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Electricity in the brain.

SINCE THE 1980s, there has been increasing interest in the use of electrical stimulation to manage a variety of neurological and other disorders. In many parts of the world, high-frequency electrical stimulation is now used to treat symptoms of Parkinson's disease, epilepsy, depression and addiction. (This is a separate treatment from electroconvulsive therapy, used for many decades to treat severe depression.) Bioelectric stimulation is also used to help manage chronic wounds and pain, and has recently been found to ease inflammation in chronic conditions such as arthritis and autoimmune diseases. A future where individual peripheral nerve fibres can be stimulated to manage specific health conditions is rapidly approaching. The use of highly localised bioelectric stimulation, rather than body-wide medicines, to manage disease is an exciting prospect with potentially far fewer adverse effects and much more precise control.

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Understanding the role and function of this new form of therapy requires knowledge of the processes involved in neuronal signalling in the brain and nervous system. As the use of bioelectrical therapies becomes more common, nurses must be prepared to support clients in their decision-making about this treatment.

INTRODUCTION

The brain and nervous system rely on electrical signals (action potentials) for communication. All body functions are regulated by the nervous system, either through conscious control or via reflex and autonomic responses to stimuli. The central nervous system (CNS) receives sensory data via incoming (afferent) nerve pathways and regulates body function via outgoing (efferent) nerves. Essential to this process is the ability of neurons to generate and propagate action potentials.

In some chronic conditions, either as a cause or a consequence of disease, firing of action potentials in certain neurons appears to be disrupted. For example, Parkinson's disease arises as a result of dysfunction of groups of neurons in the basal ganglia that subsequently cause disruption to motor and cognitive function, as well as mood.

Bioelectrical therapies use electrical discharges to override action potentials generated within the body, thus altering nerve function in the stimulated area. In peripheral tissues, electrical stimulation causes release of neuropeptides and other signalling molecules that affect function of targeted tissues. It also has a direct effect on what would normally be considered non-excitable cells such as the epithelium, immune cells and fibroblasts in a healing wound.

All cells in the body have a resting membrane potential - a difference in electrical potential (charge) between the interior and exterior of the cell. Only excitable tissues are able to generate action potentials that propagate from the point of origin to distant regions of the cell. Excitable tissues in the body include central and peripheral neurons, skeletal muscle, smooth muscle and cardiac myocytes.

THE ACTION POTENTIAL

An action potential is generated by the movement of charged sodium and potassium ions across a cell membrane. It involves a reversal of the electrical charge across a section of the membrane, which then triggers the same response in an adjacent section. In order to trace the events of an action potential, we must first understand the resting membrane potential.

Resting membrane potential Cell membranes are impermeable to ions: an ion cannot diffuse freely through the lipid bilayer. Instead, cells have ion channels in their membranes. These are gated and ion-specific. This means the channels only allow passage of certain types of ions (eg sodium or potassium or chloride) and the passage of these ions can be controlled by the cell through the opening or closing of the channels. As a result, cells can maintain a difference in concentrations of ions between the inside of the cell (the intracellular fluid or ICF) and outside the cell (extracellular fluid, ECF).

The ECF (including the plasma) has predominantly sodium as its positively-charged ion and chloride as its negative ion. The ICF, in contrast, has mainly positive potassium and a large number of negatively-charged protein molecules (see Table 1). This makes the interior of the cell a more negatively charged environment than the exterior. If the difference in charge is measured using microelectrodes, and taking the outside of the cell as 0 millivolts (mV), the ICF will be about -70mV--the "-" sign indicating that the inside is negative compared to the outside. (1) (See Figure 1, next page.)

The difference in ion concentrations across the membranes creates diffusion gradients that, when the ion channels are open, allow the ions to move rapidly in or out of the cell. In the resting cell, potassium channels are open, allowing potassium to diffuse out of the cell and maintaining a negative intracellular charge. If sodium channels open, sodium moves rapidly into the cell and creates a more positive charge. This is the basis of an action potential in excitable cells such as neurons.

Generating an action potential

Some neurons and other excitable cells (eg pacemaker cells in the heart, interstitial cells of Cajal in the smooth muscle of the gut) generate action potentials spontaneously in a rhythmical pattern. These spontaneous depolarisations rely on the movement of calcium into the cells. (2) For most other excitable cells, activation of an action potential relies on the arrival of chemical signals at the dendrites or cell body. These incoming chemicals are neurotransmitters that cross the synaptic gaps between axons and their target cells (another neuron, muscle or other tissue).

A single neuron in the brain can have many connections with its neighbours and also with distant neurons via dendrites and axons that extend from the cell body. Neurons receive incoming information that can be excitatory or inhibitory. Excitatory signals will cause a change in the resting potential toward the positive (depolarisation), while inhibitory signals will cause the membrane potential to become more negative and more difficult to excite (hyperpolarisation). (See Figure 1.) When sufficient excitatory signals are received, a threshold is reached and the cell will fire an action potential.

In the first phase of the action potential (depolarisation), there is rapid opening of the sodium channels in the membrane, sodium rushes into the cell bringing a positive charge with it. The interior of the cell becomes positive compared to the ECF. (See Figure 1.) As a result of this change in charge, neighbouring sodium channels in the membrane also open, causing the action potential to be transmitted (or propagated) along the axon.

Also as an outcome of the change in charge, inactivation gates on the original sodium channels are triggered and close the channels so no further sodium can cross into the cell. Potassium channels now open, allowing potassium to flow out of the cell, taking the positive charge with it. This restores the segment of membrane back to its resting electrical state (repolarisation --see Figure 1) and even a bit lower (hyperpolarisation).

While the potassium channels remain open, and the sodium channels are inactivated, the section of membrane cannot experience another action potential--this is called a refractory period and is the mechanism which ensures action potentials only travel in one direction. Each segment of the membrane experiencing an action potential has behind it a segment in a refractory state but, in front of it, a segment that is able to fire.

Neuronal circuits

Neurons can fire action potentials at a rate of between 250 per second, for small diameter fibres, and 1000 per second for large fibres. (1) The brain contains nearly 100 billion neurons with 100 trillion connections (synapses) between them. A single neuron may connect with thousands of others, both near and distant. Synaptic plasticity describes how these connections are made and remade in the brain. While some connections are predetermined by genetics, others are subject to modification through external influences such as life experience, stress and repeated behaviours.

An action potential fired in one region of the brain can cause a response in a distant region of the brain, or trigger events in the body via pathways through the spinal cord and peripheral nerves. Groups of neurons that interconnect in this way are called circuits. (3) Complex reflex circuits allow us to move through life without thinking of the homeostatic responses required for balance, movement, and blood, nutrient and oxygen delivery that support our activities.

In the brain, distinct circuits link the subcortical and cortical structures, allowing regulation of many body functions. An example is the basal ganglia, where the main circuit links to the cortex with both excitatory and inhibitory neurotransmitters. This circuit operates through rhythmic oscillations that are severely impaired in Parkinson's disease. Abnormal activation of the circuit, caused by Parkinson's, leads to changes in synaptic connections, altered metabolism in affected areas of the brain, depletion of neurotransmitters and alterations in the number or activity of receptors. Bioelectric therapy is believed to work by correcting this abnormal firing of circuits. (4) The more targeted the therapy, the fewer adverse effects. Electroconvulsive therapy (ECT) affects all circuits in the brain, while bioelectric therapies aim to be more precise.

ELECTROCONVULSIVE THERAPY

ECT involves passing an electric current through the brain, intentionally triggering a brief seizure. It is known to be an effective therapy for mental illness in some patients, by causing changes in brain chemsitry. It has been used as a treatment for depression and other psychiatric disorders since the 1940s, when, in the absence of modern drugs, it provided the sole alternative to insulin coma or lobotomy. (5)

In the earlier years of its use, high doses of electricity were administered to conscious patients, resulting in prolonged seizures which could result in fractured limbs, cervical dislocation or cognitive impairment. Prolonged seizures also caused hypoxic brain damage. (6) ECT became less popular with the discovery of effective drugs to manage depression and psychoses.

Today, ECT is administered under light anaesthetic, using preoxygenation and skeletal-muscle-relaxant drugs, to prevent injury from the motor effects of a seizure. While ECT is regarded as being as effective or even superior to medication to manage depression, its use is only recommended for those with severe, treatment-resistant depression, mania and psychosis. (8) The Royal College of Psychiatry's guidelines also include using ECT to manage motor and affective symptoms of Parkinson's disease. (9)

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While the exact mechanism underlying ECT's therapeutic effects is not known, it was originally used to create a "blank slate", or, in modern terms, to "reboot" the brain, in the hope a massive electrical discharge of the brain's neurons would allow these to somehow reset and begin functioning normally. We now know that depression and other psychiatric disorders involve more than just abnormal firing of nerve cells. Regions of the brain remodel and lose neurons in many disorders, and levels of neurotransmitters are either depleted or increased. ECT has been demonstrated to increase the levels of neurotransmitters in the brain, especially serotonin and gamma-aminobutyric acid (GABA) transmission, while dampening cortical signals. It also induces new neuronal growth in parts of the sub-cortex most commonly associated with depressive symptoms. (5,6)

The success of ECT as a therapy requires the induction of a generalised seizure throughout the patient's brain and causes varying degrees of memory loss. This is in stark contrast to the effects of bioelectric therapies, such as deep-brain stimulation, where individual clusters of neurons (ganglia) are targeted.

BIOELECTRIC THERAPIES

The use of electric stimulation in a region of the nervous system will trigger an action potential in an axon, while at the same time causing hyperpolarisation of the cell body. Thus the axon propagates action potentials to the synapse, at a controlled rate, triggering the release of neurotransmitters within the targeted circuit. In the meantime, the cell body, where action potentials would normally be generated and, presumably, where the source of the abnormal circuit function lies, is turned off. (10)

As the stimulation continues over time, synaptic remodelling occurs in the targeted circuits. It is also thought that changes occur in the local blood supply, the number of neurons and amounts of neurotransmitters, as well as the way the neurons respond to incoming signals. (4)

Deep brain stimulation

Deep brain stimulation (DBS) involves inserting electrodes into the brain and passing an electric current through them. The electrodes are directed at subcortical structures such as the basal ganglia, and require precise placement for the therapy to succeed. DBS has been used successfully to manage movement disorders in Parkinson's disease, dystonia and essential tremor. It is also being used (more experimentally) for epilepsy, depression, obesity, schizophrenia, obsessive-compulsive disorder, Tourette syndrome and addiction. (11,12)

While the electrical stimulus of DBS is highly localised, its effects are seen in other regions of the brain as the subcortical ganglia have projections to the cortex. The exact location to place electrodes for best therapeutic effect is not known for many of the conditions proposed to benefit from DBS. Functional brain scanning (magnetic resonance imaging or positron-emission tomography) has been used to determine which areas of the brain are more or less active in people with the particular condition. But a much better understanding of the interconnections within the brain is required for absolute certainty in this therapy.

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High-frequency DBS is the most commonly used form of the therapy but its impact is acute--the effect will only last while the electrodes are active. Recent research has looked at the impact of low-frequency DBS alongside blockade of specific neurotransmitter receptors as a possible long-term treatment that induces synaptic remodelling and abolition of addictive behaviours. (11)

DBS is not yet an exact science: electrical current may not be well targeted or may spread to other regions of the brain, causing adverse effects. Poor electrode placement is often blamed for absent or reduced therapeutic responses in some people, but it may be that some people are just not helped by the treatment. Research into why this may be is lacking. (3,4) DBS also carries a risk of brain haemorrhage, infection following insertion, and malfunction of the embedded leads going from the control unit to the electrodes.

Transcranial stimulation

Less invasive forms of bioelectric therapy are found with transcranial electromagnetic stimulation and transcranial direct current stimulation. For these, an electric current is generated by instruments outside the skull that are sufficiently powerful to affect superficial neuronal activity in the region being treated. Repeated therapy induces changes in neuronal activity and connections in the brain.

Transcranial magnetic stimulation is used for managing migraine and major treatment-resistant depression. Experimentally, there is evidence to support its benefit in neuropathic pain, schizophrenia and the restoration of function following stroke. It involves the generation of a magnetic field using a coil above a region of the cortex. Repeated stimulation generates an electrical field in the cortex, with subsequent increases in action potentials in the affected neurons. (13) There are few adverse effects (although there is a risk of seizures), but long-term effects of this therapy have not been investigated. (14)

Transcranial direct current stimulation (tDCS) appears to act in a more subtle manner by causing hyperpolarisation or depolarisation of the resting membrane potential in neurons--thus making it easier or more difficult for the neurons to fire an action potential. (15) This therapy has been used successfully to treat migraine and help patients recover from strokes. It is, however, the subject of much hype concerning improved cognition when used by healthy subjects--better performance is promised in language, memory and maths--to the point where it is possible to purchase tDCS machines on the internet and self-administer. Also promised are modification of negative moods, suppression of bad habits and accelerated learning. (15) However, a recent review of research has suggested tDCS is not as effective as first thought, or at least the studies of its effects have not addressed critical methodological issues, (16) so these claims are hard to endorse, based on current evidence.

Vagal nerve stimulation

The vagus nerve innervates the visceral organs of the body (eg heart, lungs, gut) and carries both afferent and efferent fibres to and from the brainstem. The brainstem connects to the rest of the brain, including cortical, subcortical and cerebellar structures, so stimulation of the vagus may activate a variety of brain regions or, downstream, many of the body's internal organs.

Vagal nerve stimulation (VNS) is used to manage refractory epilepsy, where it may act by increasing the seizure threshold by triggering widespread release of inhibitory neurotransmitters in the brain. (17) VNS is also suggested for managing resistant depression, migraine, Alzheimer's, multiple sclerosis, hypertension, obesity, diabetes and heart failure. All these indicate the reach of the vagus nerve in the body and brain.

Bioelectric therapies and inflammation: One increasingly researched field is the effect of VNS on immune function. The immune system is commonly seen as independent of the nervous system, but this is not strictly true. When a tissue releases inflammatory cytokines in response to injury, action potentials are triggered via the vagus nerve to the brainstem. This is the first step in a reflex arc that modulates our inflammatory response to injury. Animal studies have shown that in the spleen, triggering of this reflex arc causes the vagus to release neurotransmitters that act on immune cells (T-cells and macrophages) to reduce production of inflammatory mediators. (18) A number of people with rheumatoid arthritis have been successfully treated with VNS and international studies are in progress to evaluate this therapy for managing inflammatory bowel disease. (19)

BIOELECTRIC THERAPY AND WOUND CARE

There is a difference in charge across intact epithelial surfaces, generated by epithelial cells. When a wound is inflicted, this electrical field is disrupted and there is a flow of positive electrical charge from the edges to the centre of a wound. Cells involved in wound healing migrate in response to this bioelectric signal. Electrical fields in wounds may even override other signalling mechanisms such as growth factors. (20) The survival of the bioelectrical signal in a wound relies on the maintenance of a moist wound environment.

The use of Localised electric currents at the wound surface has been demonstrated to accelerate healing in acute wounds. (21) Microelectric stimulation of cells in the area of a wound may support and promote healing through a number of mechanisms. Cells are stimulated to migrate, proliferate and differentiate--all essential elements of the normal healing process.

There is also evidence that bioelectric therapy in the wound increases cellular energy resources and protein synthesis, increases the rate of angiogenesis and may even stimulate regeneration in some tissues rather than scarring. (22) The electrical field is believed to trigger opening of voltage-sensitive calcium channels on cell membranes, which in turn causes an increase in receptors for proliferative signals such as insulin and other cytokines. (23)

The level of stimulation is very important in wound healing--high voltage stimulation can inhibit protein synthesis, damage cell function and even kill cells altogether. (23) There is evidence that low levels of bioelectrical stimulation may inhibit bacterial growth in wounds and enhance the efficacy of antimicrobials applied to wound surfaces. (23)

Chronic wounds, such as pressure ulcers and leg ulcers, may benefit from electrical stimulation in all phases of healing. Unfortunately, there is considerable variation in the duration, type and amount of current being used in both research and practice, so results cannot be readily compared. (24) Generally, the research agrees bioelectrical stimulation accelerates healing of chronic wounds. This may lead to significant cost savings for health services: modelling in the United Kingdom's National Health Service suggests savings of 180 million [pounds sterling] over a 16-week period. (25) However, this form of therapy is underused. (24)

Easing pain

The gate control theory of pain hypothesises that pain signals through the spinal cord can be blocked by the presence of stronger incoming signals from other sensory neurons. This is the rationale underlying transcutaneous electrical nerve stimulation (TENs) therapy, which has been used as an analgesia for acute pain for many years.

The development of chronic pain involves changes in cell function and synaptic remodelling of the dorsal root ganglia in the spinal cord. As a result, there is sensitisation and abnormal firing of neurons through the spinal cord and up to the brain. This leads to action potentials being more readily fired in response to mild or even normally non-painful stimuli. Bioelectric stimulation of the dorsal root ganglia, either directly or transcutaneously, may help inhibit or reverse these changes, either through direct effect on the neurons, or through modulation of immune responses. (26) Stimulation of the spinal cord has been reported to ease both chronic and neuropathic pain, but the results are variable and may wear off over time. (28)

THE FUTURE

The ability to target specific pathways in peripheral nerves, the brain and spinal cord opens a new horizon in therapeutics. Drug therapy suffers the limitation that, once administered, a drug is widely distributed throughout the body and may cause effects not related to the intended therapeutic actions. Miniature implantable devices that can be attached to individual nerve fibres or inserted into specific locales in the brain or spinal cord, and that can modulate their output based on feedback of neuronal function are an exciting prospect.

DBS is already used to manage symptoms of Parkinson's disease and appears a viable potential treatment for depression, Alzheimer's and other central nervous disorders. Vagal nerve stimulation may be the future in managing arthritis, inflammatory bowel disease, obesity, diabetes and asthma. However, to deliver effectively targeted therapy, researchers need a better understanding of the functional anatomy of the brain and nerves supplying the organs, lymphatic system and gut. More importantly, long-term safety of these therapies needs to be assessed, including the impact bioelectric stimulation has on normal neuronal structure and function. (28)

Currently, bioelectric therapies are being used in a number of healthcare settings, but their popularity is limited. Nurses may encounter these therapies or interest from patients who are looking for alternatives to drugs to treat their conditions. We need to be able to address concerns and provide information about bioelectric therapy, and be prepared to help implement these treatments when appropriate.

References

(1) Totora, G. & Derrickson, B. (2014) Principles of anatomy and physiology (14th ed). Hoboken, New Jersey: Wiley.

(2) Takaki, M. (2013) Gut pacemaker cells: the interstitial cells of Cajal. Journal of Smooth Muscle Research; 39:5, pp137-161.

(3) Lozano, A. & Mayberg, H. (2015) Treating depression at the source. Scientific American; 312: 2, pp5863.

(4) Okun, M. (2014) Deep brain stimulation: entering the era of neural-network modulation. The New England Journal of Medicine; 371: 15, pp1369-1373.

(5) Kalapatapu, R. (2015) Electroconvulsive therapy, http://emedicine.medscape.com/article/1525957overview. Retrieved 03/3/15.

(6) Melding, P. (2006) Electroconvulsive therapy in New Zealand: terrifying or electrifying? The New Zealand Medical Journal, 119: 1237, pp66-74.

(7) Lisanby, S. (2007) Electroconvulsive therapy for depression. New England Journal of Medicine; 357: 19, pp1939-1945.

(8) Royal Australian and New Zealand College of Psychiatrists. (2013) Position Statement 74: Electroconvulsive therapy. www.ranzcp.org/Files/Resources/College_Statements/Position_Statements/74-Electroconvulsive-Therapy-GC2012- 3.aspx. Retrieved 03/3/15.

(9) Scott, A. (2005) College guidelines on electroconvulsive therapy: an update for prescribers. British Journal of Psychiatry; 11: 2, pp150-156.

(10) Gubellini, P. et al. (2009) Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behaviour. Progress in Neurobiology; 89, pp79-123.

(11) Creed, M., Pascoli, V.J. & Luscher, C. (2015) Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science; 347: 6222, pp659-664.

(12) Schlaepfer, T., George, M. & Mayberg, H. (2010) World Federation of Societies of Biological Psychiatry guidelines on brain stimulation treatments in psychiatry. World Journal of Biological Psychiatry; 11, pp2-18.

(13) Fitzgerald, P. (2012) Transcranial magnetic stimulation-based methods in the treatment of depression. www.australianprescriber.com/magazine/35/2/59/61. Retrieved 03/3/15.

(14) National Institute for Health and Care Excellence. (2014) Transcranial magnetic stimulation for treating and preventing migraine, www.nice.org.uk/guidance/ipg477. Retrieved 03/3/15.

(15) Bikson, M. & Toshev, P. (2014) Your electric pharmacy. Scientific American Mind; 25: 6, pp56-61.

(16) Horvath, J., Forte, J. & Carter, 0. (2015) Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiolgic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review. Neurophysiologica; 66, pp213-236.

(17) Rielo, D. (2013) Vagus nerve stimulation, http://emedicine.medscape.com/article/1186123overview#al. Retrieved 03/3/15.

(18) Rosas-Ballina, M. et al. (2011) Acetylcholine-synthesising T cells relay neural signals in a vagus nerve circuit. Science. 334: 6052, pp98-101.

(19) Tracey, K. (2015) Shock medicine. Scientific American. 312: 3, pp22-29.

(20) Guo, A. et al. (2010) Effects of physiological electric fields on migration of human dermal fibroblasts. Journal of Investigative Dermatology; 130, pp2320-2327.

(21) Harding, K. et al. (2012) Efficacy of a bio-electric dressing in healing deep, partial-thickness wounds using a porcine model. Ostomy and Wound Management; 58: 9, pp50-55.

(22) Poltawski, L. & Watson, T. (2009) Bioelectricity and microcurrent therapy for tissue healing - a narrative review. Physical Therapy Reviews; 14: 2, pp102-114.

(23) Kloth, L. (2005) Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. International Journal of Lower Extremity Wounds; 4: 1, pp23-44.

(24) Kawasaki, L. et al. (2014) The mechanisms and evidence of efficacy of electrical for healing or pressure ulcer: A systematic review. Wound Repair and Regeneration; 22, pp161-173.

(25) Clegg, J. & Guest, J. (2007) Modelling the cost-utility of bio-electric stimulation therapy compared to standard care in the treatment of elderly patients with chronic non-healing wounds in the UK. Current Medical Research and Opinion; 23, pp8871-883.

(26) Krames, E. (2015) The dorsal root ganglion in chronic pain and a target for neuromodulation: a review. Neuromodulation; 18, pp24-32.

(27) Kumar, K. et al. (2014) Current challenges in spinal cord stimulation. Neuromodulation; 17: suppl 1), pp22-35.

(28) Birmingham, K. et al. (2014) Bioelectronic medicines: a research roadmap. Nature Reviews Drug Discovery; 13, pp399-400.

LEARNING OUTCOMES

After reading this article and completing the accompanying online learning activities, you should be able to:

* Explain the normal action potential.

* Outline proposed actions of electrical stimulation on neurons and other cells.

* Describe the evidence for bioelectric therapy in the management of disease.

Earn two hours of CPD

By reading this article and doing the associated online learning activities, you can receive a certificate for two hours of continuing professional development (CPD).

Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article.

These articles are supplied by CPD4nurses, an independent education company. CPD4nurses is not an NZNO service.

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Table 1. Concentration of ions across the cell membrane
in millimoles per litre (mmol/L)

                                        Extracellular
                        Intracellular     fluid &
Ion                         fluid          plasma

Sodium ([Na.sup.+])          20              145

Potassium ([K.sup.+])        150              4

Chloride ([Cl.sup.-])         4              110

Negatively charged          many             few
proteins
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Title Annotation:CPD + nurses
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Geographic Code:8NEWZ
Date:Apr 1, 2015
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