A microchannel neuroprosthesis for bladder control after spinal cord injury in rat

A severe complication of spinal cord injury is loss of bladder function (neurogenic bladder), which is characterized by loss of bladder sensation and voluntary control of micturition (urination), and spontaneous hyperreflexive voiding against a closed sphincter (detrusor-sphincter dyssynergia). A sacral anterior root stimulator at low frequency can drive volitional bladder voiding, but surgical rhizotomy of the lumbosacral dorsal roots is needed to prevent spontaneous voiding and dyssynergia. However, rhizotomy is irreversible and eliminates sexual function, and the stimulator gives no information on bladder fullness. We designed a closed-loop neuroprosthetic interface that measures bladder fullness and prevents spontaneous voiding episodes without the need for dorsal rhizotomy in a rat model. To obtain bladder sensory information, we implanted teased dorsal roots (rootlets) within the rat vertebral column into microchannel electrodes, which provided signal amplification and noise suppression. As long as they were attached to the spinal cord, these rootlets survived for up to 3 months and contained axons and blood vessels. Electrophysiological recordings showed that half of the rootlets propagated action potentials, with firing frequency correlated to bladder fullness. When the bladder became full enough to initiate spontaneous voiding, high-frequency/amplitude sensory activity was detected. Voiding was abolished using a high-frequency depolarizing block to the ventral roots. A ventral root stimulator initiated bladder emptying at low frequency and prevented unwanted contraction at high frequency. These data suggest that sensory information from the dorsal root together with a ventral root stimulator could form the basis for a closed-loop bladder neuroprosthetic. Copyright © 2013, American Association for the Advancement of Science

Protease-activated receptors: mechanisms by which proteases sensitize TRPV channels to induce neurogenic inflammation and pain

Proteolytic enzymes comprise approximately 2 percent of the human genome [1]. Given their abundance, it is not surprising that proteases have diverse biological functions, ranging from the degradation of proteins in lysosomes to the control of physiological processes such as the coagulation cascade. However, a subset of serine proteases (possessing serine residues within their catalytic sites), which may be soluble in the extracellular fluid or tethered to the plasma membrane, are signaling molecules that can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors (GPCRs). These serine proteases include members of the coagulation cascade (e.g., thrombin, factor VIIa, and factor Xa), proteases from inflammatory cells (e.g., mast cell tryptase, neutrophil cathepsin G), and proteases from epithelial tissues and neurons (e.g., trypsins). They are often generated or released during injury and inflammation, and they cleave PARs on multiple cell types, including platelets, endothelial and epithelial cells, myocytes, fibroblasts, and cells of the nervous system. Activated PARs regulate many essential physiological processes, such as hemostasis, inflammation, pain, and healing. These proteases and their receptors have been implicated in human disease and are potentially important targets for therapy. Proteases and PARs participate in regulating most organ systems and are the subject of several comprehensive reviews [2, 3]. Within the central and peripheral nervous systems, proteases and PARs can control neuronal and astrocyte survival, proliferation and morphology, release of neurotransmitters, and the function and activity of ion channels, topics that have also been comprehensively reviewed [4, 5]. This chapter specifically concerns the ability of PARs to regulate TRPV channels of sensory neurons and thereby affect neurogenic inflammation and pain transmission [6, 7].

Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status

A framework for understanding the complexity of cancer development was established by Hanahan and Weinberg in their definition of the hallmarks of cancer. In this review, we consider the evidence that parabens can enable development in human breast epithelial cells of 4/6 of the basic hallmarks, 1/2 of the emerging hallmarks and 1/2 of the enabling characteristics. Hallmark 1: parabens have been measured as present in 99% of human breast tissue samples, possess oestrogenic activity and can stimulate sustained proliferation of human breast cancer cells at concentrations measurable in the breast. Hallmark 2: parabens can inhibit the suppression of breast cancer cell growth by hydroxytamoxifen, and through binding to the oestrogen-related receptor gamma (ERR) may prevent its deactivation by growth inhibitors. Hallmark 3: in the 10nM to 1M range, parabens give a dose-dependent evasion of apoptosis in high-risk donor breast epithelial cells. Hallmark 4: long-term exposure (>20weeks) to parabens leads to increased migratory and invasive activity in human breast cancer cells, properties which are linked to the metastatic process. Emerging hallmark: methylparaben has been shown in human breast epithelial cells to increase mTOR, a key regulator of energy metabolism. Enabling characteristic: parabens can cause DNA damage at high concentrations in the short term but more work is needed to investigate long-term low-doses of mixtures. The ability of parabens to enable multiple cancer hallmarks in human breast epithelial cells provides grounds for regulatory review of the implications of the presence of parabens in human breast tissue.

Motor imagery-induced EEG patterns in individuals with spinal cord injury and their impact on brain–computer interface accuracy

Objective. Assimilating the diagnosis complete spinal cord injury (SCI) takes time and is not easy, as patients know that there is no ‘cure’ at the present time. Brain–computer interfaces (BCIs) can facilitate daily living. However, inter-subject variability demands measurements with potential user groups and an understanding of how they differ to healthy users BCIs are more commonly tested with. Thus, a three-class motor imagery (MI) screening (left hand, right hand, feet) was performed with a group of 10 able-bodied and 16 complete spinal-cord-injured people (paraplegics, tetraplegics) with the objective of determining what differences were present between the user groups and how they would impact upon the ability of these user groups to interact with a BCI. Approach. Electrophysiological differences between patient groups and healthy users are measured in terms of sensorimotor rhythm deflections from baseline during MI, electroencephalogram microstate scalp maps and strengths of inter-channel phase synchronization. Additionally, using a common spatial pattern algorithm and a linear discriminant analysis classifier, the classification accuracy was calculated and compared between groups. Main results. It is seen that both patient groups (tetraplegic and paraplegic) have some significant differences in event-related desynchronization strengths, exhibit significant increases in synchronization and reach significantly lower accuracies (mean (M) = 66.1%) than the group of healthy subjects (M = 85.1%). Significance. The results demonstrate significant differences in electrophysiological correlates of motor control between healthy individuals and those individuals who stand to benefit most from BCI technology (individuals with SCI). They highlight the difficulty in directly translating results from healthy subjects to participants with SCI and the challenges that, therefore, arise in providing BCIs to such individuals

Motor imagery induced EEG patterns in spinal cord injury patients and their impact on Brain-Computer Interface accuracy

OBJECTIVE: Assimilating the diagnosis complete spinal cord injury (SCI) takes time and is not easy, as patients know that there is no 'cure' at the present time. Brain-computer interfaces (BCIs) can facilitate daily living. However, inter-subject variability demands measurements with potential user groups and an understanding of how they differ to healthy users BCIs are more commonly tested with. Thus, a three-class motor imagery (MI) screening (left hand, right hand, feet) was performed with a group of 10 able-bodied and 16 complete spinal-cord-injured people (paraplegics, tetraplegics) with the objective of determining what differences were present between the user groups and how they would impact upon the ability of these user groups to interact with a BCI. APPROACH: Electrophysiological differences between patient groups and healthy users are measured in terms of sensorimotor rhythm deflections from baseline during MI, electroencephalogram microstate scalp maps and strengths of inter-channel phase synchronization. Additionally, using a common spatial pattern algorithm and a linear discriminant analysis classifier, the classification accuracy was calculated and compared between groups. MAIN RESULTS: It is seen that both patient groups (tetraplegic and paraplegic) have some significant differences in event-related desynchronization strengths, exhibit significant increases in synchronization and reach significantly lower accuracies (mean (M) = 66.1%) than the group of healthy subjects (M = 85.1%). SIGNIFICANCE: The results demonstrate significant differences in electrophysiological correlates of motor control between healthy individuals and those individuals who stand to benefit most from BCI technology (individuals with SCI). They highlight the difficulty in directly translating results from healthy subjects to participants with SCI and the challenges that, therefore, arise in providing BCIs to such individuals.

Effects of aluminium chloride and aluminium chlorohydrate on DNA repair in MCF10A immortalised non-transformed human breast epithelial cells

Use of underarm aluminium (Al)-based antiperspirant salts may be a contributory factor in breast cancer development. At the 10th Keele meeting, Al was reported to cause anchorage-independent growth and double strand DNA breaks in MCF10A immortalised non-transformed human breast epithelial cells. We now report that exposure of MCF10A cells to Al chloride or Al chlorohydrate also compromised DNA repair systems. Longterm (19–21 weeks) exposure to Al chloride or Al chlorohydrate at a 10−4 M concentration resulted in reduced levels of BRCA1 mRNA as determined by real-time RT-PCR and BRCA1 protein as determined by Western immunoblotting. Reduced levels of mRNA for other DNA repair genes (BRCA2, CHK1, CHK2, Rad51, ATR) were also observed using real-time RT-PCR. Loss of BRCA1 or BRCA2 gene function has long been associated with inherited susceptibility to breast cancer but these results suggest that exposure to aluminium-based antiperspirant salts may also reduce levels of these key components of DNA repair in breast epithelial cells. If Al can not only damage DNA but also compromise DNA repair systems, then there is the potential for Al to impact on breast carcinogenesis.

Designing care bundle documentation to support the recognition and treatment of acute kidney injury: a route to quality improvement

The chapter describes development of care bundle documentation, through an iterative, user-centred design process, to support the recognition and treatment of acute kidney injury (AKI). The chapter details stages of user and stakeholder consultation, employed to develop a design response that was sensitive to user experience and need, culminating in simulation testing of a near final prototype. The development of supplementary awareness-raising materials, relating to the main care bundle tool is also discussed. This information design response to a complex clinical decision-making process is contrasted to other approaches to promoting AKI care. The need for different but related approaches to the working tool itself and the tool’s communication are discussed. More general recommendations are made for the development of communication tools to support complex clinical processes.