Abstract

Magnesium (Mg2+) is the fourth most abundant cation in the whole body and the second most abundant cation within the cell. Numerous cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways are regulated by Mg2+. Our understanding of how cells regulate Mg2+ homeostasis and transport has registered significant progress in recent time. Yet, several aspects of Mg2+ homeostasis within cellular organelles, and the nature of the Mg2+ extrusion mechanisms at the cell membrane are still undefined. The present work attempts to provide a comprehensive and updated review of the mechanisms regulating cellular Mg2+ homeostasis in eukaryotic cells under physiological conditions and the modifications these mechanisms undergo in various human and animal pathologies.

Introduction

Mammalian cells contain high concentrations of total and free magnesium ion (Mg2+). These concentrations are essential to regulate numerous cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways. While the increasing number of observations supports a key regulatory role for Mg2+ within the cell, our understanding of how Mg2+ homeostasis is regulated at the cellular and subcellular level remains sketchy and incomplete. There are both conceptual and methodological reasons for this limitation. The relative slow turnover of Mg2+ across the plasma membrane or other biological membranes in the absence of metabolic and hormonal stimuli, the absolute abundance of total and free Mg2+ within the cell, and the limited occurrence of significant changes in free [Mg2+] have all contributed for a long time to the assumption that cellular Mg2+ concentration does not change significantly, and is consistently at a level adequate for its role as a co-factor for various cellular enzymes and proteins.

William Barnes (1801—1886) wrote poems in Standard English from an early age. Suddenly, in his early 30s, he began to write poems in the local dialect: “I wrote the first of my Dorset poems … when I was kept to my room in an ailing from a chill. It was one of the dialogues called an eclogue, and was printed in the poet's corner of the Dorset County Chronicle where almost all of them first came out,” he wrote in a notebook now at St John's College, Cambridge. This is not the place for a detailed discussion of the eclogue as a literary form; suffice to say here that the word has come to denote a dialogue between country people, that it takes its form from the Idylls of Theocritus and its name from the Eclogues of Virgil, that it became progressively more artificial over time, moving away from its earthy roots and weighed down by the conventions of the pastoral tradition, and that Barnes restored it to its former vigour and naturalism.

The poem was an immediate success, and became the first in a series of eight eclogues published within the next two years, each originally with a Latin title and an English subtitle:

1. 1. Rusticus Dolens: Inclosures of Common, 2 January 1834

2. [...]

INTRODUCTION

Abnormal thrombus formation is central to the acute pathophysiology of both arterial and venous disease. Formation of thrombus superimposed upon the surface of ruptured atherosclerotic plaque, producing vessel occlusion and resulting tissue ischemia, is the common mechanism leading to acute symptoms and presentation in patients with arterial disease. Likewise deep vein thrombosis and pulmonary embolism, important community causes of morbidity and mortality, both result from abnormal thrombus formation in the venous circulation. An understanding of conditions that may pre-dispose to abnormal thrombus formation, including a knowledge of how the presence of these conditions may or may not impact on patient management, is important for all clinicians involved in the management of vascular disease.

First used in 1937, and then also in the first description of inherited antithrombin deficiency, the term ‘thrombophilia’ can be defined as an increased tendency to develop thrombosis, which may be either acquired or inherited. Thrombophilic conditions vary both in prevalence and in the magnitude of the associated increase in risk of thrombosis. The discovery during the 1990's of the high prevalence factor V Leiden and prothrombin gene point mutations that predispose to thrombosis, meant that an underlying thrombophilic condition could be found in approximately 50% of unselected patients with venous thrombosis. This fact, along with the belief that the presence of such a condition may influence prognosis and may therefore help guide patient management, has led to a significant increase in laboratory testing for inherited thrombophilia.

Anthropology in Adelaide pre-Yuendumu

The arrival of Frederic Wood Jones in Adelaide caused a great deal of excitement when he became Curator of the South Australia Museum in 1919. He was a dominant figure in medical science and anthropology and “was a gifted comparative anatomist and illustrator, as well as a fluent orator and writer” (Southcott, 1986). At the time, there was an enthusiastic group of men from several disciplines pursuing their interests in the physical and cultural anthropology of Central Australian Aboriginal people. Wood Jones succeeded Archibald Watson in 1920 as the Elder Professor of Anatomy at The University of Adelaide.

Since the settlement of South Australia there had been numerous studies of Aboriginal people, particularly by staff of the South Australian Museum. Tindale (1986) provided an excellent summary of previous anthropological research in the 19th and 20th centuries, including an extensive list of references. Among the group of Adelaide scientists in the 1920s was Thomas Draper Campbell, then a dental surgeon aged 27 years. Clearly influenced by Wood Jones, Campbell joined him on field expeditions.

Two significant events occurred in 1926: the formation of the Anthropological Society of South Australia by Wood Jones, Campbell and John B Cleland; and the establishment of the Board for Anthropological Research, following a recommendation by Wood Jones to the Council of The University of Adelaide. Wood Jones resigned the same year to accept a professorial appointment at the University of Hawaii.

Abstract

Specific and non-specific mitogens stimulate the proliferation of cultured fibroblasts. They also stimulate other responses that are part of a coordinate response, some members of which are essential for proliferation and others that are not. The synthesis of protein is an early response to mitogens and its continuation through the G1 period drives the accumulation of protein which is required for the initiation of DNA synthesis hours later. The parabola-like curve for dependence of protein synthesis on intracellular Mg2+ concentration is similar to that of cell-free ribosome preparations, and is later reflected in the initiation of DNA synthesis. Hence, DNA synthesis is dependent on the rate of protein synthesis which is regulated by the concentration of intracellular Mg2+. Presumably free Mg2+ is an indicator of the fraction of ATP4− that is complexed with Mg2+ as MgATP2−, which is the immediate regulatory form. Uridine uptake is determined by its phosphorylation which is also dependent on intracellular Mg2+ in the coordinate response, but unlike protein synthesis, neither influences DNA synthesis nor exhibits downturn at a high Mg2+ concentration. Intracellular free Mg2+ determines the onset of protein synthesis in activated frog oocytes and its rate in lymphocytes. Mg2+ regulation of protein synthesis is effected through the PI 3-K pathway at mTOR phosphorylation of two translation-regulating proteins. Regulation of proliferation by Mg2+ is lost in transformed cells. Mg2+ and MgATP2− apparently play a central role in the regulation of metabolism in a wide variety of cells and developmental stages across the animal kingdom.

BACKGROUND

Abdominal aortic aneurysms (AAAs) are present in 5 to 10% of men over the age of 65, and elective surgical intervention has long been the mainstay of treatment. There is widespread consensus that operative repair is the treatment of choice in larger AAAs, where the risk of rupture increases with the size of the aneurysm. However, even elective operations carry a significant mortality risk, and the UK small aneurysm trial has shown that for smaller aneurysms (between 4 and 5.5cm) there is no difference in outcome between operation and no intervention. Currently such patients are treated with best medical therapy, but there has been considerable research into finding a pharmacological treatment to prevent aneurysm expansion and rupture.

SCREENING PROGRAMMES

A major obstacle to the prevention of mortality and morbidity associated with aneurysms has been the fact that the majority are asymptomatic, and therefore often remain undetected. Abdominal aortic aneurysms have tended to present either as emergencies or as a result of their increasing size, and it has been shown that larger aneurysms grow more rapidly than their smaller counterparts and are at greater risk of rupture. These patients would therefore benefit most from operative repair rather than medical intervention. In order for a medical treatment to be of benefit, it needs to be targeted at aneurysms that are small and asymptomatic. The most obvious way of doing this would be the initiation of a mass screening programme, and indeed, the Multicentre Aneurysm Screening Study (MASS) has shown that as many as 88% of screen-detected aneurysms are below the threshold for surgery.

Abstract

Traumatic injury to the central nervous system (CNS) is a leading cause of morbidity and mortality, and represents a significant public health issue. Despite intensive research, no effective neuroprotective therapy exists, and survivors of CNS injury, including traumatic brain injury (TBI) and spinal cord injury (SCI), can be left with severe disabilities that require long-term rehabilitation. Much of the damage that occurs after TBI and SCI develops over time with the primary injury initiating a secondary injury cascade made up of deleterious biochemical and pathophysiological reactions. This delayed development of secondary injury provides a vital opportunity for therapeutic intervention and considerable effort is currently being directed toward identifying these injury factors and developing interventions that may potentially prevent their actions. Magnesium (Mg2+) decline has been identified as playing a key role in the secondary injury process, in part because of its central role in the regulation of a large number of known injury factors and that its decline is associated with the development of motor and cognitive deficits. Mg2+ administration has been extensively investigated both preclinically in TBI and SCI and clinically as a neuroprotectant in TBI with varied success. This chapter focuses on the role of Mg2+ in TBI and SCI pathophysiology, with particular emphasis on Mg2+ as a potential therapeutic agent.

Abstract

Hearing loss is a major public health problem with a large number of causes. Among them, noise-induced hearing loss, drug ototoxicity and sudden sensorineural hearing loss have been proven to result in part from metabolic disorders. Metabolic disorders have multiple origins such as: ionic, ischemic, excitotoxic and production of cochlear free radicals causing cell death, via necrosis or apoptosis. The efficacy of magnesium, administered either to prevent or to treat hearing damages has been demonstrated in several studies in animals and in humans, particularly in noise-induced hearing loss. The exact mechanism by which Mg2+ acts is not fully known. Different hypotheses exist including calcium antagonism, vasodilatation, antioxidant and anti-NMDA properties. Because it is a relatively safe and well-known treatment, magnesium therapy, alone or in association, could be of a great interest to improve auditory recovery.

Introduction

According to the World Health Organization, 278 million people worldwide have moderate to profound hearing loss in both ears. Besides pathologies of unknown origin such as sudden hearing loss and Meniere's disease, hearing loss has so many known causes, it would be arduous to list them all.

Previous chapters have shown that governments often gave consent when developers proposed building projects that would contravene heritage legislation or principles of development control affecting heritage buildings. Moreover, governments themselves sometimes initiated such projects. The Bannon Government was first elected during the state's deepest recession since the Great Depression, and the Premier sought economic growth through major events and building projects. Local governments also stretched the boundaries of development approval, often granting concessions to the developers of major projects that spoiled the character and streetscapes of Adelaide the most. Many Adelaide councillors expressed the view from time to time that the constraints of the City of Adelaide Plan were not intended to apply to major projects. For example, in a debate on the REMM-Myer development, Lord Mayor Condous spoke of a ‘too rigid maintenance of the City of Adelaide Plan’, indicating a willingness to bend the rules for the largest commercial project of its day. Developers of major projects invested large sums of money, and many on the council believed they deserved special consideration. In the 1980s, as heritage registers were being developed, heritage protection was subordinated to economic growth at both state and local government levels.

Abstract

In the general deterioration of physiological functions that takes place in aging, the prevalence of cognitive impairments, and particularly of those related to learning and memory, makes these deficits a major concern of public health. Although the exact nature of cellular and molecular substrates underlying learning and memory still remains an open issue for the neurobiologist, the current hypothesis views it is determined by the capacity of brain neuronal networks to express short- and long-term changes in synaptic strength. Accordingly, the capacity of functional plasticity is impaired in the brain of aged memory-deficient animals. Short-term changes in synaptic transmission closely depend on transmitter release and neuronal excitability while long-term modifications are mainly related to the activation of the N-methyl-D-aspartate receptor (NMDA-R), a subtype of glutamate receptors. Because transmitter release, neuronal excitability and NMDA-R activation are modulated by magnesium (Mg2+), a change in brain Mg2+ homeostasis could affect synaptic strength and plasticity in neuronal networks and consequently could alter memory capacities. In addition, alteration of brain Mg2+ levels could be regarded as a possible mechanism contributing to cognitive aging. According to these postulates, long-term increase in Mg2+ levels facilitates the conversion of synapses to a plastic state while learning and memory capacities are enhanced in adult animals fed with a diet enriched in Mg2+-L-threonate, a treatment that significantly elevates brain Mg2+ levels. Because Mg2+-L-threonate also improves learning and memory in aged animals, the regulation of brain Mg2+ homeostasis may therefore be regarded as a relevant target for the development of new pharmacological strategies aimed at minimizing cognitive aging.

Abstract

Subarachnoid hemorrhage caused by a ruptured aneurysm accounts for only 5% of strokes, but occurs at a fairly young age and carries a worse prognosis. Delayed cerebral ischemia is an important cause of death and dependence after aneurysmal SAH. The current mainstay of preventing delayed cerebral ischemia is nimodipine and maintenance of normovolemia, but even with this strategy delayed cerebral ischemia occurs in a considerable proportion of patients. Magnesium is an inexpensive, easily available neuroprotective agent that reduces cerebral vasospasm and infarct volume after experimental subarachnoid hemorrhage. In a meta-analysis of all randomized clinical trials, magnesium shows a tendency to reduce the occurrence of delayed cerebral ischemia and poor outcome after subarachnoid hemorrhage, but the question if magnesium is advantageous in subarachnoid hemorrhage patients is still in abeyance. Currently a large phase III trial aiming for 1200 patients is being conducted that will hopefully provide definite evidence whether magnesium treatment is beneficial in subarachnoid hemorrhage patients.

Subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) caused by a ruptured aneurysm accounts for only 5% of strokes, but occurs at a fairly young age and carries a worse prognosis than other types of stroke (van Gijn et al, 2007). The cardinal feature is a history of unusually severe headache that started suddenly, but patients frequent deteriorate into unconsciousness shortly after onset.

INTRODUCTION

The incidence of diabetes continues to grow at a staggering pace. The United States' Centers for Disease Control and Prevention estimate that 23.6 million people or 7.8% of the U.S. Population has diabetes, with 1.6 million new cases being diagnosed each year. These figures are even more astonishing when one considers worldwide estimates. Close to 4 million deaths in the 20–79 year old age group may be attributed to diabetes in 2010, accounting for 6.8% of global all-cause mortality in this age group. The number of people with diabetes worldwide is expected to reach 366 million people by 2030, more than double the estimated 177 million people affected with the disease in 2000. The increased disease prevalence is accompanied by an increase in associated comorbidities. The literature estimates that patients with diabetes have nearly a 25% lifetime risk of developing a foot ulcer with more than 50% of these ulcers becoming infected and requiring hospitalization. In fact, at least 20% of all diabetes-related hospital admissions are due to diabetic foot ulcers. Associated with foot ulcers and infection is the incidence of amputation. It has been conservatively reported that, worldwide, a major amputation takes place every 30 seconds with over 2500 limbs lost per day. At least 60% of all non-traumatic lower extremity amputations are related to complications of diabetes. People with diabetes who have had one amputation have a 68% risk of having another in the next 5 years and have a 50% mortality rate in the 5 years following the initial amputation.