Clinical manifestation of systemic amyloidosis.
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If failure is considered as a single event (e.g. collapse of a bridge), regardless of the time, only its probability is of interest. If we want to know when the failures can occur, their time characteristics are also important. In this chapter, time-dependent failures will be dealt with. Here, one must distinguish between unrepaired and repaired objects depending on whether the failed object is discarded or repaired and again put into service.
The basic quantity for unrepaired objects is the
Function
(a) Failure function
The
The
the unit is s-1 or h-1. The right-hand side of Equation (4) indicates how the probability density can be determined from empirical data,
Useful information on reliability is obtained from a very simple characteristic, the average or
The mean time to failure can be calculated from operational records as the average of the group of measured times to failure,
Remark: Equation (6) is appropriate if all objects have failed. If components with very long life are tested, the tests are usually terminated after some predefined time or after failure of certain fraction of all components. In such cases, modified formulas for
If a repairable item fails, it is repaired and again put into operation. After the next failure, it is again repaired and put into operation, etc. One can thus speak of a flow of operations and repairs (Fig. 2). If we denote each interval as “uptime”
If data for a high number of values
Flow of operations (uptimes,
The mean time between failures and mean time to repair can be used to characterize the probability that the object will be serviceable at a certain instant or not. The
where ∑
The coefficient of availability simply says what part of the total time is available for useful work. It also expresses the average probability that the object will be able to fulfill the expected task at any instant.
The complementary quantity,
says how many percent of the total time are downtimes. It also expresses the probability that the object will not be able to perform its function at a demanded instant. For example,
It must reminded here that the time of a repair is not always the same as the downtime when the object (e.g. a machine) does not work. In addition to the net time of the repair, some logistic times are often necessary, which sometimes last much longer than the repair.
A very important reliability characteristic is
The failed item is discarded. This is typical of simple unrepairable objects, such as lamp bulbs, screws, windows, integrated circuits, and many inexpensive parts. Also, a living being cannot be repaired, if it has died. Some objects could be repaired after failure but are not, because of economic reasons. Thus, the term nonrepaired objects can be used as more universal.
Failure rate expresses the probability of failure during a time unit but is related only to those objects that have remained in operation until the time
The fraction of failed objects,
Equation (1) relates mutually three variables: λ,
The separation of the variables leads to the differential equation of first order,
The integration and transformation lead to the following expression for the probability of operation as a function of time:
The probability of failure is
With respect to Equations (12) to (17), any of the four quantities
The mean time to failure can be calculated using Equation (5).
After a failure, the object is repaired and continues working. In complex systems, the failed part can also be replaced by a good one to reduce the downtime. The number of working objects remains constant, so that
The monitoring of operation and repairs of a certain machine has given the following durations of operations and repairs:
Tasks.
Determine the mean time between failures and mean time to repair.
Determine the coefficient of availability (
Express the average probability (in %) that the machine (a) will be able to work at any instant (
Mean time between failures
Coefficient of availability
The probability that the machine will be able to work at any instant equals the coefficient of availability;
In a town,
The coefficient of availability can be calculated as the number of operable buses,
Amyloidosis is a group of disorders that share the common feature of deposition into tissues of any one of a number of different proteins. The uniform underlying pathobiology is the finding that in each case, the protein—termed amyloid—deposited into the target organ has undergone abnormal three-dimensional folding. The abnormal folding of the peptide results in accumulation in tissues as micro-fibrillary structures. The deposition of amyloid protein, regardless of which specific protein forms the amyloid, results in disruption in the function of the organ in which the amyloid protein is deposited. The common histopathologic feature of all amyloidosis is the finding, by light microscopy, of amorphous protein in one or more organs, typically initially recognized upon histologic review of a biopsy, as an amorphous pink material on Hematoxylin and Eosin staining (Figure 1). Per the International Society of Amyloidosis 2016 nomenclature guidelines, amyloid fibrils must exhibit affinity for the histologic stain Congo red, showing green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. At least 36 different proteins can undergo abnormal folding and result in deposition of amyloid, causing clinical disease. It is conventional to describe a particular amyloid protein as “Amyloid Protein AX,” where the X is a suffix to the designation, based on the identity of the amyloid protein. The more commonly encountered subtypes are, for example Amyloid Protein AL, Amyloid Protein AA, and Amyloid Protein ATTR, as discussed below. This chapter is an overview of the different categories of amyloidosis, with a focus on the clinical features, prognosis, and management of focal or systemic amyloidosis. Symptoms depend on the type and amount of amyloid protein, and are often variable. The manifestations depend on the identity of the underlying protein that forms the amyloid fibrils, the burden of amyloid, and the organs involved, as well as comorbidities of an individual patient (see Table 1).
Photomicrographs of a lymph node biopsy with AL amyloidosis. Panel A: 10× magnification of a left axillary lymph node biopsy stained using Hematoxylin and Eosin, demonstrating amorphous pink material typical of amyloid infiltration. White areas are fat that has been leached from the tissue in processing. Panel B: 10× magnification of the same lymph node stained using Congo red, viewed by light microscopy.
Fatigue Edema at one or more sites Lightheadedness upon standing (due to orthostatic hypotension) Diarrhea Focal pain (due to peripheral neuropathy) |
Edema at one or more sites (due to either heart failure, nephrotic syndrome, or both) Focal mass lesions (amyloid deposition focally) Orthostatic hypotension (due to autonomic nerve dysfunction) enlarged tongue (macroglossia) Purpura (due to either coagulation disorder, skin fragility due to amyloid infiltration, or both) |
Clinical manifestation of systemic amyloidosis.
Worldwide, AA amyloidosis is the most common type of systemic amyloidosis. Although AA amyloid currently is the most common form of amyloidosis, the incidence is decreasing over time in western countries. This has been attributed to a significant decrease in chronic infections, as well as improved therapies for inflammatory diseases. A review from the UK in 2013 estimated in excess of 8.0 per million cases of amyloidosis every year and AA being second most common (18%) [1]. The underlying causes of systemic AA amyloidosis include a wide range of inflammatory diseases, including but not limited to chronic inflammatory disorders, infections, and malignancy (Table 2). The amyloid fibril AA is most often a result of abnormal folding and aggregation of serum apolipoprotein A (SAA), which is an acute phase reactant—that is, the level becomes elevated in the blood in response to inflammation [2]. AA amyloid fibrils form through a process of cleavage, misfolding, and aggregation into a highly ordered abnormal β-sheet conformation. Amyloid fibrils associate anatomically with other moieties, including glycosaminoglycans and serum amyloid P component (SAP), forming deposits that disrupt the structure and function of tissues and organs [3].
Chronic disorders [64, 65, 66] | Infections | Malignancy [74] |
---|---|---|
Rheumatoid arthritis (RA) Alzheimer’s disease Juvenile idiopathic arthritis Ankylosing spondylitis Psoriasis and psoriatic arthritis Still disease [67] Behçet syndrome [68] Familial Mediterranean fever Crohn’s disease Castleman disease [69] Cryopyrin-associated periodic syndromes (CAPS) [70] TNF-receptor–associated periodic fever syndrome Vasculitis | Leprosy [71] Osteomyelitis Tuberculosis [72] Chronic bronchiectasis [73] | Hodgkin disease Non-Hodgkin lymphoma Renal cell carcinoma Gastrointestinal cancers Lung cancer [75] Urogenital carcinoma Mesothelioma [76] |
Causes of AA amyloidosis.
In the healthy, physiological state in humans, the serum SAA concentration is relatively low, but the level increases about a thousand fold during an inflammatory reaction. In humans, SAA is expressed in three different isoforms: SAA1, SAA2 and SAA4 and are encoded by different genes. SAA1 and SAA2 are solely expressed in liver and are entirely bound to plasma High Density Lipoprotein in plasma [4]. Inflammation increases the secretion of cytokines, including IL-1, IL-6 and TNF, which in turn increases the production of SAA [5]. SAA functions to transport and recycle cholesterol from sites of tissue injury, thereby modulating the immune response. Not all individuals with high SAA levels develop amyloidosis; it appears that certain polymorphisms and mutations in the SAA genes predispose to abnormal protein folding and therefore amyloid formation [6]. The formation of amyloid fibril from precursor SAA protein is the result of complex interaction with glycosaminoglycans, including most prominently heparan sulfate [7]. Impairing this interaction or the degrading of heparan sulfate by a heparinase has been shown to prevent formation of amyloid fibrils, and this has led to an area of research for potential treatment.
More recently, a protein named A Leukocyte Chemotactic factor 2 (ALECT2) protein has been shown to be a cause of AA amyloidosis, with a propensity to cause renal amyloidosis [8]. The human ALECT2 gene, discovered only in 2008, has been localized to chromosome 5 (5q31.1-q32) [9]. ALECT2 is being increasingly recognized as a cause of AA amyloidosis.
Inherited forms of AA amyloidosis arise due to mutations in a variety of proteins that can undergo abnormal folding and consequent deposition into tissues, resulting in organ dysfunction. These include mutations in the genes encoding transthyretin, the fibrinogen A α-chain, apolipoprotein A-I, apolipoprotein A-II, and lysozyme [10]. These mutations appear to account for the vast majority of relatively rare familial amyloidosis. Each of these has clinical characteristics that are somewhat peculiar to the specific etiology of the inherited disorder.
Amyloidosis may be localized, or systemic. The clinical symptoms of AA amyloidosis depend on the organ involved by the amyloid fibril. Liver and spleen are the most common sites of deposition, but they are asymptomatic until late in the course of the disease. Hepatosplenomegaly and adrenal insufficiency are common in the advanced stage of AA amyloidosis. Renal involvement damages the glomerular membrane, resulting in nephrotic syndrome and proteinuria. Proteinuria is one of the earliest signs of AA amyloidosis, and seen in approximately 95% of patients with AA amyloidosis [2, 11]. Persistent, untreated renal damage results in end stage renal disease (ESRD), requiring some form of renal substitute therapy—either dialysis or renal transplantation. Cardiac involvement is by deposition of fibrils into cardiac muscle, but clinical cardiac dysfunction is extremely rare in AA amyloidosis, occurring in only 2% of patients in most series [12]. Gastrointestinal involvement results in diarrhea, malabsorption and pseudo obstruction of the bowel. There are several reports of thyroid gland involvement, manifesting as goiter [13].
Treatment of AA amyloidosis is challenging due to diverse underlying causes. Ideally, in inflammatory disorders—whether chronic infectious disease (e.g., mycobacterium tuberculosis, staphylococcal osteomyelitis, and other chronic infections), autoimmune disease (e.g., rheumatoid arthritis, scleroderma, and other immune mediated inflammatory diseases), idiopathic (e.g., sarcoidosis), and chronic low-grade malignancy (e.g., B and T cell low-grade lymphomas, Hodgkin disease) the treatment of AA amyloidosis is the treatment of the underlying disease process. The role of controlling inflammation is also essential in the management of AA amyloidosis in patients with chronic rheumatologic diseases. In the era of advanced therapies, the incidence of rheumatic arthritis leading to AA amyloidosis has declined significantly; this was at one time among the most common causes. Specific treatments such as surgical excision in Castleman disease, high dose colchicine for familial Mediterranean fever (FMF) and effective therapy for tuberculosis have shown to significantly reduce serum SAA levels thereby improvement in end organ dysfunction. Treatments of malignancy with chemotherapy and surgery have shown to reverse organ function.
Several anti-inflammatory agents have been studied as potential therapy to reduce the levels of SAA. Tocilizumab, a monoclonal antibody against IL-6 has been successful in significantly reducing circulating levels of SAA when used in autoimmune diseases. A recent series showed significant reduction in acute phase reactants as well as an improvement in proteinuria in patients treated with Tocilizumab for FMF [14].
In vitro studies have shown low molecular weight heparin to impair amyloid deposition by impeding the structural changes necessary for fibril formation. Eporsidate, a sulfonated small molecule similar to heparin sulfate binds competitively to glycosaminoglycan and reduces inflammation and amyloid deposition. This was initially studied as an agent to retard progressive renal failure, and it resulted in a favorable response in a phase II clinical trial [15]. Unfortunately, a phase III trial did not meet the targeted endpoints, and so Eporsidate has not been developed further to date [16]. Dimethyl sulfoxide (DMSO) is a derivative of intercellular low-density lipoprotein, which reduces levels of acute phase reactants including SAA, and has been shown to improve symptoms in patients with gastrointestinal involvement by AA amyloid [17].
Anti-SAP antibody, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid (CPHPC) was studied in Al and AA amyloidosis with favorable responses in an open label study [18]. A recent phase Ib trial of SAP inhibitor, Miridesap followed by humanized monoclonal antibody Dezamizumab against SAP showed clearance of amyloid fibrils in liver and spleen, confirmed by I-SAP scintigraphy [19]. Further studies are ongoing and these treatments are a real potential for future management of amyloidosis.
AL amyloidosis results from the deposition of abnormally folded immunoglobulin light chains into tissues. The formation of amyloid fibrils from immunoglobulin light chains requires abnormal three-dimensional folding of the light chain, resulting in filaments of β-sheets of relatively insoluble protein [20]. AL amyloid may arise from either polyclonal immunoglobulin light chains or, much more commonly, from monoclonal immunoglobulin light chains. In order for polyclonal AL amyloidosis to result, however, the light chains must fold abnormally—in order to form amyloid and accumulate in target organs. Further, the local concentration of these peptides must, in general, be high. In AL amyloidosis, whether polyclonal or monoclonal, the specific light chains have a peptide sequence that results in a predisposition to abnormal folding of the peptide. In some cases, this appears to be due to genetic polymorphisms in the light chain gene structure. Among the variable regions of the light chain gene products, several (Vλ1, Vλ2, Vλ3, Vλ6, and Vκ1) are over-represented as amyloid protein, suggesting that these peptide sequences have a predilection to fold abnormally and become amyloid. In monoclonal AL amyloidosis, the tendency of monoclonal light chain to fold abnormally may be due, rather, to a mutational event attributable to genomic instability of the clone, rather than a genetic polymorphism in the light chain sequence. Several laboratories have demonstrated that peptide sequences from patients with different levels of secreted light chain have distinct differences in the location of non-conservative mutations in the light chain genes. This implies that the location of non-conservative mutations may be one determinant of the amyloidogenic propensity of light chains in some cases. Three-dimensional structure analyses and site-mutagenesis experiments indicate that both replacement of conserved polar residues in light chains, and loss of hydrogen bonding sites, are common features seen in amyloidogenic immunoglobulin light chains [21, 22, 23, 24]. Separately, there is evidence that posttranslational modification of light chains can influence the propensity for amyloid to accumulate, including peptide glycosylation, lysine modification, and rate of proteolysis. Impaired function of metalloproteases that degrade extracellular matrix proteins have been implicated in the propensity of amyloid to accumulate. There is also strong evidence that glycosaminoglycans of the extracellular matrix—particularly heparan sulfate, but also dermatan sulfate and chondroitin sulfate, interact with amyloid protein, providing a scaffold for the polymerized amyloid fibrils [25]. The relative concentration of these glycosaminoglycans appears to impact on the propensity of amyloid to be deposited. It should be noted that in a recent series from China, Huang and Liu reported that immunoglobulin heavy chain amyloidosis accounted for 3.7% of cases of amyloidosis, as compared to AL amyloidosis accounting for 93% of cases. In that report, AA amyloidosis accounted for only 2.2% of all patients with systemic amyloidosis [26].
The Mayo Clinic pioneered the use of Mass Spectroscopy and High Performance Chromatography to identify the specific proteins present in amyloid tissue specimens. They have applied that technology to determine, from patient samples, whether a patient’s amyloid is AA or AL, and to further characterize if an AL specimen is entirely kappa or lambda light chains—consistent with a monoclonal process; or if the AL amyloid is an approximately equal mix of both kappa and lambda light chains—suggesting a polyclonal process. In a 2013 report, Grogg and colleagues identified two patients with pulmonary amyloidosis in whom Liquid Chromatography-Mass Spectroscopy documented equal amounts of kappa and of lambda light chain in the amyloid deposits. In addition, the polyclonal identity of the amyloid was demonstrated by immunohistochemical staining for kappa and lambda light chains, and polymerase chain reaction amplification of immunoglobulin gene sequence showed only a polyclonal population in these patients [27]. In 2016, the Mayo Clinic studied in detail a patient with localized amyloidosis of the oropharynx. Liquid Chromatography and Mass Spectroscopy documented polyclonal AL amyloid, with equal proportions of kappa and lambda light chains present. No monoclonal protein was identified, and no monoclonal lymphoid or plasma cell population was present. Thus, this group has well documented the process of localized amyloidosis attributable to polyclonal light chain deposition. In that report they also summarized data regarding an additional 17 patients identified from the medical literature with isolated amyloidosis of the palate [28]. In three of those seventeen cases, a plasma cell dyscrasia was present (MGUS in two and myeloma in one). Similarly, Wey and colleagues from Taiwan reported a patient with Sjogren’s syndrome complicated by localized, cutaneous nodular amyloidosis of the legs. In this case, C-reactive protein 0.12 mg/dL antinuclear antibody titer, anti-centromere antibody titer, and anti-Ro/SSA antibody titer were all pathologically elevated and polyclonal gammaglobulinemia was detected by serum immune-electrophoresis [29]. Thus, multiple investigators have substantiated the observation that AL amyloid can be polyclonal. Definitive data regarding the relative incidence of monoclonal versus polyclonal AL amyloid is not available. However, it does appear from these cases that polyclonal AL amyloidosis seems to be a more indolent process and less aggressive than AL amyloidosis, and is most often a localized process. In these cases, local therapy appears likely to control the disease. Nonetheless, there are documented cases of systemic polyclonal AL amyloidosis with multi-organ involvement and relatively poor prognosis as compared to age-matched individuals without amyloidosis.
Localized amyloidosis is much rarer than systemic amyloidosis, predominantly affects the skin or mucosal tissues (86%), and is usually of the AL subtype (98%). It is generally accepted that localized AL amyloidosis results from monoclonal light chains. However, the most recent amyloid nomenclature developed by the International Society of Amyloidosis in 2014 does not distinguish between monoclonal and polyclonal sources.
In contrast to polyclonal AL amyloidosis, monoclonal AL amyloidosis is typically an aggressive, multi-organ disease with a generally poor prognosis. The disease process is driven by production of a monoclonal immunoglobulin light chain—hence the name AL (amyloid, light chain). As noted previously, only a minority of monoclonal light chain gammopathy results in amyloidosis. The exonic coding sequence for the specific light chain will most often have either a mutation, or a polymorphism, that results in abnormal protein folding, in order for the light chain to be deposited as amyloid and cause organ dysfunction, as previously discussed. AL amyloid is found both extracellularly and intracellularly, in affected organs. Kyle and colleagues at the Mayo Clinic reported that the incidence of AL amyloid in Olmsted County, Minnesota, was in the range of 3–5 cases per million annually [30]. Others have estimated the annual incidence to be in the range of 10–14 patients per million. In contrast, it is estimated that the annual incidence of MGUS in men is 120 per 100,000 population at the age of 50 years, and increases to 530 per 100,000 population at the age of 90 years. The incidence of multiple myeloma is in the range of 85 cases per million annually in the United States. Thus, only a very small minority of patients with MGUS or overt multiple myeloma develop clinical AL amyloidosis. The average age at diagnosis of patients with AL amyloidosis is approximately 64. The disease appears to occur more commonly in males than females [31].
Presenting signs and symptoms of amyloidosis are the consequences of specific organ involvement. Cardiac involvement occurs in the majority of patients diagnosed as having AL amyloidosis, most typically presenting with symptoms and signs of heart failure syndrome but with a preserved left ventricular ejection fraction. In an excellent recent review, Gertz reported that 71% of patients with AL amyloidosis seen at the Mayo Clinic had cardiac involvement, with 58% having kidney disease [32]. Renal involvement most often includes nephrotic range proteinuria; in an early series reported by Kyle in 1975, of all patients reviewed in that series with any type of amyloidosis, approximately 90% had some degree of proteinuria. Neurologic involvement occurs in approximately 25% of patients, and may include peripheral neuropathies, including, most commonly carpet tunnel syndrome; or autonomic neuropathy—most prominently orthostatic hypotension but also including anhydrosis [33]. Organ enlargement is common, with as many as half of patients having hepatomegaly, and an enlarged tongue (macroglossia) occurs in approximately a quarter of patients. Kyle also described purpura, particularly periorbital purpura, as a notable finding.
AL amyloid is most commonly a systemic disorder. However, there are cases of AL amyloidosis localized to a single site. The sites of localized AL amyloid reported include the skin, the larynx, the gastrointestinal tract, and the urinary bladder. Diagnosis must be confirmed by tissue biopsy, in order to demonstrate the presence of the amyloid by Congo red histologic staining. When a clinician encounters a patient over the age of 60 with suspected systemic AL amyloidosis, serum protein electrophoresis is essential to determine if a monoclonal serum para-protein is present. If a monoclonal protein is either suspected or identified, then serum protein immune-electro fixation or immunoelectrophoresis is indicated. Once a monoclonal serum paraprotein is identified, bone marrow biopsy and aspirate should be obtained in order to assess the percentage of clonal plasma cells infiltrating of the marrow, and determine if the patient meets the criteria for diagnosis of multiple myeloma or a lymphoplasmacytic lymphoma. In patients with a clonal AL amyloid, treatment to eradicate the clone of plasma cells or lymphocytes producing the light chain, if successful, will prevent synthesis of new immunoglobulin light chains, and, if the patient can be supported to survive long enough, organ recovery may occur over time as the relatively insoluble amyloid is ultimately metabolized and broken down.
The clinical features of AL amyloidosis are extremely variable from one patient to the next; nearly every organ can potentially be involved. However, the disease has a stereotypic pattern of presentation in many cases. As noted earlier, systemic AL amyloidosis involves the heart in approximately 70–80% of cases, depending on the series. The most common clinical presentation of symptomatic organic heart disease due to AL amyloidosis is heart failure syndrome, with dyspnea and often leg swelling (edema), although angina pectoris (chest pain due to ischemia) may also occur, as well as arrhythmias. Prior to onset of clinically evident heart disease, nearly all patients with cardiac involvement by amyloidosis will have an elevated serum level of N-terminal Pro-natriuretic peptide Type B (NT-ProBNP). Progressive elevation of the Pro-BNP correlates with progressively poorer prognosis, and the level of Pro-BNP is a criterion for risk stratification and prognosis in several staging systems for cardiac amyloidosis. Similarly, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are sensitive (although not specific) markers of myocardial damage. The degree of elevation of these proteins are additional markers of myocardial cell damage in cardiac amyloidosis [34]. A characteristic finding on electrocardiogram is decreased voltage in the limb leads, as compared to normal; however, this is not a consistent finding even in patients with biopsy proven cardiac amyloidosis. Imaging of the heart by echocardiogram may demonstrate the characteristic amyloidosis findings of pathologically increased ventricular wall thickness, as well as a granular, sparkling appearance of the myocardium on three-dimensional echocardiographic imaging. Again, there is the caveat that early in the disease process these findings may not be evident. A longitudinal “strain” pattern may also be present, but again is not a specific finding for amyloidosis [35]. Technetium-99 pyrophosphate scanning of the heart, particularly with single photon emission computed tomography (SPECT), is a sensitive imaging technique that will show retention of the radionuclide in cases of cardiac amyloidosis; this is widely considered a diagnostic study of choice. Technetium-99 pyrophosphate scanning of the heart can often distinguish between ATTR amyloid and AL amyloid. Magnetic Resonance Imaging of the heart using the contrast agent gadolinium for enhancement, a more costly approach than echocardiogram or Technetium-99 scan, can provide evidence of cardiac amyloidosis. Delayed enhancement pulse sequences following infusion of the gadolinium will most often demonstrate a diffuse and irregular hyper-enhancement of the myocardium in patients with cardiac amyloidosis. Subendocardial late gadolinium enhancement (LGE) occurs more commonly in AL amyloidosis, and transmural LGE more commonly in ATTR cardiac amyloidosis. In this context, even greater specificity may be achieved using a Magnetic Resonance Imaging technique termed “myocardial nulling.” This technique exploits the observation that gadolinium contrast accumulates excessively and abnormally in myocardial tissue, that has accumulated amyloid, and the findings are quite specific for amyloidosis of the heart.
Several groups have developed staging systems that stratify cardiac prognosis in patients with AL amyloidosis. The Mayo Clinic group Cardiac Staging System stratifies patients based on the combination of NT-proBNP together with either the cTnT or the cTnI. These parameters may be used to assess prognosis at the time of initial diagnosis, and often form a part of eligibility criteria for clinical trials [36].
As noted, clinically evident heart disease in AL amyloidosis manifests most often as congestive heart failure syndrome, despite preservation of the left ventricular ejection fraction. The symptoms most often include fatigue and exertional dyspnea, as well as edema due to heart failure, in some cases. Signs may include a lateral shift of the cardiac point of maximal impulse, as well as adventitial heart sounds and murmurs. Cardiomegaly may be evident on chest radiogram. Due to amyloid deposition, a fraction of patients will have electrical conduction abnormalities, and resultant cardiac arrhythmias. Such arrhythmias may result in sudden cardiac death, if the abnormal rhythm does not result in non-lethal signs or symptoms first.
Second to cardiac manifestations, the most common organ clinically involved by systemic AL amyloidosis are the kidneys. Kidney disease due to amyloid seen in approximately 50–60% of patients, depending on the series. The organ tropism of AL amyloid correlates with the variable region gene sequence, and the IGLV6-57 gene sequence appears to predispose to renal involvement. Within the affected kidney, amyloid deposits are seen prominently in the glomeruli, with additional amyloid seen in blood vessels, in tubular-basement membranes, and in the interstitial space. Uptake of amyloid by mesangial cells induces a functional change in phenotype resulting in cellular dysfunction. In experimental models, uptake of amyloid results in a transformation of a mesangial cell from a smooth muscle cells to a macrophage phenotype. Renal dysfunction clinically is typically manifest first as a protein wasting process, which typically progresses to nephrotic range proteinuria. Nephrotic range proteinuria results in edema and with time leads to chronic kidney disease with progressive edema, followed by electrolyte disorders and progressively worsening glomerular filtration rate [37]. Because of urinary loss of natural anticoagulants such as Protein C, which has a relatively short half-life, venous thrombosis may occur in patients with Amyloidosis and renal disease. Both renal involvement by AL amyloidosis, and cardiac disease due to AL amyloidosis, contribute to the generalized weakness experienced by a majority of patients who have AL amyloidosis.
The nervous system is clinically involved in AL amyloidosis in approximately 20% of patients. The most common neurologic process seen is a sensory peripheral neuropathy, which is often painful. Dysautonomia is also seen, particularly manifesting as orthostatic hypotension due to amyloid damaging the autonomic regulation of blood pressure. Orthostatic hypotension can be disabling, and may result in falls and therefore fractures. Patients with severe orthostatic hypotension may remain bedridden to avoid symptoms, and are then at risk both for developing decubitus ulcers, as well as venous thromboses. Myopathy may also occur because of AL amyloid deposition, and may present as pseudo-hypertrophy, or may clinically mimic other muscle wasting diseases [38].
The gastrointestinal tract is involved by AL amyloidosis. In a recent report from Stanford University Medical Center, Yen and colleagues reported that in a retrospective analysis of 583 patients with amyloidosis, approximately 16% had gastrointestinal symptoms. They observed that 50% of patients with amyloid had nausea, vomiting, or abdominal pain. In this cohort, approximately 82% of patients had AL amyloid. A classic finding reported in the earliest descriptions of amyloidosis is macroglossia, an enlarged tongue. However, it is estimated that this is seen in only about 15% of patients [39]. Malabsorption is often seen in amyloidosis of the gastrointestinal tract, with consequence diarrhea, abdominal discomfort, and weight loss on this basis.
Patients with kappa light chain AL amyloidosis have been reported to have a greater propensity for hepatic involvement than lambda light chain amyloidosis [40]. In contrast, dominant soft-tissue and bone involvement is associated with the IGLV3-1 gene, and in some reports, the Kappa 1 light chain. Hepatic involvement is typically manifest as hepatomegaly, and biopsy typically documents the presence of amyloid [41]. Splenomegaly is also common, particularly when hepatomegaly is present, and splenomegaly may result in blood cell sequestration in the spleen, with cytopenias.
Amyloid infiltration has been reported in virtually every gland, although these reports suggest that direct endocrine dysfunction due to amyloidosis is relatively less common than involvement by the heart, kidneys, and neurologic systems [42]. Amyloidosis of the breast have been reported, as well as amyloidosis of the seminal vesicles also occurs. Amyloidosis can infiltrate the pancreas, and amyloid infiltration of the adrenal gland may result in adrenal insufficiency. Similarly, amyloid infiltration of the pituitary gland can result in polyendocrine dysfunction.
Cutaneous AL amyloidosis is well described, and most often presents as either hemorrhagic bullous lesions, or, classically, as purpura or ecchymosis. Among the early classic descriptions of cutaneous manifestations of amyloidosis is the phenomenon of periorbital purpura [43].
Patients with AL amyloidosis may have one or more acquired coagulopathies, resulting in a bleeding diathesis. This may be due to impaired synthesis of clotting proteins by a liver involved by amyloid infiltration; however, adsorption of coagulation proteins, most commonly Factor X, but other factors as well, results in increased clearance of coagulation proteins and a bleeding disorder. Other than Factor X, adsorption of Factor V and of von Willebrand factor have been reported in a number of series. In such cases, frequent infusion of the deficient factor can temporarily control bleeding [44]. An algorithm for diagnostic evaluation is seen in Figure 2.
Diagnostic algorithm of systemic amyloidosis.
Management of AL amyloidosis is, in the first instance, management of end-organ dysfunction, with the goal to support the patient. However, definitive therapy requires eradication of the clone of B cells producing the immunoglobulin light chains that are misfolded and deposited as amyloid. Clinical trials have documented that the combination of the alkylating anti-neoplastic agent l-phenylalanine mustard (Melphalan) together with a potent corticosteroid such as Prednisone or Dexamethasone, can suppress production of new light chains, and, with adequate time, alter the balance of production and very slow degradation of AL amyloid. High dose Melphalan with autologous hematopoietic rescue was compared to conventional dose Melphalan plus dexamethasone in a prospective, randomized clinical trial published in 2007 [45]. That study reported inferior survival for patients randomized to high dose chemotherapy with autologous hematopoietic rescue (autologous transplant). However, in the past decade, the morbidity and mortality from autologous transplant has declined, and the risk-benefit ratio appears to have improved. An analysis by the Center for International Blood and Marrow Transplant Research (CIBMTR) published in 2015 reported that five-year overall survival following autologous transplant for AL amyloidosis had improved from 55% during the period of 1995–2000, to 77% in the time period from 2007 to 2012. Thus, outcome for transplant now appears superior to outcome from conventional dose anti-neoplastic therapy [46]. However, there have been no new prospective randomized clinical trials of autologous transplant versus non-transplant therapy. Newer therapies that are effective in reducing the burden of neoplastic plasma cells producing AL amyloid include proteasome inhibitors, and monoclonal antibodies that target plasma cells, such as daratumumab, an anti-CD38 monoclonal antibody. There are being studied, with promising results; however, no mature randomized data is available as of this writing from use of the agents. Anti-SAP antibody is a promising modality that appears to remove AL amyloid with relative efficiency; however, this agent remains investigational as of this writing [47].
Hereditary transthyretin amyloidosis is an autosomal dominant, progressive, life-threatening disease caused by mutations in the gene encoding transthyretin. Transthyretin (TTR) is a homotetramer plasma transport protein secreted primarily by liver but also in retinal pigment epithelium and choroid plexus. It functions to transport thyroxine and retinol-binding protein and hence the name transthyretin [48]. ATTR amyloidosis results from deposition of abnormal TTR protein, which is a result of destabilized TTR-tetramer misfolding and fibril formation. ATTR amyloidosis can be hereditary or wild type. There are more the 130 mutations identified worldwide in the hereditary form with the most common being Val30Met mutation [49]. ATTR amyloidosis is a rare disease but recently it has been identified more commonly from advances in diagnostics. Wild type ATTR, occasionally called senile systemic amyloidosis because of the late age of onset is reported at an incidence of 10% in people more than 80 years of age [50].
Phenotypically the ATTR results in clinical syndrome with respect to the organ involved. The three main clinical entities are polyneuropathy, cardiomyopathy and leptomeningeal disease. Fiber length-dependent neuropathy is pathognomonic of the disease. In the initial phase, small fiber neuropathy results in pain, paresthesia, allodynia, hyperalgesia, dysesthesia and impaired sensation to temperature. In later stages, large fiber dysfunction results in loss of vibration sense and balance, ultimately leading to difficulty with ambulation from progressive motor weakness [51]. Autonomic dysfunction results in orthostatic hypotension, neurogenic bladder, sexual dysfunction and gastrointestinal symptoms such as diarrhea and/or constipation [52]. Some patients with wild type ATTR develop carpel tunnel syndrome as their initial presentation and are also related to specific TTR mutations such as Leu58His, Ile84Ser and Tyr114His [53].
Familial amyloid cardiomyopathy occurs commonly with Val122Ile TTR mutation and they present with EKG abnormalities, heart failure, intractable arrhythmias and conduction abnormalities. Echocardiogram reveals a granular sparkling with ventricular and septal wall thickening [54]. MRI can show a classical late gadolinium enhancement but cardiac scintigraphy by Technetium-99 m pyrophosphate has the highest sensitivity and specificity in diagnosis [55]. Leptomeningeal amyloidosis occurs in patients with Asp18Gly, Ala25Thr and Tyr114Cys mutations. TTR protein is secreted by choroid plexus and gets deposited in cerebral and subarachnoid blood vessels and leptomeninges [49, 56]. Symptoms include transient ischemic attack, cerebral infarction or hemorrhage, subarachnoid hemorrhage, hydrocephalus, ataxia, spastic paralysis, convulsion, and dementia. Isolated leptomeningeal involvement is infrequent and occurs in patients harboring Val30Met mutation [57]. Ocular, renal and isolated gastrointestinal involvements are also reported in ATTR amyloidosis.
Once untreatable, hereditary ATTR amyloidosis is now primarily treated with liver transplantation, especially in Japan where it has shown better survival benefit and life expectancy. Liver transplantation is not widely practiced outside Japan due to low availability of living donors [58]. The transplantation replaces the abnormal TTR protein to a wild type protein. Overall studies have shown better outcomes in patients with early disease and Val30Met mutation compared to late onset and non-Val30Met patients. Leptomeningeal disease and retinal involvement do not improve by liver transplantation. Cardiac involvement continues to progress even after liver transplantation in some cases due to deposition of wild type ATTR.
Although liver transplantation has better outcome, not all patients are eligible due to advanced disease and multiple other sites of involvement. The tetramer destabilization is the initial step in the process of amyloid fibril formation and this was studied as a potential for treatment. Tafamidis, a benzoxazole derivative binds to thyroxine-binding sites of transthyretin and inhibits the dissociation of tetramers thereby blocking the rate-limiting step in monomer formation. In a randomized double-blinded phase II/III study in patients with polyneuropathy, Tafamidis did not meet the co-primary endpoints in the intention to treat population but did show significant improvement of neuropathy improvement score and quality of life in efficacy-evaluable population [59]. In another Phase III study for patients with ATTR related cardiomyopathy, Tafamidis was superior to placebo in decreasing the all-cause mortality and cardiovascular-related hospitalizations [60]. It is approved in both Europe and Japan for use in familial amyloid polyneuropathy and received FDA approval in the United States in 2018 for treatment of transthyretin cardiomyopathy. Difunisal, a nonsteroidal anti-inflammatory drug used to treat pain and osteoarthritis was studied as an agent to stabilize the amyloid tetramer. It functions by binding to the T4 binding site in TTR. In a phase II/III study it had significant improvement in neuropathy score in patients with amyloid polyneuropathy [61].
RNA interference is a phenomenon in which the gene expression is blocked by small RNA molecules. This approach has been studied in several diseases by introducing a small RNA into the cell and obscures a gene hence forth potentially inactivating the gene. Partisan is a RNA interference molecule developed to block production of abnormal TTR protein in liver. In a phase III trial, patients with hereditary transthyretin amyloidosis neuropathy received Partisan (dose 0.3 mg/kg every 3 weeks) and had statistically significant improvement in modified Neuropathy Impairment Score+7 [62].
Antisense oligonucleotides (ASO) are chemically modified oligonucleotides designed to selectively bind the RNA in the cell and prevent the target protein expression by interfering with translation. A phase III trial is ongoing for ISIS-TTRRx, an ASO specific to TTR mRNA [63].
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Rehabilitation",slug:"physical-medicine-and-rehabilitation"},numberOfBooks:5,numberOfSeries:0,numberOfAuthorsAndEditors:91,numberOfWosCitations:41,numberOfCrossrefCitations:41,numberOfDimensionsCitations:81,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"1122",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"7879",title:"Spinal Cord Injury Therapy",subtitle:null,isOpenForSubmission:!1,hash:"674d4925395d0e0c564f092bda8c6482",slug:"spinal-cord-injury-therapy",bookSignature:"Antonio Ibarra, Elisa García-Vences and Gabriel Guízar-Sahagún",coverURL:"https://cdn.intechopen.com/books/images_new/7879.jpg",editedByType:"Edited by",editors:[{id:"72488",title:"Dr.",name:"José Juan Antonio",middleName:null,surname:"Ibarra Arias",slug:"jose-juan-antonio-ibarra-arias",fullName:"José Juan Antonio Ibarra Arias"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7540",title:"Different Areas of Physiotherapy",subtitle:null,isOpenForSubmission:!1,hash:"a73ff9538d7b2ff3aab93e411b669463",slug:"different-areas-of-physiotherapy",bookSignature:"Mintaze Kerem Gunel",coverURL:"https://cdn.intechopen.com/books/images_new/7540.jpg",editedByType:"Edited by",editors:[{id:"98035",title:"Prof.",name:"Mintaze",middleName:null,surname:"Kerem Gunel",slug:"mintaze-kerem-gunel",fullName:"Mintaze Kerem Gunel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6546",title:"Treatment of Brachial Plexus Injuries",subtitle:null,isOpenForSubmission:!1,hash:"24a8e7c7430e86f76fb29df39582855a",slug:"treatment-of-brachial-plexus-injuries",bookSignature:"Vicente Vanaclocha and Nieves 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Paraplegia",subtitle:null,isOpenForSubmission:!1,hash:"e44be7b6bdc95169c2e6d3bee44a7ca8",slug:"topics-in-paraplegia",bookSignature:"Yannis Dionyssiotis",coverURL:"https://cdn.intechopen.com/books/images_new/3805.jpg",editedByType:"Edited by",editors:[{id:"76883",title:"PhD.",name:"Yannis",middleName:null,surname:"Dionyssiotis",slug:"yannis-dionyssiotis",fullName:"Yannis Dionyssiotis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:5,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"46005",doi:"10.5772/57189",title:"Animal Models in Traumatic Spinal Cord Injury",slug:"animal-models-in-traumatic-spinal-cord-injury",totalDownloads:3684,totalCrossrefCites:10,totalDimensionsCites:15,abstract:null,book:{id:"3805",slug:"topics-in-paraplegia",title:"Topics in Paraplegia",fullTitle:"Topics in Paraplegia"},signatures:"Mahdi Sharif-Alhoseini and Vafa Rahimi-Movaghar",authors:[{id:"169162",title:"Dr.",name:"Vafa",middleName:null,surname:"Rahimi-Movaghar",slug:"vafa-rahimi-movaghar",fullName:"Vafa Rahimi-Movaghar"}]},{id:"54351",doi:"10.5772/67470",title:"The Effects of Motor Imagery After a Variety of Motor Learning Times on Excitability of Spinal Motor Neurons and Accurate Motion",slug:"the-effects-of-motor-imagery-after-a-variety-of-motor-learning-times-on-excitability-of-spinal-motor",totalDownloads:1167,totalCrossrefCites:1,totalDimensionsCites:8,abstract:"Purpose: This study aimed to examine the effects of motor imagery on the excitability of spinal motor neurons and accurate motion. Subjects and Methods: About 30 healthy volunteers were recruited. F-waves were recorded at rest, while touching a sensor and motor imagery conditions. Also, the pinch force was measured before and after motor imagery. Furthermore, the subjects mastered the 50% MVC pinch force with learning times of 10 s, 30 s, 1 min, and 2 min beforehand. Results: Spinal motor neuron excitability with motor imagery after motor learning for 10 s, 30 s, 1 min, and 2 min was significantly increased as compared to other conditions. Accurate motion in the pinch task after motor imagery was better maintained than in the pinch task before motor imagery with motor learning times of 30 s and 1 min. However, with learning times of 10s and 2 min, the subject?s ability to sustain accurate motion in the pinch task after motor imagery was significantly decreased as compared to that of the pinch task before motor imagery. Conclusion: Motor imagery increases spinal motor neuron excitability. To maximally improve accurate motion using motor imagery, it is important to practice and master motor learning beforehand",book:{id:"6249",slug:"neurological-physical-therapy",title:"Neurological Physical Therapy",fullTitle:"Neurological Physical Therapy"},signatures:"Yuki Fukumoto and Yoshibumi Bunno",authors:[{id:"196577",title:"Mr.",name:"Yoshibumi",middleName:null,surname:"Bunno",slug:"yoshibumi-bunno",fullName:"Yoshibumi Bunno"},{id:"197857",title:"Mr.",name:"Yuki",middleName:null,surname:"Fukumoto",slug:"yuki-fukumoto",fullName:"Yuki Fukumoto"}]},{id:"66670",doi:"10.5772/intechopen.85424",title:"Current Developments in Antioxidant Therapies for Spinal Cord Injury",slug:"current-developments-in-antioxidant-therapies-for-spinal-cord-injury",totalDownloads:1075,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"When spinal cord injury (SCI) occurs, numerous sources of reactive oxygen species and nitrogen species may be active within first minutes or hours and even reactivate few days later. Free radical formation and lipid peroxidation (LP) have been described as an important mechanism in the beginning and accelerated progress in the development of diverse pathologies, importantly in those related to central nervous system. The compromise of molecules and cellular structures due to the oxidative state of microenvironment in SCI may determinate survival or apoptosis of resident and infiltrating cells and polarization toward an inflammatory response, which lead to an extension of damaged tissue and loss of neuronal function, or a regulatory/regenerative response. The investigation of new antioxidant agents and their action at a molecular level begins to reveal mechanisms that, if correctly modulated, promise an improvement in recovery of functions with respect to conventional pharmacological therapies. In this chapter, we will review the general mechanisms of oxidative stress and lipid peroxidation, those antioxidant treatments in experimental development and clinical phase, as well as their achievements and limitations.",book:{id:"7879",slug:"spinal-cord-injury-therapy",title:"Spinal Cord Injury Therapy",fullTitle:"Spinal Cord Injury Therapy"},signatures:"Jonathan Vilchis Villa, Dulce M. Parra Villamar, José Alberto Toscano Zapien, Liliana Blancas Espinoza, Juan Herrera García and Raúl Silva García",authors:[{id:"280747",title:"Ph.D.",name:"Raúl",middleName:null,surname:"Silva García",slug:"raul-silva-garcia",fullName:"Raúl Silva García"},{id:"280748",title:"Dr.",name:"Jonathan",middleName:null,surname:"Vilchis Villa",slug:"jonathan-vilchis-villa",fullName:"Jonathan Vilchis Villa"},{id:"280751",title:"BSc.",name:"Liliana",middleName:null,surname:"Blancas Espinoza",slug:"liliana-blancas-espinoza",fullName:"Liliana Blancas Espinoza"},{id:"280754",title:"MSc.",name:"José Alberto",middleName:null,surname:"Toscano Zapien",slug:"jose-alberto-toscano-zapien",fullName:"José Alberto Toscano Zapien"},{id:"288703",title:"MSc.",name:"Juan",middleName:null,surname:"Herrera García",slug:"juan-herrera-garcia",fullName:"Juan Herrera García"},{id:"299206",title:"Dr.",name:"Dulce M.",middleName:null,surname:"Parra Villamar",slug:"dulce-m.-parra-villamar",fullName:"Dulce M. Parra Villamar"}]},{id:"47090",doi:"10.5772/58625",title:"Functional Electrical Stimulation in Paraplegia",slug:"functional-electrical-stimulation-in-paraplegia",totalDownloads:4706,totalCrossrefCites:0,totalDimensionsCites:4,abstract:null,book:{id:"3805",slug:"topics-in-paraplegia",title:"Topics in Paraplegia",fullTitle:"Topics in Paraplegia"},signatures:"Aris Papachristos",authors:[{id:"170551",title:"Dr.",name:"Aris",middleName:null,surname:"Papachristos",slug:"aris-papachristos",fullName:"Aris Papachristos"}]},{id:"62054",doi:"10.5772/intechopen.78722",title:"Tension in Peripheral Nerve Suture",slug:"tension-in-peripheral-nerve-suture",totalDownloads:865,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Avoiding suture tension in peripheral nerve coaptation seems to be a clinical dogma since 30 years, although experimental data are weak and clinical practice shows good functional outcome after peripheral nerve repair by direct coaptation under “reasonable” tension, defined by local anatomic feasibility and the use of specific suture material. In this article, we focus on the microsurgical technique of nerve stump coaptation and the distribution of tension through epineural sutures with various suture materials; we also analyze the impact on the different nerve tissue layers, the limit of this approach and its combination with other tissue releasing techniques like paraneurolysis, adjacent joint flexion, or bone shortening.",book:{id:"6546",slug:"treatment-of-brachial-plexus-injuries",title:"Treatment of Brachial Plexus Injuries",fullTitle:"Treatment of Brachial Plexus Injuries"},signatures:"Jörg Bahm, Tobias Esser, Bernd Sellhaus, Wissam El-kazzi and Frederic Schuind",authors:null}],mostDownloadedChaptersLast30Days:[{id:"63594",title:"Physical Rehabilitation in the Management of Symptomatic Adult Scoliosis",slug:"physical-rehabilitation-in-the-management-of-symptomatic-adult-scoliosis",totalDownloads:2227,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Scoliosis is prevalent in elderlies over the age of 60. Of the different curve types, the thoracolumbar curve is the most common curve type operated upon, as it is associated with marked trunk shift and disability. Current physiotherapy treatments consist of electrotherapy, aquatic exercises, core-strengthening exercises, and dry needling. Outcome of these treatments has not been satisfactory. Long-term successful rate of conservative treatment of symptomatic adult scoliosis is low, as the treatment addresses symptoms but not the biomechanics involved in adult scoliosis. Recent studies have shown that physiotherapeutic scoliosis-specific exercises (PSSE) and bracing stabilized the curves in 80% of the subjects. Thus PSSE and bracing should be added to the standard physiotherapy care in the management of symptomatic adult scoliosis. For asymptomatic patients with thoracolumbar curve that has an increased risk of progression, PSSE should be considered as preventative exercises. Patients who do not respond to conservative treatments and have significant spinal stenosis should be referred for surgery.",book:{id:"7540",slug:"different-areas-of-physiotherapy",title:"Different Areas of Physiotherapy",fullTitle:"Different Areas of Physiotherapy"},signatures:"Shu-Yan Ng, Tsz-Ki Ho and Yin-Ling Ng",authors:[{id:"204673",title:"Dr.",name:"Shu Yan",middleName:null,surname:"Ng",slug:"shu-yan-ng",fullName:"Shu Yan Ng"}]},{id:"54213",title:"Physical Therapy for Cerebellar Ataxia",slug:"physical-therapy-for-cerebellar-ataxia",totalDownloads:6338,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Ataxia, the incoordination and balance dysfunction in movements without muscle weakness, causes gait and postural disturbance in patients with stroke, multiple sclerosis, and degeneration in the cerebellum. The aim of this article was to provide a narrative review of the previous reports on physical therapy for mainly cerebellar ataxia offering various opinions. Some systematic reviews and randomized control trial studies, which were searched in the electronic databases using terms “ataxia” and “physical therapy,” enable a strategy for physical therapy for cerebellar ataxia. Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.",book:{id:"6249",slug:"neurological-physical-therapy",title:"Neurological Physical Therapy",fullTitle:"Neurological Physical Therapy"},signatures:"Akiyoshi Matsugi",authors:[{id:"196990",title:"Ph.D.",name:"Akiyoshi",middleName:null,surname:"Matsugi",slug:"akiyoshi-matsugi",fullName:"Akiyoshi Matsugi"}]},{id:"65842",title:"Treatment of Neuropathic Pain in Brachial Plexus Injuries",slug:"treatment-of-neuropathic-pain-in-brachial-plexus-injuries",totalDownloads:1471,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Brachial plexus injuries are commonly followed by chronic pain, mostly with neuropathic characteristics. This is due to peripheral nerve lesions, particularly nerve root avulsions, as well as upper limb amputations, and complex regional pain syndrome (CRPS). The differential diagnosis between CRPS and neuropathic pain is essential as the treatment is different for each of them. Medical treatments are the first step, but for refractory cases there are two main types of surgical alternatives: ablative techniques and neuromodulation. The first group involves destruction of the posterior horn deafferented neurons and usually provides a better pain control but has a 10% complication rate. The second group provides pain control with function preservation but with limited effectiveness. Each case has to be thoroughly evaluated to apply the treatment modality best suited for it.",book:{id:"6546",slug:"treatment-of-brachial-plexus-injuries",title:"Treatment of Brachial Plexus Injuries",fullTitle:"Treatment of Brachial Plexus Injuries"},signatures:"Nieves Saiz-Sapena, Vicente Vanaclocha-Vanaclocha, José María Ortiz-Criado, L. 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The CIMT comprises of task practice with the affected limb, constraint of the unaffected limb, and transfer package to foster compliance and increase the amount of task repetition. It helps to reestablish normal motor control through facilitating changes in physiological functions of the brain, improvement in real-world arm use, and movement precision and quality. However, its protocols vary. Some protocols use number of hours and others use number of repetitions to determine the intensity or the amount of task practice. This chapter argued that CIMT is effective, but the protocols that use a number of hours of task practice are not clear and are resource intensive; and as such they could interfere with the process of clinical decision making. Consequently, it proposed the use of a number of repetitions of task practice to determine the intensity or the amount of task practice and extending the application of CIMT to those with severe impairments after stroke.",book:{id:"7540",slug:"different-areas-of-physiotherapy",title:"Different Areas of Physiotherapy",fullTitle:"Different Areas of Physiotherapy"},signatures:"Auwal Abdullahi",authors:[{id:"252115",title:"Mr.",name:"Auwal",middleName:null,surname:"Abdullahi",slug:"auwal-abdullahi",fullName:"Auwal Abdullahi"}]},{id:"63762",title:"Postural Control in Individuals with Parkinson’s Disease",slug:"postural-control-in-individuals-with-parkinson-s-disease",totalDownloads:1475,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Parkinson’s disease is the second most common neurodegenerative disorder in the elderly population. It is a complex, progressive, multisystem disease associated with motor and nonmotor impairments. Postural instability is a crucial component of functional mobility, often overlooked by both clinicians and patients with Parkinson’s disease. It is a refractory drug complication for which rehabilitation is the most effective nonpharmacological aid. However, many interventions are based on empirical experience. Improving knowledge on the pathophysiology of postural control disorders is crucial to understand the multifaceted components affected and thus design specific rehabilitation protocols. This chapter intends to offer a comprehensive overview of the current knowledge on this topic starting from the pathophysiology of postural control disorders occurring in various ecological conditions to the most innovative multidisciplinary rehabilitation approaches.",book:{id:"7540",slug:"different-areas-of-physiotherapy",title:"Different Areas of Physiotherapy",fullTitle:"Different Areas of Physiotherapy"},signatures:"Marialuisa Gandolfi, Nicola Valè, Mirko Filippetti, Eleonora Kirilova Dimitrova, Christian Geroin, Alessandro Picelli and Nicola Smania",authors:[{id:"48223",title:"Prof.",name:"Nicola",middleName:null,surname:"Smania",slug:"nicola-smania",fullName:"Nicola Smania"},{id:"48224",title:"Dr.",name:"Alessandro",middleName:null,surname:"Picelli",slug:"alessandro-picelli",fullName:"Alessandro Picelli"},{id:"48225",title:"Dr.",name:"Marialuisa",middleName:null,surname:"Gandolfi",slug:"marialuisa-gandolfi",fullName:"Marialuisa Gandolfi"},{id:"96546",title:"BSc.",name:"Christian",middleName:null,surname:"Geroin",slug:"christian-geroin",fullName:"Christian Geroin"},{id:"252052",title:"Dr.",name:"Nicola",middleName:null,surname:"Valè",slug:"nicola-vale",fullName:"Nicola Valè"},{id:"252054",title:"Dr.",name:"Eleonora",middleName:null,surname:"Dimitrova",slug:"eleonora-dimitrova",fullName:"Eleonora Dimitrova"},{id:"252056",title:"Dr.",name:"Mirko",middleName:null,surname:"Filippetti",slug:"mirko-filippetti",fullName:"Mirko Filippetti"}]}],onlineFirstChaptersFilter:{topicId:"1122",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:320,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:16,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. 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Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. 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That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}}]}},subseries:{item:{id:"19",type:"subseries",title:"Animal Science",keywords:"Animal Science, Animal Biology, Wildlife Species, Domesticated Animals",scope:"The Animal Science topic welcomes research on captive and wildlife species, including domesticated animals. The research resented can consist of primary studies on various animal biology fields such as genetics, nutrition, behavior, welfare, and animal production, to name a few. Reviews on specialized areas of animal science are also welcome.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11415,editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",institutionString:null,institution:{name:"Universidade Paulista",institutionURL:null,country:{name:"Brazil"}}},{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBfcQAG/Profile_Picture_1631354558068",institutionString:"Universidad Michoacana de San Nicolás de Hidalgo",institution:{name:"Universidad Michoacana de San Nicolás de Hidalgo",institutionURL:null,country:{name:"Mexico"}}},{id:"161556",title:"Dr.",name:"Maria Dos Anjos",middleName:null,surname:"Pires",slug:"maria-dos-anjos-pires",fullName:"Maria Dos Anjos Pires",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS8q2QAC/Profile_Picture_1633432838418",institutionString:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}},{id:"209839",title:"Dr.",name:"Marina",middleName:null,surname:"Spinu",slug:"marina-spinu",fullName:"Marina Spinu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLXpQAO/Profile_Picture_1630044895475",institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",institutionURL:null,country:{name:"Romania"}}},{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",institutionString:'Scientific Veterinary Institute "Novi Sad"',institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}]},onlineFirstChapters:{paginationCount:14,paginationItems:[{id:"82457",title:"Canine Hearing Management",doi:"10.5772/intechopen.105515",signatures:"Peter M. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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