\r\n\t• Role of technological innovation and corporate risk management \r\n\t• Challenges for corporate governance while launching corporate environmental management among emerging economies \r\n\t• Demonstrating the relationship between environmental risk management and sustainable management \r\n\t• Contemplating strategic corporate environmental responsibility under the influence of cultural barriers \r\n\t• Risk management in different countries – the international management dimension \r\n\t• Global Standardization vs local adaptation of corporate environmental risk management in multinational corporations. \r\n\t• Is there a transnational approach to environmental risk management? \r\n\t• Approaches towards Risk management strategies in the short-term and long-term.
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He is an Editorial Board Member of the International Journal of Human Resource as well as a member of the British Academy of Management (UK), Chinese Economists Society (USA), World Economic Association (UK), American Economic Association (USA), and an Ambassador of the International MBA program of Chongqing University, PR China, for Pakistan. \nHis research focuses on corporate social responsibility, human resource management, strategic management, and business management.",institutionString:"Binjiang College, Nanjing University of Information Science &Technology, Wuxi, Jiangsu",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],coeditorOne:{id:"288698",title:"Prof.",name:"Larisa",middleName:null,surname:"Ivascu",slug:"larisa-ivascu",fullName:"Larisa Ivascu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRfMOQA0/Profile_Picture_1594716735521",biography:"Dr Larisa IVAȘCU is currently an associate professor at the Politehnica University of Timisoara. 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1. Introduction
Aneuploidy is a state in which cells have an abnormal and unbalanced number of chromosomes. An aneuploid cell can have one or more extra chromosomes, called hyperploid, or it could have lost one or more chromosomes, which is called hypoploid. Following this definition of aneuploidy, a cell that has doubled its complete genome without dividing is called tetraploid and not aneuploid, because a balanced genome is still present.
Aneuploidy is well known from cancer and systemic trisomies such as Down syndrome. Indeed, at least two out of three cancers exhibit aneuploidy [1–3]. Although it has been shown that aneuploidy causes stress and reduces cellular fitness [4–7], cancer cells have somehow found a way to cope with aneuploidy and manage to proliferate despite the detrimental consequences of aneuploidy. This is known as the aneuploidy paradox [6]. Perhaps by selecting numerical chromosomal abnormalities that promote tumor progression in addition to other structural genomic rearrangements, cancer cells can survive and keep growing [8, 9]. The profound effect that aneuploidy has on healthy cells is emphasized by the fact that, besides sex-chromosome abnormalities, in humans, only three systemic autosomal trisomies are compatible with life: trisomy 21 causing Down syndrome, trisomy 13 causing Patau’s syndrome and trisomy 18 causing Edward’s syndrome [10–12]. The viability of these systemic aneuploidies can probably be explained by the fact that these three chromosomes contain the lowest number of genes of all human autosomes. Even though these trisomies can be compatible with life, the majority of such trisomic pregnancies end with a miscarriage, and the children that do survive until birth suffer from severe cognitive and developmental defects [13].
But what is the origin of aneuploid cells? Aneuploidy is the result of chromosomal instability (CIN) and can arise when errors occur during DNA replication or mitosis. To prevent such errors, cells have evolved many checkpoints and mechanisms that ensure faithful replication of DNA and proper chromosome segregation. One of these checkpoints, the spindle assembly checkpoint (SAC), ensures that chromosome segregation is prevented until all chromosomes are properly attached to the mitotic spindle. Therefore, when the SAC fails, daughter cells can end up with gained or lost chromosomes. Furthermore, merotelic attachments—chromosome attachments where one of the sister chromatids is attached to both spindle poles—can result in aneuploidy even with a functional SAC. Finally, several other mechanisms, such as cohesion defects, multipolar spindles and lagging chromosomes, can all lead to incorrect chromosome segregation and thus aneuploidy [14].
Many tumor cells have inactivated the tumor suppressor p53, a key transcription factor in the DNA damage response and other cell cycle checkpoints. When functional, stresses such as DNA damage lead to activation of p53. P53 then induces a cell cycle arrest and activates DNA repair or induces apoptosis when the damage cannot be repaired. Loss of p53 makes cells more tolerant of aneuploidy [15] and allows them to propagate despite DNA damage or short telomeres [16].
When telomeres become too short, following proliferation or due to defects in telomere function, cells exit the cell cycle [17]. Loss of p53 overcomes this tumor suppression mechanism and allows cells to proliferate with critically short telomeres. This results in end-to-end fusion of sister chromatid telomeres, resulting in dicentric chromosomes. Dicentric chromosomes are likely to missegregate during mitosis, thus resulting in aneuploidy and DNA breaks. Such broken chromosomes can trigger a so-called breakage-fusion-bridge (BFB) cycle, which can continue over many cell divisions, leading to large duplications and deletions and very heterogeneous aneuploidy in cells [18]. Altogether, many processes, alone or in combination, can yield cells with whole chromosome or segmental chromosomal changes.
2. Aneuploidy during development and aging
Studying aneuploidy in the brain is complicated by the largely postmitotic state of adult neurons, limiting the methods that can be used. Therefore, many studies have used methods like interphase FISH, or DNA dyes such as DAPI or PI in combination with, for example, flow cytometry to determine the DNA/genome content of individual cells. Given the detrimental effect that aneuploidy has on cells, one would expect somatic cells of the brain to be perfectly euploid. A publication by Rehen et al. in 2001 challenged this view [19]. In this study, the authors quantified aneuploidy in embryonic mouse neuroblasts, adult cortex and lymphocytes using spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH). They found ~33% of the 220 mouse neuroblast metaphase cells studied to be aneuploid as assessed by SKY, the great majority of which was hypoploid (98%). In contrast, of the adult mouse lymphocytes only 3% of the metaphase cells were identified as being aneuploid. In the same study, X and Y chromosome aneuploidy was assessed using FISH in adult mouse brain. They found X or Y chromosome aneuploidy occurring in 1.2% of the brain cells examined. The same rate of aneuploidy was found when comparing total adult nuclei with nuclei ≥10 μm, which are likely to be neurons. In comparison, the rate of X and Y chromosome aneuploidy in the mouse neuroblasts was ~10% (of which ~8% loss and 2% gain) [19]. In summary, these results suggest a high rate of aneuploidy in the developing mouse brain, and a much lower but still significant number of aneuploid cells in the adult mouse brain [20, 21]. A number of other studies reported similar aneuploidy rates in the developing human brain using interphase FISH. Aneuploidy rates up to 30–35% in the (developing) human brain were found, some studies reporting mainly chromosome losses [22, 23], another mainly chromosome gains [21]. The cause of aneuploidy in the developing brain was speculated to be mitotic segregation defects, since in dividing mouse neuronal progenitor cells lagging chromosomes and multipolar spindles have been found [24]. In contrast, there is little consistency in the aneuploidy rates reported in adult human brain. For example, the percentages of aneuploidy range from 0 up to 40: no aneuploidy was found in 2 normal brains (n = 200/chromosome/sample) [25], ~4% aneuploidy of chromosome 21 (n = 500–1000 per sample) [26], 1.3–7.0% aneuploidy per chromosome (n ≥ 500 for adult and ≥1000 for embryonic samples for each chromosome) [22] and 40% aneuploidy in the normal human brain (n = NA) [27]. All of these studies used FISH to count the chromosomes. A study performed by the group of Rehen, which combined several techniques, reported that aneuploid neurons seem to be integrated into the brain circuity like euploid cells and that aneuploid neurons can be activated and seem to be functional [28]. Taken together, although the rate of aneuploidy reported varies widely, most reports state that, especially in the developing brain, aneuploid cells are present at detectable frequencies in the normal brain.
But if aneuploid cells are present in large numbers in the developing brain, and in lower quantities in the adult human brain, what happens during aging? An increase in aneuploidy for chromosome 17 and 21 was found in the hippocampus of aged individuals compared to young controls [29]. In sharp contrast, another study determined the number of cells with a DNA content above the diploid level in brain samples ranging from 30 to 90 years of age. They found a decrease in the number of cells exceeding the diploid level with age [30], but suggested that this might be due to a biased selection of “healthy aging” brains. Taken together, there appears to be little consensus on whether aneuploid cells are present in adult brains, their frequency, and changes during aging. An overview of previous studies on aneuploidy in the brain is shown in Table 1. To explain the high rates of aneuploidy in the brain, several of the above-discussed studies hypothesized that aneuploidy in fact might contribute to neuronal diversity. The human brain consists of approximately 100 billion neurons forming an estimated 0.15 quadrillion (1015) synapses, and there is a very high diversity of neurons [31]. Human brains have a high level of cellular heterogeneity, and it has been estimated that our brains might have as many as 10,000 different types of neurons [32]. All these different neurons work together to allow us to perform complex tasks. It is suggested that the presence of aneuploid neurons could be one of the mechanisms providing more variability and complexity to the human brain [14, 32–34].
Species/cell type
Technique(s) used
Chromosomes studied
Main conclusions
Reference
Mouse neuroblasts and adult cortical cells
SKY, FISH, FACS
All chromosomes
~33% aneuploidy in neuroblasts, of which 98% hypoploidy, 1.2% X/Y aneuploidy in adult cortical cells
Mouse embryonic and adult cerebral and cerebellar cortex
FISH
1, 7, 18
~1% (cerebral) and 0.1% (cerebellar) aneuploidy per chromosome in 14 weeks and 6-month-old mice, ~30% aneuploidy per chromosome (chr. 1 and 18) in embryonic mouse brain
If our brain indeed contains aneuploid cells, where do they originate? As discussed above, aneuploid cells are usually formed when something goes wrong with DNA replication or in mitosis. Aneuploid cells could therefore be generated during early development when there is a high rate of cell division, or later in life during normal or abnormal cell division. We can think of a number of explanations. First, since especially in the developing brain high rates of aneuploid cells have been found, defective clearance of these cells could explain their presence in the adult brain [35]. During brain development, many more cells are formed than end up in the adult brain suggesting the existence of strong selection for certain cell types [36]. This process possibly includes negative selection for aneuploid cells, which could explain the much lower rate of aneuploidy reported in the adult brain than in the developing brain. Failure to select for diploid cells during this selection could result in aneuploid cells being present in the adult brain [37, 38]. Indeed, in vitro experiments have shown that the differentiation of pluripotent stem cells into neural progenitor cells by retinoic acid (RA) is accompanied by increased levels of aneuploidy and micronuclei [39]. Second, it has been hypothesized that cell cycle reentry and failure to complete the cell cycle of neurons might be involved in neurodegeneration [40–43]. Neurons might attempt to reenter the cell cycle, replicate their DNA but fail to complete cell division. The main evidence for this hypothesis is the observation that postmitotic neurons in AD brains sometimes stain positive for cell cycle markers such as PCNA, cyclins and cyclin depended kinases (CDKs) [44–50]. As a consequence of reentering the cell cycle, the presence of tetraploid cells in the brain is expected. These cells have completed DNA replication but are unable to complete mitosis. But whether tetraploid cells are indeed present in the brain is still under debate [51, 52]. By counting fluorescent signals from probes directed at either chromosome 11, 18 or 21, Yang et al., found that 3.7% of the hippocampal cells in six AD brains have displayed three or four fluorescent signals. Although the fluorescent probes were not combined on individual cells, no distinction was made between three and four fluorescent signals, and no neuronal marker or DNA counter stain was used; the researchers conclude from these results that 3.7% of the hippocampal cells in these AD brains have a fully or partially replicated genome. But these results can also reflect single chromosome aneuploidies [51]. In contrast, a study performed by Westra et al. failed to find any tetraploid neurons in the cells studied [52], the only cells with four fluorescent signals were nonneuronal, and no difference was found between AD and control samples. Also, this hypothesis of aberrant cell cycle reentry is not supported by the single chromosome aneuploidies found of which, in most cases, only one copy of one chromosome is lost or gained in a cell. Third, the limited amount of neurogenesis taking place in the adult brain could potentially be a source of aneuploid neurons [39, 53]. In summary, aneuploid neurons in the adult brain can have originated in the developing brain and escaped clearing mechanisms, or formed due to cell cycle reentry and failed mitosis of adult neurons although the evidence for this hypothesis is contrasting.
4. Aneuploidy in neurodegeneration
Because human brain tissue is inaccessible in vivo, many researchers used peripheral cells, such as lymphocytes and fibroblasts, to study the correlation between genomic damage and neurodegenerative diseases such as AD. Several studies with conflicting results have been published: some show a correlation between AD and increased peripheral aneuploidy [54–58], while others report no difference [59, 60]. Counting the presence of micronuclei is a way to assess genome stability. Micronuclei are formed when chromosome segregation is flawed, causing a part of or a whole chromosome to end up outside of the nucleus in a so-called micronucleus. Therefore, the number of micronuclei present is a marker for chromosome missegregation. Interestingly, AD patients were found to have increased numbers of micronuclei in their lymphocytes, mostly containing whole chromosomes [61]. More specifically, AD patients were reported to have increased rates of trisomy 21 in lymphocytes, while missegregation rates for chromosome 13 were unaltered, when compared to healthy controls [62]. Similarly, patients suffering from AD were found to exhibit frequent copy number changes for chromosomes 17 and 21 in buccal cells [29].
Since neurons are postmitotic, methods requiring dividing cells to determine chromosome copy numbers cannot be used when studying aneuploidy in neurons. Most studies therefore make use of fluorescence in situ hybridization (FISH)-based methods to count chromosomes in brain cells. When comparing control brain with early and late AD samples using slide-based cytometry (SBC), PCR amplification of alu repeats, and chromogenic in situ hybridization (CISH), a twofold increase in neurons with a DNA content between 2 and 4 n was found [41]. Also in preclinical stages of AD, an increased number of neurons with a more than diploid DNA content have been reported [63]. Iourov et al. found no overall significant difference in aneuploidy rates when looking at copy number changes of seven autosomes (chromosomes 1, 7, 11, 13, 14, 17 and 18) and the X and Y chromosome. But a specific increase in chromosome 21 aneuploidy in neurons of AD brain samples was identified, of which 60% where gains and 40% loss of chromosome 21 [64]. On the other hand, in a recent study, a twofold increase in X chromosome aneuploidy was found in AD neurons when compared to age matched controls [65]. To summarize, although again the rates of aneuploidy and which chromosomes are affected differ between studies, the overall trends suggest that aneuploidy might be increased in AD [66].
5. The possible link between Down syndrome and Alzheimer’s disease
Down syndrome is the most common autosomal systemic aneuploidy. Besides the observation of increased levels of trisomy 21 in the brains of AD patients, Down syndrome and AD have more in common. First, Down syndrome patients are much more likely to develop AD and at an earlier age than genetic euploid individuals [67]. This could be related to the fact that the amyloid precursor protein (APP) gene, mutations in which are known to cause early onset AD, is located on chromosome 21 [68]. Also, in the brains of individuals with Down syndrome over 40 years of age protein aggregates, plaques and tangles, are present in amounts that are also observed in AD patients brains [69]. On the other hand, not all patients with trisomy 21 over 40 develop AD, although all of them develop plaques and tangles [70]. Second, it has been found that young mothers (<35 years) of a child with Down syndrome have increased chromosomal instability, as shown by having more micronuclei [71], and more chromosomal missegregation events in their lymphocytes [72]. In the great majority of cases (95%) the extra chromosome 21 originates from a maternal nondisjunction event [73, 74]. Moreover, Schupf et al. found that young mothers of a child with Down syndrome have a fivefold increased risk to develop AD, while the risk was not increased in mothers who had a child with Down syndrome at a later age (>35 years). It is therefore hypothesized that some women might have a genetic susceptibility to chromosome nondisjunction, increasing the risk of both getting a child with Down syndrome as well as developing AD [75, 76]. Lastly, also mouse models for Down syndrome display characteristics of AD [67]. For example, the widely used mouse model Ts65Dn, which has an extra copy of a large part of Mmu16, the mouse homolog of a large part human chromosome 21 including APP, displays increased levels of APP and Aβ, as well as progressive memory decline and neurodegeneration in adult mice [77–79].
6. How can aneuploid cells play a role in neurodegeneration?
Aneuploidy was shown to reduce cellular fitness [80]. It was therefore suggested that aneuploid cells might be selectively affected by cell death in the brains of AD patients. According to this hypothesis, a decrease in aneuploidy rates might be expected as the disease progresses. This is in line with the observation by Arendt et al. of decreased hyperploidy in severe AD compared to mild AD [63]. It must be noted that in this study, the total amount of DNA was studied with a DNA dye, rather than the rate of aneuploidy. On the other hand, if aneuploid cells remain present in the aging brain, aneuploidy could contribute to neurodegenerative diseases through proteotoxic stress. Misfolding of proteins leads to proteotoxic stress, the formation of protein aggregates and possibly neurodegeneration. Being aneuploid is a heavy burden for a cell. Having an extra copy of a chromosome generally means that the genes on this chromosome are transcribed and translated at the same rate compared to the two “normal” copies. Therefore, the cell has to deal with this 50% extra mRNA and protein [4, 7]. All these extra proteins have to be folded into the right conformation or processed by the protein degradation machinery. This leads to increased pressure on chaperones and the protein degradation machinery [5, 6]. Since protein aggregates are thought to play an important role in the development and progression of many neurodegenerative diseases, their formation might be stimulated by excess proteins that overload the protein folding and degradation machinery. Trisomy 21 has been reported to be more prevalent in the brains of AD patients. The extra copy of the APP gene on chromosome 21, which encodes the β-amyloid protein, could trigger the formation of amyloid plaques resulting in proteotoxic stress and ultimately cell death [68].
7. Low levels of aneuploidy found in the brain using single cell sequencing
Recently, it became possible to use single cell next generation sequencing (NGS) to look at aneuploidy in individual cells (Figure 1) [81, 82]. Compared to the classic method for measuring aneuploidy using FISH, single cell sequencing has some important advantages [83]. First, FISH studies are in most cases limited to examining only a few chromosomes per cell. Therefore, the total rate of aneuploidy is usually determined by extrapolating the aneuploidy rates of the few chromosomes that are studied, possibly resulting in an over- or underestimation of the frequency of aneuploidy. With single cell sequencing, the copy number of all chromosomes in each single cell can be determined more accurately. Each chromosome is sampled thousands of times, whereas with FISH the chromosomes are usually measured only once or twice. Although spectral karyotyping (SKY) can also be used to count all chromosomes within a cell, this method requires metaphase chromosomes and thus dividing cells, while single cell sequencing can be performed on nondividing cells [84]. Moreover, SKY is more likely to overestimate chromosome loss, due to chromosomes being washed away from the slide onto which they were dropped. This could explain the high rates of hypoploid cells found using SKY [19]. Second, since with FISH the karyotype is determined by simply counting the number of fluorescent spots, in several ways this can lead to errors in chromosome counts. Failure of the probe to hybridize can lead to underestimation, while nonspecific binding results in overestimation of aneuploidy rates.
Figure 1.
Single cell sequencing of a female cell with trisomy of chromosome 21 (A) and a male diploid cell (B). Plots are made using Aneufinder [89].
Fortunately, the development of single cell sequencing protocols has allowed studies of all chromosomes in single, nondividing cells. For this approach, libraries are made of individual cells or nuclei. In most cases, library preparation starts with a whole genome amplification step. This can be problematic because uneven amplification of genomic DNA may result in a sequencing bias. Next, the DNA is fragmented either mechanically, such as by sonication, or enzymatically, for example with restriction enzymes. To enable binding of the fragments to the sequencing flow cell, adapters are ligated to either end of the fragmented DNA. Also, individual barcodes can be introduced to allow pooling (multiplexing) of more than one library on a flow cell, thus significantly reducing sequencing costs. After sequencing, the individual reads are split into libraries for each individual cell based on the cellular barcode (demultiplexing), and the copy numbers of individual chromosomes can be determined by comparing the read density on each chromosome. An extra copy of a chromosome is expected to result in 50% increase in read density, while loss of a chromosome leads to a 50% reduction of the read density on that chromosome [66, 85, 86]. Depending on the sequencing depth, single cell sequencing can, in addition to whole chromosome aneuploidies, also reveal smaller copy number changes. Since single cell sequencing is often combined with FACS sorting of single nuclei, micronuclei will be lost when sorting nuclei. Also, this method is relatively expensive and thereby limits large-scale sequencing projects. Even though only few studies so far used next generation sequencing based on karyotype cells, the results are contrasting some of the earlier FISH-based findings in that the rate of aneuploidy found was in general much lower than was reported previously. For instance, Knouse et al. identified one aneuploid brain cell of the 43 sequenced cells, and all of the nine neurons sequenced were euploid [87]. Another study found five neurons to be aneuploid out of the 100 neurons that passed the quality criteria [81]. Also, only one chromosomal gain and 2 losses were identified in 110 sequenced frontal cortex neurons of 3 individuals [82]. Finally, the largest study determined aneuploidy rates in postmortem frontal cortex neurons of normal human brain and samples from patients affected with AD. Interestingly, a very limited number of aneuploid neurons was found; <1% aneuploidy both in controls and AD [66]. All of these single cell sequencing studies use cells of which the chromosome copy numbers are known as validation of the method: human male trisomy 21 fibroblasts [82], human male trisomy 18 neurons [81], mouse trisomy 16 brain cells [87] and human female trisomy 21 neurons [66]. In each case, the known aneuploidy as well as the correct number of X chromosomes, male or female, was detected with 100% accuracy, confirming the sensitivity of single cell sequencing. Studying aneuploidy in the developing human brain with single cell sequencing remains to be done. But also here, the lack of aneuploidy reported in the 36 mouse neuronal progenitor cells sequenced might be an indication that also the embryonic aneuploidy levels have been overestimated [87]. Taken together, the results of single cell sequencing studies are in sharp contrast to the previously reported aneuploidy rates. How can these conflicting results obtained with different techniques be explained? As mentioned before, studies of aneuploidy in the human brain are complicated. Selecting a tissue or cell type as valid control is difficult, as no tissue is similar to brain tissue. Usually, lymphocytes are used as control. This potentially introduces problems, as the isolation of cells or nuclei from such very different sources requires very different experimental approaches: lymphocytes are isolated as single, unattached cells, while brain tissue needs some sort of mechanical or enzymatic dissociation to obtain individual cells or nuclei. On the other hand, brain tissue sections can also be used, but in this case, the inevitable cuts through nuclei can give rise to incorrect chromosome counts. While differences in handling of the tissue or cells may explain some of the reported differences, this explanation does not apply when comparing aneuploidy in normal and diseased brain samples.
8. Conclusion
The frequency of neuronal aneuploidy in the normal healthy brain remains a matter of debate. Although many studies report a certain level of aneuploidy, this is not confirmed by more recent reports using single cell sequencing. Whether the number of aneuploid cells is increased or decreased with aging and in neurodegenerative diseases remains to be conclusively shown. Aneuploid neurons could be involved in neurodegeneration because an incorrect karyotype could cause proteotoxicity via protein misfolding and aggregation. Single cell sequencing is a promising tool to address questions about aneuploidy in the brain and should provide more definite answers in the years to come.
\n',keywords:"Alzheimer’s disease, aneuploidy, brain, neurodegeneration, single cell sequencing",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54576.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54576.xml",downloadPdfUrl:"/chapter/pdf-download/54576",previewPdfUrl:"/chapter/pdf-preview/54576",totalDownloads:824,totalViews:409,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"December 2nd 2016",dateReviewed:"February 14th 2017",datePrePublished:null,datePublished:"August 30th 2017",dateFinished:null,readingETA:"0",abstract:"Aneuploidy, a state in which cells exhibit copy number changes of (parts of) chromosomes, is a hallmark of cancer cells and, when present in all cells, leads to miscarriages and congenital disorders, such as Down syndrome. In addition to these well-known roles of aneuploidy, chromosome copy number changes have also been reported in some studies to occur in neurons in healthy human brain and possibly even more in Alzheimer’s disease (AD). However, the studies of aneuploidy in the human brain are currently under debate as earlier findings, mostly based on in situ hybridization approaches, could not be reproduced by more recent single cell sequencing studies with a much higher resolution. Here, we review the various studies on the occurrence of aneuploidy in brain cells from normal individuals and Alzheimer’s patients. We discuss possible mechanisms for the origin of aneuploidy and the pros and cons of different techniques used to study aneuploidy in the brain, and we provide a future perspective.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54576",risUrl:"/chapter/ris/54576",book:{slug:"chromosomal-abnormalities-a-hallmark-manifestation-of-genomic-instability"},signatures:"Hilda van den Bos, Diana C.J. Spierings, Floris Foijer and Peter M.\nLansdorp",authors:[{id:"203168",title:"M.Sc.",name:"Hilda",middleName:null,surname:"Van Den Bos",fullName:"Hilda Van Den Bos",slug:"hilda-van-den-bos",email:"h.van.den.bos@umcg.nl",position:null,institution:null},{id:"203169",title:"Dr.",name:"Diana CJ",middleName:null,surname:"Spierings",fullName:"Diana CJ Spierings",slug:"diana-cj-spierings",email:"d.c.j.spierings@umcg.nl",position:null,institution:null},{id:"204784",title:"Dr.",name:"Floris",middleName:null,surname:"Foijer",fullName:"Floris Foijer",slug:"floris-foijer",email:"f.foijer@umcg.nl",position:null,institution:null},{id:"204785",title:"Prof.",name:"Peter M",middleName:null,surname:"Lansdorp",fullName:"Peter M Lansdorp",slug:"peter-m-lansdorp",email:"p.m.lansdorp@umcg.nl",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Aneuploidy during development and aging",level:"1"},{id:"sec_3",title:"3. Origin of aneuploid cells in the brain",level:"1"},{id:"sec_4",title:"4. Aneuploidy in neurodegeneration",level:"1"},{id:"sec_5",title:"5. The possible link between Down syndrome and Alzheimer’s disease",level:"1"},{id:"sec_6",title:"6. How can aneuploid cells play a role in neurodegeneration?",level:"1"},{id:"sec_7",title:"7. Low levels of aneuploidy found in the brain using single cell sequencing",level:"1"},{id:"sec_8",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Duijf PHG, Benezra R. The cancer biology of whole-chromosome instability. Oncogene. 2013 Oct;32(40):4727-36.'},{id:"B2",body:'Weaver BAA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006 Dec;18(6):658-67.'},{id:"B3",body:'Duijf PHG, Schultz N, Benezra R. Cancer cells preferentially lose small chromosomes. Int J Cancer. 2013 May;132(10):2316-26.'},{id:"B4",body:'Oromendia AB, Dodgson SE, Amon A. Aneuploidy causes proteotoxic stress in yeast. 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European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
'},{corresp:null,contributorFullName:"Peter M. Lansdorp",address:null,affiliation:'
European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
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\n
1. Introduction
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The ankle joint is the most commonly affected joint in sports of which lateral ankle sprains are the most common. The sports in which lateral ankle sprains are a frequent occurrence are football, basketball, running, volleyball, tennis, badminton, ballet/dance, etc. In many sports the rate of injury is as high as 70%. Unilateral ankle sprains are reported in 52%, whereas for bilateral ankle sprains, the number is 48%. The recurrence rate of ankle injury in athletes is 73% [1]. The incidence is high between 15 and 19 years of age with no significant difference in the gender [2].
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2. Biomechanics
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The lateral ankle compartment comprises the anterior talofibular ligament (ATFL), the calcaneofibular ligament (CFL), and the posterior talofibular ligament (PTFL). The most commonly injured ligament is the ATFL as it is the weakest of all three ligaments. In frequency of injury, the ATFL is followed by the calcaneofibular ligament CFL [3]. The PTFL is rarely injured as it is the strongest of all the three ligaments. The most common mechanism of injury in lateral ankle sprains is when, in forced plantar flexion, inversion occurs with excessive ankle supination. In that position the ankle joint is the most unstable. In the course of the inversion, the body’s center of gravity moves over the ankle leading to ankle sprains [2]. There are three clinical grades of lateral ankle sprains [4, 5, 6].
Grade I—Mild. There is an incomplete tear of ATFL with little swelling and tenderness, minimal or no functional loss, and no mechanical joint instability.
Grade II—Moderate. Complete tear of ATFL with or without an incomplete tear of CFL with moderate pain, swelling, and tenderness over the involved structures; some joint motion is lost, and joint instability is mild to moderate.
Grade III—Severe. Complete tears of ATFL and CFL with marked swelling, hemorrhage, and tenderness. There is loss of function, and joint motion and instability are markedly abnormal.
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3. Chronic ankle instability (CAI)
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Athletes with chronic ankle instability give a history of two or three severe ankle sprains with the main complaint being intermittent giving out of the ankle. The athlete often complains of difficulty and apprehension on uneven surfaces. Even mild exacerbations lead to short-term dysfunction. It is characterized by residual ankle instability as a result of either mechanical ankle stability or functional ankle instability or a combination of both [6].
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4. Mechanical and functional instability
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Mechanical instability (MI) and functional instability (FI) are both due to recurrent lateral ankle sprains. Mechanical instability is defined as an increase in the accessory movements in the joint leading to hypermobility. Residual MI usually results from a tear or lengthening of one of the ligamentous structures supporting the joint and suggests a suboptimal healing process after injury. A lesser known phenomenon is hypomobility leading to ankle instability. Joint hypomobility can be intra-articular or extra-articular, giving rise to restricted range of motion at the ankle. Hypomobility occurs at the subtalar, talocrural joint, distal tibiofibular joint, and proximal tibiofibular joint [7, 8].
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As the joint develops MI, proprioceptive changes occur, which result in alterations in defense mechanism to prevent injuries, thus leading to CAI. FI can result in balance deficits, joint position sense deficits, delayed peroneal muscle reaction time, altered common peroneal nerve function, strength deficits, a decreased range of motion (ROM), sinus tarsi syndrome, and anterolateral impingement syndrome.
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5. Rehabilitation
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Early mobilization of ankle sprains as compared with cast immobilization has been shown to be more comfortable as it results in less pain and provides for an earlier return to work. Cast immobilization does not improve healing compared with an active mobilization rehabilitation program and may have negative implications in relation to muscle wasting and stiffness. Functional treatment is considered better in achieving more effective mobilization and an earlier return to daily activities. Lateral ankle sprains respond well to the conservative treatment which includes initially RICE—rest, ice, compression, and elevation—followed by early mobilization. Rehabilitation focuses on restoring ROM, strength, balance, and normal gait patterns. Functional rehabilitation begins on the day of injury and continues until pain-free gait and activities are attained. Functional rehabilitation has four aspects: ROM, strengthening, proprioception, and activity-specific training. Ankle joint stability is a prerequisite to the institution of functional rehabilitation. Since Grade I and Grade II injuries are considered stable, functional rehabilitation should begin immediately.
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5.1 Reduce pain and swelling
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5.1.1 Rest
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Rest is prescribed to avoid undue stress on the joint. It is required to reduce the metabolic demands on the injured tissue and thus avoid increased blood flow. It also helps in avoiding stress on the injured tissue that might disrupt the fragile fibrin bond, which is the first element of the repair process. Rest can be applied selectively to allow some general activity, but athletes must avoid stressful activities.
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5.1.2 Ice
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Cryotherapy involves a nice bath with a temperature of 4°–10°C for 12–20 min, one to three times per day, and applying an ice pack to the injured area for 15–20 min, one to three times per day. Ice therapy should be started immediately after the injury and ice application initiated within day 0 or day 1. Both have shown better results and return to full activity as compared to when the ice was applied after 48 h. Ice application should provide deep penetration to gain full benefits. Also the ice should not be held immobile in one area or frostbites may occur.
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Ice application causes vasoconstriction which decreases blood flow and therefore swelling to the injured area. The lowering of tissue temperature decreases the metabolism and the chemical actions of cells and thus lowers the oxygen and nutrient needs in the affected area. Decreased blood flow limits edema; there is less histamine release and therefore less capillary breakdown than would normally be present after injury. There is better lymphatic drainage from the injured area because of the lower pressure on the extravascular fluid (Table 1).
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Stage
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Duration (min)
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Sensation
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Stage 1
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1–3
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A cold feeling is noted
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Stage 2
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2–7
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Burning or aching
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Stage 3
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5–12
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Local numbness and anesthesia (decreased conductivity of regional nerve fibers)
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Stage 4
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12–15
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Reflex deep tissue vasodilation without an increase in metabolism
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Table 1.
Cryotherapy generates four stages of sensation [9].
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Hence, the rationale of minimum 15 min of cryotherapy per treatment.
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5.1.3 Compression and elevation
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Compression and elevation work better in combination with cryotherapy. Compression with an adhesive bandage and a foot elevation of more than 45° is the standard prescribed treatment for lateral ankle sprains. Compression can also be achieved by both adhesive and nonadhesive tapes, but it is important to renew them timely as the compression wears off with time. Normally a nonadhesive tape should be renewed after 3 days, and an adhesive tape should be renewed after 5 days [10]. This prevents swelling and immobilizes the injured area which prevents further injury and thus promotes healing. Passive exercises can be started in stage 3 which is the local numbness stage in which the athlete experiences less discomfort when exercising.
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5.2 Improve range of motion (ROM)
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5.2.1 Range of motion exercises
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Range of motion exercises include both active and passive exercises. Achilles tendon stretching should be started within 48–72 h in a pain-free range irrespective of weight-bearing status of the athlete to avoid the tissue from contracting. Self-passive stretches can also be given with the help of a towel. Next, the stretches should be extended to weight-bearing position, which can be done by standing on an inclined surface and asking the athlete to shift his/her weight forward. The stretches should be maintained 15–30 s, repeated 10 times, and should be done 3–5 times per day. Passive exercises are followed by active ROM exercises whereby the athlete can do alphabet letter exercises, i.e., drawing letters in the air both in upper and lower cases. The exercises should be done 2–3 times per hour, 4–5 times per day. Stationary biking can also be included to improve dorsiflexion and plantar flexion motion in a controlled environment while providing a cardiovascular workout for the athlete.
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5.2.2 Manual therapy
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Manual therapy is started within 48 h after the injury when ankle dorsiflexion is restricted. To improve range, a gentle oscillating passive joint mobilization is given. Here the talus is moved posteriorly. By the convex concave rule, when the talus is moved posteriorly, the convex talus rolls upward and slides posteriorly on the concave surface of the crux, thus improving the dorsiflexion range. In a technique described by Maitland [11], with the athlete in supine position, the affected foot is taken in the available pain-free ROM in dorsiflexion. Gentle oscillations are then given to the joint to avoid pain and spasm. The oscillations are given for 60 s, 2 or more times with a rest of 10 s taken in between.
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Mobilization with movement is another technique of manual therapy suggested by Mulligan [12] which helps with increasing the ROM actively. In this technique the athlete position is high kneeling with weight-bearing on the affected limb or standing with the affected foot placed forward. In both positions the ankle is in neutral position. A padded belt is used for mobilization and is placed in such a way that the bottom of the belt is leveled with the inferior margin of the medial malleolus. The position of the mobilization belt allows the examiner to fix the talus and calcaneus with his/her hands and draws the tibia forward on the talus, thereby creating a relative posterior talar glide. Once the glide is given, the athlete actively dorsiflexes the ankle in a pain-free range. The glide should be maintained throughout the movement. Two sets of 10 repetitions, separated by a 2-min rest, are performed. Once ROM is achieved and swelling and pain are controlled, the athlete is ready to proceed to the strengthening phase of rehabilitation. Guidelines suggest that a normal ROM should be achieved within 2 weeks after injury [13].
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5.3 Improve strength
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Strengthening of weakened muscles is essential for a quick recovery and thus helps in preventing re-injury. An eversion to inversion strength ratio >1.0 is an important indicator of ankle sprain injury [14, 15]. Exercises should focus on strengthening the peroneal muscles because insufficient strength in this group of muscles has been associated with CAI and recurrent injury. However, all muscles of the ankle should be targeted, and all exercises should be performed bilaterally. When the training is performed bilaterally, we can expect substantial strength gains in both extremities. Strengthening begins with isometric exercises performed against an immovable object in four directions of ankle movement and is progressed to dynamic resistive exercises (isotonic exercises) using ankle weights, surgical tubing, or resistance bands.
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With a structured rehabilitation program, the athlete can create continuous goals and more easily appreciate improvements. A daily adjustable progressive resistance exercise (DAPRE) strength progression, originally described by Knight [16] and later modified by Perrin and Gieck [17], can be used to create a structured progression of exercises for the athletes. The strengthening exercises should be performed with an emphasis on the eccentric component. Athletes should be instructed to pause 1 s between the concentric and eccentric phases of exercise and perform the eccentric component over a 4-s period. Concentric contraction refers to the active shortening of the muscle with resultant lengthening of the resistance band, while eccentric contraction involves the passive lengthening of the muscle by the elastic pull of the band. Resistive exercises should be performed (2–3 sets of 10–12 repetitions) in all four directions twice a day. As weight-bearing strengthening exercises, toe raises, heel walks, and toe walks should be incorporated to regain strength and coordination. Toe curling exercises with paper or towel and marble picking should also be included for strengthening of the foot musculature (Table 2).
The athlete should proceed to the next line when he/she can lock out (complete with correct form) the 4th set 10 times.
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5.4 Improve proprioception and balance
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Once the athlete achieves full weight-bearing without pain, proprioceptive training is started for the recovery of balance and postural control. Various devices have been designed for this phase of rehabilitation. Their use in performance with a series of progressive drills has effectively returned athletes to a high functional level. As somatosensory and visual feedback is altered, the athlete must develop consistent motor patterns even with inconsistent feedback. Furthermore, the athlete can be tested under various visual and support conditions. The simplest device for proprioceptive training is the wobble board. The athlete is instructed to stand on the wobble board on one foot and shift his or her weight, causing the disc’s edge to scribe a continuous circular path. These exercises can be progressed by having the athlete use different-sized hemispheres and by varying visual input. A common progression when performing balance exercise is to move from a position of non-weight-bearing to weight-bearing, bilateral stance to unilateral stance, eyes open to eyes closed, firm surface to soft surface, uneven or moving surface. Another variant is when the therapist manually moves the ankle and foot through various positions and then asks the athlete to actively and passively replicate the joint angles. This helps improving joint position sense. As the body is trained to sense directions from perturbation, sensory input is received from all parts of the body and sent to the central nervous system via afferent pathways. Therefore, conscious and unconscious appreciation is important to protect functional joint stability. Proprioception is useful for preventing injury in slow, moderately quick, or even quick tasks; however, it may not be adequate for forces that challenge the neuromuscular system at the highest levels. The therapist should also focus on variability of speed and intensity while training proprioception and balance (Table 3).
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No material
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Ball
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Balance board
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Ball + balance board
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Exercise 1 One-legged stance with the knee flexed. Step out on the other leg with the knee flexed, and keep balance for 5 s. Repeat 10 times for both legs Variations 1 2 3 4
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Exercise 3 *Make pairs. Both stand in one-legged stance with the knee flexed. Keep a distance of 5 m. Throw and/or catch a ball 5 times while maintaining balance. Repeat 10 times for both legs Variations 1 2
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Exercise 5 One legged stance on the balance board with the knee flexed. Maintain balance for 30 s and change stance leg. Repeat twice for both legs Variations 1 2 3 4
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Exercise 10 Athlete stands with both feet on the balance board. Throw and/or catch a ball 10 times with one hand while maintaining balance. Repeat twice
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Exercise 2 One-legged stance with the hip and the knee flexed. Step out on the other leg with the hip and knee flexed, and keep balance for 5 s. Repeat 10 times for both legs Variations 1 2 3 4
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Exercise 4 *Make pairs. Stand both in one-legged stance with the hip and knee flexed. Keep a distance of 5 m. Throw and/or catch a ball 5 times while maintaining balance. Repeat 10 times for both legs Variations 1 2
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Exercise 6 One-legged stance on the balance board with the hip and knee flexed. Maintain balance for 30 s and change stance leg. Repeat twice for both legs Variations 1 2 3 4
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Exercise 11 Athlete stands in one-legged stance with the knee flexed on the balance board. Throw and/or catch a ball 10 times with one hand while maintaining balance. Repeat twice for both legs Variations 1 2
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Variations on basic exercises: The standing leg is stretched The standing leg is flexed The standing is stretched and first eyes are opened, followed by eyes closed The standing leg is flexed and first eyes are open followed by eyes closed The standing leg is stretched and upper hand technique (throwing the ball from above the head) The standing leg is flexed and upper hand technique The standing leg is stretched and lower hand technique (throwing the ball while keeping the hand below the waist) The standing leg is flexed and lower hand technique *This can be done by the therapist, and the athlete or the athlete can stand opposite to the wall at a distance of 5 m
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Exercise 7 Step slowly over the balance board with one foot on the balance board. Maintain the balance board in a horizontal position while stepping over. Repeat 10 times for both legs
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Exercise 12 Athlete stands in one-legged stance with the hip and knee flexed on the balance board; the other has the same position on the floor. Throw and/or catch a ball 10 times with one hand while maintaining balance. Repeat twice for both legs Variations 1 2
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Exercise 8 Stand with both feet on the balance board. Make 10 knee flexions while maintaining balance
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Exercise 13 Athlete stands with both feet on the balance board. Throw the ball with an upper hand technique 10 times while maintaining balance. Repeat twice for both legs Variations 5 6 7 8
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Exercise 9 One-legged stance on the balance board with the knee flexed. Make 10 knee flexions while maintaining balance. Repeat twice for both legs
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Exercise 14 Athlete stands in one-legged stance with the knee flexed on the balance board. Throw the ball with an upper hand technique 10 times while maintaining balance. Repeat twice for both legs Variations 5 6 7 8
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Table 3.
Proprioceptive exercises (the variation and changes should be according to the athlete’s requirements).
Adapted from: The Effect of a Proprioceptive Balance Board Training Program for the Prevention of Ankle Sprains: A Prospective Controlled Trial [18].
\n*All the exercises done by the Athlete, can be done in pairs or the athlete can stand opposite to a wall at distance of 5 m
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5.5 Sports-specific training
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Once the distance walked by the athlete is no longer limited by pain, he/she can be put on sports-specific training or advanced training. The use of sports-specific means of training, parallel to general conditioning training, leads to considerable improvement of performance among athletes. The sports-specific training includes intricate activities like jogging which eventually progresses to running, backward running, and pattern running. Circles and figure of 8 are commonly employed patterns. These activities can also be done using ankle weight to increase the difficulty level. Star excursion balance training can also be used in which the athlete stands on the sprained ankle while using another foot to reach as far as possible in eight directions as outlined in the Star Excursion Balance Test. The exercise can consist of 8–10 rounds clockwise and counterclockwise foot reach with 3 s rest between each direction. The difficulty level can be increased by adding variations to the exercise such as with the sprained ankle (affected leg’s knee) flexed, eyes opened, followed by eyes closed. At higher speed, i.e., at an angular velocity of 120°/s, the eversion to inversion ratio is >1.0, adding to the risk of injuries [19]. Hence, resistance bands can be used to strengthen the ankle musculature, i.e., training an athlete on an isokinetic machine while tying the band on the affected ankle and with the therapist holding the other end and maintaining the resistance through the movement. This should be done for 15–20 repetitions 1–2 times/day and with increasing progression. Specific training can include functional activities on various surfaces, e.g., trampoline and foam, and in water with weights. Repetitions should be 5–20, 1–2 times/day (Figure 1).
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Figure 1.
Star excursion balance test [20]. Note: Star Excursion Balance Test for left-leg dominant participants (Posterior direction is behind athlete’s right leg). Abbreviations: A, anterior; AM, anterior-medial; M, medial; PM, posterior-medial; P, posterior; PL, posterior-lateral; L, lateral; AL, anterior-lateral.
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5.6 Criteria for return to sports
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The athlete can participate fully in the sporting activity once the pain has been reduced completely. The progression should be gradual in order to stress the ligaments without causing further harm. Full participation should be allowed once the athlete has complete range of motion, 80–90% of preinjury strength and a normal gait pattern including the ability to perform sports-specific activities such as cutting and landing without any compensation due to the injury. The athlete should be able to complete a full practice without pain or swelling.
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5.7 Taping and bracing
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Taping and bracing the ankle can be used for prevention as well as for rehabilitation. Application of tapes and braces is helpful in the prevention of lateral ankle sprains and in the recurrence of injuries. Application of a tape or a brace increases the afferent feedback from cutaneous receptors, which lead to improved ankle joint position sense. This increased stimulation results in a more appropriate positioning of the unstable ankle and protects it from re-injury. Hence it helps improve joint position sense through proprioceptive mechanism.
Taping: The major role of taping is to prevent extreme range of movements and to reduce abnormal patterns of movements of the ankle. Various techniques are in use, but the most common techniques are basket weave with stirrup and heel lock and basket weave and heel lock techniques. Taping has mechanical effects: it decreases movement of inversion and plantar flexion and increases the force required for a specific displacement in inversion and plantar flexion. Taping helps in decreasing the extent of non-weight-bearing talar tilt. It also limits the full weight-bearing talar tilt. Athletes with the greatest instability benefit most from the tape. Although taping does improve mechanical instability, the restricting effect is lost after varying periods of exercise. About 40% of taping effect is lost after 10 min of vigorous exercise like jumping, pivoting, running, etc.
Kinesio™ taping: Unlike structurally supportive tape, such as white athletic tape, Kinesio™ tape is therapeutic in nature. It differs from the traditional athletic tape with respect to its elasticity, i.e., it can be stretched up to 140% of its original length before applying it on the skin. It provides a constant pulling (shear) force to the skin unlike traditional white athletic tape. The fabric of this tape is air permeable and water resistant and can be worn for repetitive days. The proposed mechanisms in which the Kinesio™ tape works are:
It corrects muscle function by strengthening weakened muscles.
It improves circulation of blood and lymph by eliminating tissue fluid or bleeding beneath the skin by moving the muscle.
It reduces pain through neurological suppression.
It repositions subluxated joints by relieving abnormal muscle tension, helping to return the function of fascia and muscles [21].
It improves proprioception through increased stimulation to cutaneous mechanoreceptors [22].
Bracing: Ankle bracing can make a significant contribution to preventing lateral ankle sprains. It also shows a significant reduction in the frequency of ankle sprain recurrence. Ankle braces have certain advantages over tape allowing self-application without the expertise of qualified personnel. They are convenient to apply and to remove; they are reusable, readjustable, and washable. There are nonrigid and semirigid braces. The nonrigid ones are often made of canvas or a neoprene-type material, which can easily be slipped on and off, and some are with additional lacing. The semirigid braces mostly consist of bimalleolar struts made of thermoplastic materials attached by Velcro straps. Nowadays different braces are used such as lace-up braces and the Swede-O (Swede-O-Universal, North Branch, MN) and multiple models by McDavid Sports Medical Products (Woodridge, IL); lace-up braces with straps such as the ASO (Medical Specialties, Charlotte, NC), the RocketSoc (DonJoy Orthopedics, Inc., Vista, CA), and the Ankle Brace Lock (Breg, Vista, CA); and semirigid plastic braces with strapping configurations such as the Ankle Ligament Protector (DonJoy Orthopedics, Inc.), the Universal Ankle Stirrup (DonJoy Orthopedics, Inc.), the T2 Active Ankle Support (Active Ankle, Louisville, KY) and the Ultra Ankle, and the Guardian Ankle (McDavid Sports Medical Products).
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Semirigid brace like Swede-O-Universal and nonrigid brace like subtalar supports provide a better non-weight-bearing restriction in plantar flexion, dorsiflexion, and eversion than taping after 15 min of activity. A strong thermoplastic semirigid ankle brace significantly reduces talar and subtalar motions of plantarflexion, inversion, and adduction. In summary, ankle taping and bracing:
Restrict ankle range of motion.
Reduce injury and recurrence rate.
Improve proprioception.
Lose limitation of movement after exercise.
Have no negative effect on most performance tests.
Have little negative effect on other joints.
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6. Grade III lateral ankle sprains
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Grade III lateral ankle sprains occur when there is a complete rupture of both ATFL and CFL. Although the initial line of management remains a functional rehabilitation, surgery should be considered if the symptoms persist. The feeling of giving way, defined as functional instability or true mechanical instability, is frequently experienced. This can be demonstrated by provocative tests such as the anterior drawer or talar tilt (either clinically or by stress radiography). Particular attention should be directed at the diagnosis and correction of subtle subtalar instability in individuals with functional instability. Surgical repairs are aimed at the reconstruction of the normal anatomy by overlapping the existing joint capsule and lateral ligaments. The rehabilitation protocol post-surgery remains the same as that of the conservative treatment.
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7. Conclusion
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The early rehabilitation of lateral ankle ligament sprains focuses on gaining full recovery by starting it within 24–48 h post injury. Most of the sprains respond well to functional treatment. Rehabilitation programs should be structured and individualized. In the acute phase, the focus should be on controlling inflammation, reestablishing full range of motion and gaining strength. Once the athlete achieves a pain-free range of motion and weight-bearing, balance-training exercises should be included to regulate neuromuscular control. Advanced-phase rehabilitation exercises should focus on regaining normal function. These should include sports-specific exercises specific to the particular sport played by the athlete. While having a basic guideline to follow for the rehabilitation of lateral ankle sprains, it is important to remember that individuals respond differently to exercises. Therefore, each program needs to be modified to fit the individual’s needs.
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\n\n',keywords:"lateral ankle sprains, athlete, sports, rehabilitation, exercise",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70162.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70162.xml",downloadPdfUrl:"/chapter/pdf-download/70162",previewPdfUrl:"/chapter/pdf-preview/70162",totalDownloads:476,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 14th 2019",dateReviewed:"September 3rd 2019",datePrePublished:"November 22nd 2019",datePublished:"July 29th 2020",dateFinished:null,readingETA:"0",abstract:"Lateral ankle sprains are one of the most common injuries in athletes. The rate of injury is as high as 70%. The most commonly involved ligament is the anterior talofibular ligament (ATFL), followed by the calcaneofibular (CFL) and posterior talofibular ligament (PTFL). The common mechanism of injury is inversion with excessive ankle supination in forced plantarflexion when the ankle joint is in its most unstable position. There are three grades of ankle sprains: Grade I, mild with an incomplete tear of ATFL; Grade II, moderate with a complete tear of ATFL with or without an incomplete tear of CFL; and Grade III, severe with complete tear of ATFL and CFL. Grades I and II respond well to functional treatment. Functional treatment includes RICE protocol, i.e., rest, ice, compression, and elevation. It also includes range of motion and strengthening exercises, proprioceptive training, and sports-specific exercises. Bracing and taping of the ankle joint help in preventing the sprains and also reduce the recurrence of the injury. Grade III ankle injury may be treated with surgery if the symptoms persist post functional treatment. The guidelines provided for the treatment of ankle sprains are of general validity, but each athlete is different with different needs. Hence, a personalized exercise protocol should be followed to achieve best results.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70162",risUrl:"/chapter/ris/70162",signatures:"Rachana Dabadghav",book:{id:"9413",title:"Essentials in Hip and Ankle",subtitle:null,fullTitle:"Essentials in Hip and Ankle",slug:"essentials-in-hip-and-ankle",publishedDate:"July 29th 2020",bookSignature:"Carlos Suarez-Ahedo, Anell Olivos-Meza and Arie M. Rijke",coverURL:"https://cdn.intechopen.com/books/images_new/9413.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"235976",title:"M.D.",name:"Carlos",middleName:null,surname:"Suarez-Ahedo",slug:"carlos-suarez-ahedo",fullName:"Carlos Suarez-Ahedo"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"305115",title:"M.Sc.",name:"Rachana",middleName:null,surname:"Dabadghav",fullName:"Rachana Dabadghav",slug:"rachana-dabadghav",email:"rach.nik25@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Biomechanics",level:"1"},{id:"sec_3",title:"3. Chronic ankle instability (CAI)",level:"1"},{id:"sec_4",title:"4. Mechanical and functional instability",level:"1"},{id:"sec_5",title:"5. Rehabilitation",level:"1"},{id:"sec_5_2",title:"5.1 Reduce pain and swelling",level:"2"},{id:"sec_5_3",title:"5.1.1 Rest",level:"3"},{id:"sec_6_3",title:"Table 1.",level:"3"},{id:"sec_7_3",title:"5.1.3 Compression and elevation",level:"3"},{id:"sec_9_2",title:"5.2 Improve range of motion (ROM)",level:"2"},{id:"sec_9_3",title:"5.2.1 Range of motion exercises",level:"3"},{id:"sec_10_3",title:"5.2.2 Manual therapy",level:"3"},{id:"sec_12_2",title:"5.3 Improve strength",level:"2"},{id:"sec_13_2",title:"5.4 Improve proprioception and balance",level:"2"},{id:"sec_14_2",title:"5.5 Sports-specific training",level:"2"},{id:"sec_15_2",title:"5.6 Criteria for return to sports",level:"2"},{id:"sec_16_2",title:"5.7 Taping and bracing",level:"2"},{id:"sec_18",title:"6. Grade III lateral ankle sprains",level:"1"},{id:"sec_19",title:"7. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\nYeung M, Chan K, So C, Yuan W. An epidemiological survey on ankle sprain. British Journal of Sports Medicine. 1994;28(2):112-116\n'},{id:"B2",body:'\nKobayashi T, Gamada K. Lateral ankle sprain and chronic ankle instability. Foot & Ankle Specialist. 2014;7(4):298-326\n'},{id:"B3",body:'\nChan KW, Ding BC, Mroczek KJ. Acute and chronic lateral ankle instability in the athlete. Bulletin of the NYU Hospital for Joint Diseases. 2011;69(1):17-26\n'},{id:"B4",body:'\nLynch SA. Assessment of injured ankle in the athletes. Journal of Athletic Training. 2002;37(4):406-412\n'},{id:"B5",body:'\nFerran N, Maffulli N. Epidemiology of sprains of the lateral ankle ligament complex. Foot and Ankle Clinics. 2006;11(3):659-662\n'},{id:"B6",body:'\nAlanen V, Taimela S, Kinnunen J, Koskinen S, Karaharju E. Incidence and clinical significance of bone bruises after supination injury of the ankle. The Journal of Bone and Joint Surgery British. 1998;80-B(3):513-515\n'},{id:"B7",body:'\nDananberg H, Shearstone J, Guillano M. Manipulation method for the treatment of ankle equinus. Journal of the American Podiatric Medical Association. 2000;90(8):385-389\n'},{id:"B8",body:'\nHetherington B. Lateral ligament strains of the ankle, do they exist? Manual Therapy. 1996;1(5):274-275\n'},{id:"B9",body:'\nHocutt J, Jaffe R, Rylander C, Beebe J. Cryotherapy in ankle sprains. The American Journal of Sports Medicine. 1982;10(5):316-319\n'},{id:"B10",body:'\nCapasso G, Maffulli N, Testa V. Ankle taping: Support given by different materials. British Journal of Sports Medicine. 1989;23(4):239-240\n'},{id:"B11",body:'\nMaitland GD. Peripheral Manipulation. 2nd ed. Sydney, New South Wales, Australia: Butterworths; 1977. p. 282\n'},{id:"B12",body:'\nMulligan B. “NAGS”, “SNAGS”, “MWMS”, etc. Wellington, NZ: Plane View Press; 1995\n'},{id:"B13",body:'\nVan Dijk CN. CBO-guideline for diagnosis and treatment of the acute ankle injury. National Organization for Quality Assurance in Hospitals. Nederlands Tijdschrift voor Geneeskunde. 1999;143(42):2097-2101\n'},{id:"B14",body:'\nWilkerson GB, Pinerola JJ, Caturano RW. Invertor vs. evertor peak torque and power deficiencies associated with lateral ankle ligament injury. The Journal of Orthopaedic and Sports Physical Therapy. 1997;26:78-86\n'},{id:"B15",body:'\nBaumhauer JF, Alosa DM, Renström FH, Trevino S, Beynnon B. A prospective study of ankle injury risk factors. American Journal of Sports Medicine. 1995;223:564-570\n'},{id:"B16",body:'\nKnight KL. Knee rehabilitation by the daily adjustable progressive resistive exercise technique. The American Journal of Sports Medicine. 1979;7:336-337\n'},{id:"B17",body:'\nPerrin DH, Gieck JH. Principles of therapeutic exercise. In: Perrin DH, editor. The Injured Athlete. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1999. pp. 123-139\n'},{id:"B18",body:'\nVerhagen E, van der Beek A, Twisk J, Bouter L, Bahr R, van Mechelen W. The effect of a proprioceptive balance board training program for the prevention of ankle sprains. The American Journal of Sports Medicine. 2004;32(6):1385-1393\n'},{id:"B19",body:'\nDabadghav R. Correlation of ankle eversion to inversion strength ratio and static balance in dominant and non-dominant limbs of basketball players. Journal of Sports Medicine and Physical Fitness. 2016;56(4):422-427\n'},{id:"B20",body:'\nHardy L, Huxel K, Brucker J, Nesser T. Prophylactic ankle braces and star excursion balance measures in healthy volunteers. Journal of Athletic Training. 2008;43(4):347-351\n'},{id:"B21",body:'\nKase K, Tatsuyuki H, Tomoki O. Development of Kinesio™ tape Kinesio™ taping perfect manual. Kinesio Taping Association. 1996;6-10:117-118\n'},{id:"B22",body:'\nMurray H. Effects of Kinesio™ Taping on Muscle Strength After ACL-Repair. Journal of Orthopaedic and Sports Physical Therapy. 2000;30:1-3. Available from: https://performance.nd.edu/assets/114689/kinesio_study_acl_repair.pdf [Accessed: 31 July 2019]\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Rachana Dabadghav",address:"rach.nik25@gmail.com",affiliation:'
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