This is a very good book and a very important one. The list of authors (107) reads like the ‘Who’s Who’ of spinal cord medicine. The volume is much more than an update of previous volumes of the ‘Handbook’, which also dealt with this topic and were published in 1976 and 1992. New developments have produced important and exciting changes that have altered the subject almost beyond recognition. This statement is true as regards the clinical achievments including diagnosis, prognosis and rehabilitation, but not quite so accurate as regards pre-clinical research. The 38 chapters form five sections. The first section, on development and anatomical perspectives, deals with the growth and maturation of the spinal cord. A good overview of the embryology, both cellular and molecular, is followed by a description of maldevelopment and the implications of molecular and genetic defects. The anatomy and biomechanisms are dealt with in terms of fundamental principles applied to the spinal column and spinal cord, and lead on to spinal cord injury. This is a good base for the following chapters that form the second section and which deal with the diagnosis, prognosis and monitoring of spinal cord trauma. Hopefully, in the future, there will be clinical trials of therapeutic interventions (but more of that later), and this will require accurate and quantitative measurement. The standard and recognized method is the ASIA scale, but this has limitations, and the best potential lies with neurophysiology and with advanced high-resolution neuroimaging techniques.This is dealt with in two excellent and comprehensive chapters. The majority of spinal cord injury outcome measures are understandably related to the younger population. However, the increasingly ageing population in most countries has to be addressed. This is a problem in the entire field of medicine. Specifically, in spinal cord injury, the average age of injury has increased and is still increasing. A short but notable chapter deals with the pathophysiology of the ageing nervous system, the aetiology and clinical presentation, complications and mortality and outcome. The third section deals with acute spinal cord injury: medical and surgical treatment, management and rehabilitation. These are useful straightforward reviews but are also good accounts of exciting developments. It is pointed out, and it cannot be over-emphasized, that spinal cord injury, although interrupting motor and sensory long tracts, still leaves neuronal networks intact below the site of the lesion. This is potentially a much more fruitful area of study than the conventional, and so far fruitless, pursuit of axonal repair. Chapter 20, on the changing field of rehabilitation, gives a brief account of how neural activity has a role in central nervous system (CNS) development and plasticity, but this important subject could have been improved to a great extent. A chapter on spinal cord stimulation (SCS) should have given more prominence to Cook, who, in the early 1970s, was the first to demonstrate improvement in neurological deficit with SCS. He was carrying out this procedure for pain on a young sufferer with multiple sclerosis when to his great surprise he saw a marked improvement in spasticity with consequent improvement in ambulation. The speed of change suggested that this was almost certainly due to an increase in inhibition. Cook took his observations to the neurologists in his hospital and later to the neurological societies in New York. They refused to even investigate this. Subsequent studies (elsewhere) demonstrated recordable and reproducible neurophysiologcal changes at spinal and brain-stem levels and eventually led to the formation of the International Neuromodulation Society. What Cook had observed was no more than that reported by Frohlich and Sherrington in 1902: after decerebration in cat, dog and Macaque, stimulation of the lower thoracic and lumbar region of the spinal cord showed ‘..an effect...constant and regular...evoked marked inhibition of the rigidity..’. Cook deserves much greater recognition. Section 4 is concerned with chronic-stage rehabilitation, and overlaps with the previous section. In fact, it is difficult to see why the two sections were separated. ‘Rehabilitation strategies that optimize spontaneous repair and promote neurological recovery are becoming mainstream’. Is this perhaps rather optimistic? ‘Spontaneous repair’ and ‘neurological recovery’ risks undue raising of hopes. This is based on a single case report about 11 years ago. Nevertheless, this is an interesting section that, in this chapter, deals with the effect of activity including electrical stimulation on synapses. Although the field is not exactly comprehensively covered, a good trenchant point is made: that conventional rehabilitation of spinal cord disease ignores the beneficial effects of afferent feedback and stimulation, which is aninteresting and potentially exciting concept that brings into focus the undamaged, but altered, central nervous system. The final section, section 5, deals with preclinical research ‘bridging the gap between bench and bedside.’ This is the longest section in 15 chapters and approximately one-third of the total volume.The first chapter in this section sets out the goals for therapy, discusses protocols and gives an algorithm for discovery through to clinical use. The authors point out that no clinical trial so far has been shown to be effective (reviewer’s emphasis). An outstanding and thoughtful chapter follows, again emphasizing the improvement in animals and man with appropriate afferent input, and discusses the challenges to be met. However, there is some inconsistency among the contributors, which, though understandable, is somewhat confusing. Chapter 25 states that ‘basic research in spinal cord repair is promising’. A more realistic description might state the opposite. Further chapters point out that there are no satisfactory solutions. Indeed, chapter 33 begins with ‘so far, there is no clinical procedure for inducing severed nerve fibres to regenerate’. Further on, the authors state that ‘the grandfather of the transplantation strategies was espoused by Santiago Ramon y Cajal in the 19th century’. Spinal Cord (2013) 51, 797–799 & 2013 International Spinal Cord Society All rights reserved 1362-4393/13

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Handbook of clinical neurology

This review covers current knowledge of selenium in the dietary intake, its bioavailability, metabolism, functions, biomarkers, supplementation and toxicity, as well as its relationship with diseases and gut microbiota specifically on the symbiotic relationship between gut microflora and selenium status. Selenium is essential for the maintenance of the immune system, conversion of thyroid hormones, protection against the harmful action of heavy metals and xenobiotics as well as for the reduction of the risk of chronic diseases. Selenium is able to balance the microbial flora avoiding health damage associated with dysbiosis. Experimental studies have shown that inorganic and organic selenocompounds are metabolized to selenomethionine and incorporated by bacteria from the gut microflora, therefore highlighting their role in improving the bioavailability of selenocompounds. Dietary selenium can affect the gut microbial colonization, which in turn influences the host's selenium status and expression of selenoproteoma. Selenium deficiency may result in a phenotype of gut microbiota that is more susceptible to cancer, thyroid dysfunctions, inflammatory bowel disease, and cardiovascular disorders. Although the host and gut microbiota benefit each other from their symbiotic relationship, they may become competitors if the supply of micronutrients is limited. Intestinal bacteria can remove selenium from the host resulting in two to three times lower levels of host's selenoproteins under selenium-limiting conditions. There are still gaps in whether these consequences are unfavorable to humans and animals or whether the daily intake of selenium is also adapted to meet the needs of the bacteria.

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Selenium in Human Health and Gut Microflora: Bioavailability of Selenocompounds and Relationship With Diseases.

Selenium (Se) is known to contribute to several vital physiological functions in mammals: antioxidant defense, fertility, thyroid hormone metabolism, and immune response. Growing evidence indicates the crucial role of Se and Se-containing selenoproteins in the brain and brain function. As for the other essential trace elements, dietary Se needs to reach effective concentrations in the central nervous system (CNS) to exert its functions. To do so, Se-species have to cross the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCB) of the choroid plexus. The main interface between the general circulation of the body and the CNS is the BBB. Endothelial cells of brain capillaries forming the so-called tight junctions are the primary anatomic units of the BBB, mainly responsible for barrier function. The current review focuses on Se transport to the brain, primarily including selenoprotein P/low-density lipoprotein receptor-related protein 8 (LRP8, also known as apolipoprotein E receptor-2) dependent pathway, and supplementary transport routes of Se into the brain via low molecular weight Se-species. Additionally, the potential role of Se and selenoproteins in the BBB, BCB, and neurovascular unit (NVU) is discussed. Finally, the perspectives regarding investigating the role of Se and selenoproteins in the gut-brain axis are outlined.

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Selenium at the Neural Barriers: AReview.

The second brain: The connection between gut microbiota composition and multiple sclerosis

The stress response is an important tool in an organism's ability to properly respond to adverse environmental conditions in order to survive. Intense acute or chronic elevation of glucocorticoids, a class of stress hormone, can have deleterious neurological effects, however, including memory impairments and emotional disturbances. In recent years, the protective role of the antioxidant micronutrient selenium against the negative impact of externally applied stress has begun to come to light. In this review, we will discuss the effects of stress on the brain, with a focus on glucocorticoid action in the hippocampus and cerebral cortex, and emerging evidence of an ability of selenium to normalize neurological function in the context of various stress and glucocorticoid exposure paradigms in rodent models.

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Stress and the Brain: An Emerging Role for Selenium

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). The persistent inflammation is being mainly attributed to local oxidative stress and inflammasome activation implicated in the ensuing demyelination and axonal damage. Since new control measures remain necessary, we evaluated the preventive and therapeutic potential of a beta-selenium-lactic acid derivative (LAD-βSe), which is a source of organic selenium under development, to control experimental autoimmune encephalomyelitis (EAE) that is an animal model for MS. Two EAE murine models: C57BL/6 and SJL/J immunized with myelin oligodendrocyte glycoprotein and proteolipid protein, respectively, and a model of neurodegeneration induced by LPS in male C57BL/6 mice were used. The preventive potential of LAD-βSe was initially tested in C57BL/6 mice, the chronic MS model, by three different protocols that were started 14 days before or 1 or 7 days after EAE induction and were extended until the acute disease phase. These three procedures were denominated preventive therapy -14 days, 1 day, and 7 days, respectively. LAD-βSe administration significantly controlled clinical EAE development without triggering overt hepatic and renal dysfunction. In addition of a tolerogenic profile in dendritic cells from the mesenteric lymph nodes, LAD-βSe also downregulated cell amount, activation status of macrophages and microglia, NLRP3 (NOD-like receptors) inflammasome activation and other pro-inflammatory parameters in the CNS. The high Se levels found in the CNS suggested that the product crossed the blood-brain barrier having a possible local effect. The hypothesis that LAD-βSe was acting locally was then confirmed by using the LPS-induced neurodegeneration model that also displayed Se accumulation and downmodulation of pro-inflammatory parameters in the CNS. Remarkably, therapy with LAD-βSe soon after the first remitting episode in SJL/J mice, also significantly downmodulated local inflammation and clinical disease severity. This study indicates that LAD-βSe, and possibly other derivatives containing Se, are able to reach the CNS and have the potential to be used as preventive and therapeutic measures in distinct clinical forms of MS.

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Organic Selenium Reaches the Central Nervous System and Downmodulates Local Inflammation: A Complementary Therapy for Multiple Sclerosis?

Multiple sclerosis is an autoimmune disease that affects the myelinated central nervous system (CNS) neurons and triggers physical and cognitive disabilities. Conventional therapy is based on disease-modifying drugs that control disease severity but can also be deleterious. Complementary medicines have been adopted and evidence indicates that yeast supplements can improve symptoms mainly by modulating the immune response. In this investigation, we evaluated the therapeutic potential of Saccharomyces cerevisiae and its selenized derivative (Selemax) in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice submitted to EAE induction were orally supplemented with these yeasts by gavage from day 0 to day 14 after EAE induction. Both supplements determined significant reduction in clinical signs concomitantly with diminished Th1 immune response in CNS, increased proportion of Foxp3+ lymphocytes in inguinal and mesenteric lymph nodes and increased microbiota diversity. However, Selemax was more effective clinically and immunologically; it reduced disease prevalence more sharply, increased the proportion of CD103+ dendritic cells expressing high levels of PD-L1 in mesenteric lymph nodes and reduced the intestinal inflammatory process more strongly than S. cerevisiae. These results suggest a clear gut-brain axis modulation by selenized S. cerevisiae and suggest their inclusion in clinical trials.

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Selenization of S. cerevisiae increases its protective potential in experimental autoimmune encephalomyelitis by triggering an intestinal immunomodulatory loop.

Juliana Helena dos Santos de Toledo

Papers

Organic Selenium Reaches the Central Nervous System and Downmodulates Local Inflammation: A Complementary Therapy for Multiple Sclerosis?

Selenization of S. cerevisiae increases its protective potential in experimental autoimmune encephalomyelitis by triggering an intestinal immunomodulatory loop.