physiological end points such as proliferation, cytokine production, and other responses to stimulation. We demonstrated that acidic compartments in addition to the endoplasmic reticulum were the Ca(2+) stores that were sensitive to NAADP in naive T cells. NAADP was shown to evoke functionally relevant Ca(2+) signals in both naive CD4 and naive CD8 T cells. Furthermore, we examined the role of this signal in the activation, proliferation, and secretion of effector cytokines by Th1, Th2, Th17, and CD8 effector T cells. Overall, NAADP exhibited a similar profile in mediating Ca(2+) release in effector T cells as in their counterpart naive T cells and seemed to be equally important for the function of these different subsets of effector T cells. This profile was not observed for natural T regulatory cells.

rTMS is increasingly used for a variety of neuropsychiatric conditions. There are data to support 'fast' rTMS (≥10 Hz) having some positive effects on cognitive functioning, but a dearth of research looking at any such effects of 'slow' rTMS. This question is important as cognitive dysfunction accompanies many neuropsychiatric conditions and neuromodulation that potentially enhances or hinders such functioning has important clinical consequences. To determine cognitive effects of slow (≤1 Hz) rTMS, a systematic review of randomized control trials assayed cognition in neurological, psychiatric, and healthy volunteer ≤1 Hz rTMS paradigms. Both active (fast rTMS) and placebo comparators were included. 497 Records were initially obtained; 20 met inclusion criteria for evaluation. Four major categories emerged: mood disorders; psychotic disorders; cerebrovascular accidents; and 'other' (PTSD, OCD, epilepsy, anxiety, and tinnitus). Cognitive effects were measured across several domains: attention, executive functioning, learning, and psychomotor speed. Variability of study paradigms and reporting precluded meta-analytical analysis. No statistically significant improvement or deterioration was consistently found in any cognitive domain or illness category. These data support the overall safety of rTMS in not adversely affecting cognitive functioning. There are some data indicating that rTMS might have cognitive enhancing potential, but these are too limited at this time to make any firm conclusions, and the literature is marked by considerable heterogeneity in study parameters that hinder interpretation. Greater consensus is required in future studies in cognitive markers, and particularly in reporting of protocols. Future work should evaluate the effects of rTMS on cognitive training.

rTMS is increasingly used for a variety of neuropsychiatric conditions. There are data to support ‘fast’ rTMS (≥10 Hz) having some positive effects on cognitive functioning, but a dearth of research looking at any such effects of ‘slow’ rTMS. This question is important as cognitive dysfunction accompanies many neuropsychiatric conditions and neuromodulation that potentially enhances or hinders such functioning has important clinical consequences. To determine cognitive effects of slow (≤1 Hz) rTMS, a systematic review of randomized control trials assayed cognition in neurological, psychiatric, and healthy volunteer ≤1 Hz rTMS paradigms. Both active (fast rTMS) and placebo comparators were included. 497 Records were initially obtained; 20 met inclusion criteria for evaluation. Four major categories emerged: mood disorders; psychotic disorders; cerebrovascular accidents; and ‘other’ (PTSD, OCD, epilepsy, anxiety, and tinnitus). Cognitive effects were measured across several domains: attention, executive functioning, learning, and psychomotor speed. Variability of study paradigms and reporting precluded meta-analytical analysis. No statistically significant improvement or deterioration was consistently found in any cognitive domain or illness category. These data support the overall safety of rTMS in not adversely affecting cognitive functioning. There are some data indicating that rTMS might have cognitive enhancing potential, but these are too limited at this time to make any firm conclusions, and the literature is marked by considerable heterogeneity in study parameters that hinder interpretation. Greater consensus is required in future studies in cognitive markers, and particularly in reporting of protocols. Future work should evaluate the effects of rTMS on cognitive training.

As the global health burden of chronic disease increases, end-stage organ failure has become a costly and intractable problem. De novo organ creation is one of the long-term goals of the medical community. One of the promising avenues is that of tissue engineering: the use of biomaterials to create cells, structures, or even whole organs. Tissue engineering has emerged from its nascent stage, with several proof-of-principle trials performed across various tissue types. As tissue engineering moves from the realm of case trials to broader clinical study, three major questions have emerged: (1) Can the production of biological scaffolds be scaled up accordingly to meet current and future demands without generating an unfavorable immune response? (2) Are biological scaffolds plus or minus the inclusion of cells replaced by scar tissue or native functional tissue? (3) Can tissue-engineered organs be grown in children and adolescents given the different immune profiles of children? In this review, we highlight current research in the immunological response to tissue-engineered biomaterials, cells, and whole organs and address the answers to these questions.

A recurrent benign metastasizing pleomorphic salivary adenoma (PSA) is extremely rare occurring in less than 1% of patients. There are approximately 50 cases that have been reported in the literature but none with metastases to the thyroid gland. We report a case of a 68-year-old lady who was initially investigated for a space-occupying lesion in the liver but was found to have metastases in the thyroid and liver as well as recurrence of the parotid primary. The clinical findings, management, and a review of the current literature are reported. Metastases from PSAs are extraordinary. We describe the first reported metastasis from the parotid to the thyroid gland. In this case, we report an excellent outcome post-operatively and argue for the benefit of long-term follow-up.

Biocompatibility, in a tissue engineering sense, may be defined as the integration of an implanted biomaterial, into (and/or interaction with) the host tissues, in order to facilitate tissue regeneration, without provoking an adverse local, or systemic, host response (Williams, 2008). The interplay between implanted biomaterials and the host immune system (i.e., the effect of the host immune system on the implanted biomaterial and vice versa) is one of the most important determinants of the implanted material’s biocompatibility and forms the basis of the work described in this chapter. The overriding aims within this field are twofold, first, suppression of the adaptive immune response in order to prevent immune rejection and second, redirection of the host immune response toward a constructive and favorable phenotype.

Prosthetic materials, autologous tissues, cryopreserved homografts and allogeneic tissues have thus far proven unsuccessful in providing long-term functional solutions to extensive upper airway disease and damage. Research is therefore focusing on the rapidly expanding fields of regenerative medicine and tissue engineering in order to provide stem cell-based constructs for airway reconstruction, substitution and/or regeneration.Advances in stem cell technology, biomaterials and growth factor interactions have been instrumental in guiding optimization of tissue-engineered airways, leading to several first-in-man studies investigating stem cell-based tissue-engineered tracheal transplants in patients. Here, we summarize current progress, outstanding research questions, as well as future directions within the field.The complex immune interaction between the transplant and host in vivo is only beginning to be untangled. Recent progress in our understanding of stem cell biology, decellularization techniques, biomaterials and transplantation immunobiology offers the prospect of transplanting airways without the need for lifelong immunosuppression. In addition, progress in airway revascularization, reinnervation and ever-increasingly sophisticated bioreactor design is opening up new avenues for the construction of a tissue-engineered larynx. Finally, 3D printing is a novel technique with the potential to render microscopic control over how cells are incorporated and grown onto the tissue-engineered airway.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing second messenger discovered to date and has been implicated in Ca2+ signaling in human Jurkat lymphoma T cells via ryanodine receptor activation. In contrast, the role of NAADP in Ca2+ signaling or the identity of the Ca2+ stores targeted by NAADP in conventional naïve T cells has not been investigated. In the current study, we demonstrated for the first time to our knowledge the importance of NAADP in the generation of Ca2+ signals in murine conventional naïve T cells. Combining live-cell imaging methods and a pharmacological approach using the NAADP antagonist Ned-19, we addressed the impact of NAADP on the generation of Ca2+ signals evoked by TCR stimulation and the role of this signal in downstream physiological endpoints such as proliferation, cytokine production, and other responses to stimulation of murine naïve T cells. Moreover, we demonstrated that acidic stores in addition to the endoplasmic reticulum are the relevant Ca2+ stores that were sensitive to NAADP in naïve T cells.