",isbn:"978-1-83768-132-7",printIsbn:"978-1-83768-131-0",pdfIsbn:"978-1-83768-133-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"8e41aab8223c29ce69c00e8c8f6f560d",bookSignature:"Prof. Vlassios Hrissanthou",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12059.jpg",keywords:"Reservoir, Check Dam, River Flow, River Sediment Transport, Stilling Basin, Weir, Bridge Pier, Scouring, Reservoir Volume Capacity, Dimensioning Flood, Dimensioning Hydrograph, Length of Spillway",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 20th 2022",dateEndSecondStepPublish:"June 17th 2022",dateEndThirdStepPublish:"August 16th 2022",dateEndFourthStepPublish:"November 4th 2022",dateEndFifthStepPublish:"January 3rd 2023",remainingDaysToSecondStep:"a month",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Prof. Hrissanthou is the author and co-author of 48 publications in scientific journals, 88 publications in conference proceedings, and 12 book chapters published in English, Greek, and German. He is a member of the Hellenic Hydrotechical Association, the Deutsche Vereinigung fur Wasserwirtschaft, the European Water Resources Association (EWRA), the International Association of Hydrological Sciences (IAHS), and the International Association for Hydro-Environment Engineering and Research (IAHR).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"37707",title:"Prof.",name:"Vlassios",middleName:null,surname:"Hrissanthou",slug:"vlassios-hrissanthou",fullName:"Vlassios Hrissanthou",profilePictureURL:"https://mts.intechopen.com/storage/users/37707/images/system/37707.png",biography:"Dr.-Ing. Vlassios Hrissanthou is an Emeritus Professor at the Civil Engineering Department of Democritus University of Thrace (DUTH), Xanthi, Greece. He studied Civil Engineering at the Aristotle University of Thessaloniki (AUTH), Greece, obtaining the diploma of Civil Engineer in 1972. He then undertook postgraduate and doctoral studies on Hydrology and Hydraulic Structures at the University of Karlsruhe (KIT), Germany. Subsequently, he completed a postdoctoral study on Hydraulics and Hydraulic Structures at the University of the Armed Forces Munich (UniBw München), Germany. His teaching work includes the following graduate and postgraduate study courses: Fluid Mechanics, Hydraulics, Engineering Hydrology, River Engineering, Hydropower Engineering, Water Resources Management, Open Channel Hydraulics, Hydrology of Groundwater, Advanced Engineering Hydrology, Sediment Transport, Reservoir Design, Time Series Analysis, Selected Chapters of Hydropower Engineering, and Hydraulics of Stratified Flows. He has supervised a plethora of diploma, postgraduate and doctoral dissertations. He has participated as principal investigator in several competitive international, german and greek research projects, dealing amongst others with soil erosion and sediment transport. 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1. Introduction
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Non-alcoholic fatty liver disease (NAFLD) is a clinical and pathological entity with features that resemble alcohol-induced liver steatosis, but, by the definition, it occurs in patients with little or no history of alcohol consumption. NAFLD is subdivided into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). It encompasses a histological spectrum that ranges from fat accumulation in hepatocytes without concomitant inflammation or fibrosis (simple hepatic steatosis, NAFL) to hepatic steatosis with a necroinflammatory component (inflammation-induced apoptosis in hepatocytes) that may or may not have associated fibrosis. The latter condition, referred to as non-alcoholic steatohepatitis (NASH), can lead to NASH-induced liver cirrhosis (Figure 1). In addition, NASH is now recognised as the main cause of cryptogenic cirrhosis [1], as sequential association has been demonstrated in up to 75% of cryptogenic cirrhosis cases (see also Section 3 for detailed discussion of the relationships between NASH and cryptogenic cirrhosis). Liver cirrhosis may further lead to hepatocellular carcinoma (HCC), the most common primary liver cancer known for its poor clinical outcome and limited therapeutic options. Although previously it was considered that risk of HCC is limited to cirrhotic patients [2], a significant fraction of NASH-associated HCC develops in liver showing none or mild fibrosis. The association between NAFLD/NASH and increased HCC risk is supported by strong epidemiologic evidence.
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Figure 1.
Progression of NAFLD. Abbreviations: IL, interleukin; TNF, tumour necrosis factor; ROS, reactive oxygen species; Fe, accumulation of iron compounds.
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In the year 2010, the annual incidence of HCC in the population of the USA was at least 6 per 100,000. The mortality rate was almost identical to the incidence underscoring the serious prognosis [3]. Patients with NAFLD/NASH are subjected to an increased lifetime risk of HCC. In a 16-year follow-up study, the standardised incidence ratio of HCC in patients with NAFLD/NASH was 4.4 [4]. In a recent global meta-analysis, the HCC incidence among NAFLD patients reached 0.44 (range, 0.29–0.66) per 1000 person-years [5]. The HCC-related mortality rates among NAFLD patients range from 0.25 to 2.3% over 8.3 and 13.7 years of follow-up, respectively [5, 6]. NAFLD/NASH-associated HCC is believed to be the leading cause of obesity-related cancer deaths in middle-aged men in the USA [4]. Consistently, the proportion of HCC related to NAFLD/NASH is increasing worldwide and is reported to range between 4 and 22% in Western countries [7]. Although the exact burden of HCC associated with NAFLD/NASH still remains uncertain, it seems evident that NAFLD and NASH will become the most common causative/risk factors for HCC, surpassing viral or alcohol-related cirrhosis in the future [7]. In the USA, the number of NAFLD-associated HCC cases is annually growing (2004–2009) for 9% [8], while decreased burden of viral hepatitis-induced HCC might be expected due to the achievements in antiviral treatment targeting hepatitis C virus [9].
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NAFLD is the major hepatic manifestation of obesity and associated metabolic conditions. The epidemiology of NAFLD mirrors the recent spread of obesity and diabetes. With increasing prevalence of these conditions, NAFLD has become the most common liver disorder in USA [10] and other Western industrialised countries, facing high occurrence of the major risk factors for NAFLD, namely, central obesity, type 2 diabetes mellitus, dyslipidemia and metabolic syndrome [11]. In a recent meta-analysis of 86 studies, comprising 8,515,431 persons from 22 countries, the global prevalence of NAFLD was 25.24% (95% confidence interval [CI], 22.10–28.65) showing the highest occurrence in the Middle East and South America and the lowest in Africa [5]. Thus, 90% of patients suffering from morbid obesity (defined as having body mass index 40 kg/m2 or higher) and 74% patients affected by diabetes mellitus develop NAFLD. In addition, NAFLD has been observed even in non-obese, non-diabetic patients who have increased insulin levels in blood and resistance to insulin action. Consequently, NAFLD affects up to 20–30% of adults in Europe and 46% in the USA: a tremendously high prevalence for a condition that can cause any significant complications [9, 10].
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Most patients are diagnosed with NAFLD in their 40s or 50s. Studies vary in regard to the gender distribution of NAFLD, with some suggesting that it is more common in women and others suggesting more frequent occurrence in men [11, 12].
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Since 1998, non-alcoholic fatty liver disease has been considered a condition with a “two-hit” course of pathogenesis, first proposed by Day and James [13], describing the role of lipid peroxidation in liver injury. The “first hit” is the development of hepatic steatosis. It was suggested that hepatic triglyceride accumulation increased the susceptibility of the liver to the “second injury hit” by inflammatory cytokines and/or adipokines, mitochondrial dysfunction and elevated oxidative stress that together promote steatohepatitis and fibrosis [14]. Alternatively, many factors may act simultaneously leading to the development of NAFLD: this hypothesis corresponds to the multihit model proposed by Tilg and Moschen [15].
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Experimental and population studies have shown the links between NAFLD/NASH and development of HCC. However, the mechanisms by which NASH progresses to HCC are only beginning to be elucidated [14]. NASH is the most rapidly growing risk for liver transplantation because of HCC. Wong et al. in their study included 61,868 patients over the period 2002–2012 and found that the proportion of NASH-related HCC increased from 8.3 to 13.5%, an increase of near 63% [16].
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This increase is alarming as HCC already is the fifth most frequently diagnosed cancer and the second leading oncologic death cause worldwide [17], with increasing incidence and mortality rates in Europe [18]. Thus it is crucial to analyse molecular pathways involved in NASH-induced cirrhosis and HCC carcinogenesis. Focusing on the molecular events involved in pathogenetic chain of events from NASH to liver cirrhosis and HCC would provide not only better theoretical understanding of liver diseases preceding and following cirrhosis but would also allow to recognise predictive markers and treatment targets before HCC development.
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2. Common pathogenetic mechanisms of NAFLD
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Hepatic steatosis or excessive triglyceride accumulation in the liver is a prerequisite to the histological diagnosis of NAFLD. Several mechanisms may lead to steatosis, including (1) increased fat supply because of high-fat diet or excess lipolysis in adipose tissues, which increase free fatty acid (FFA) level; (2) decreased fat export in the form of very low density lipoprotein-triglyceride complex, secondary to either reduced synthesis of the relevant proteins or compromised excretion; (3) decreased or impaired β-oxidation of FFA to adenosine triphosphate and (4) increased hepatic synthesis of fatty acids through de novo lipogenesis [1, 19]. Free fatty acid delivery to the liver accounts for almost two-thirds of its lipid accumulation. De novo lipogenesis therefore only contributes to the accumulation of hepatic fat in case of NAFLD [15].
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The molecular mechanisms responsible for the accumulation of fat in the liver are complex (Figure 2). Certain inflammatory cytokines, particularly those derived from extrahepatic adipose tissues, can trigger this process. Insulin resistance appears to be at the centre for the massive metabolic dysregulations that initiate and aggravate hepatic steatosis. At a certain point, the simple steatosis transforms to steatohepatitis in about 20–30% of NAFLD patients [19]. A major feature in the transition from NAFLD to NASH is the appearance of hepatic inflammation [14]. This breakthrough-like process is mediated by the interplay of multiple hit factors and is orchestrated by rich network of miRNAs [20]. Currently, a number of common pathogenetic mechanisms have been proposed and characterised for the transition from simple steatosis to NASH [19]. A summary of these mechanisms is shown in Figure 3.
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Figure 2.
Pathogenesis of liver steatosis. Abbreviations: FFA, free fatty acids; TG, triglycerides; IL, interleukin; TNF, tumour necrosis factor; CCL2, CC motif chemokine ligand 2; VLDL, very low density lipoproteins.
Hypoxia and death of rapidly expanding adipocytes are considered important initiating factors of adipose tissue inflammation in obesity [19]. During inflammation, typical cytokines like tumour necrosis factor (TNF)-α, interleukin (IL)-6 and CC motif chemokine ligand 2 (CCL2) are secreted by inflammatory cells infiltrating adipose tissue [21]. TNF-α was the first pro-inflammatory cytokine detected in adipose tissue. TNF-α and IL-6 are involved in the regulation of insulin resistance [19]. TNF-α and IL-6 induce insulin resistance in adipocytes, stimulating triglyceride lipolysis and fatty acid release into the circulation. CCL2 recruits macrophages to the adipose tissue, resulting in even higher local cytokine production and perpetuating the inflammatory cycle [19]. In the liver, increased expression of hepatic IL-6 correlates with higher degree of insulin resistance in patients with suspected NAFLD [1].
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At the same time, extrahepatic adipocytes are compromised in their natural ability to secrete adiponectin, an anti-inflammatory adipokine that facilitates the normal partitioning of lipid to adipocytes for storage [19]. Adiponectin is a hormone secreted exclusively by adipose tissue. It has beneficial effects on lipid metabolism. In the liver, adiponectin is considered to have insulin-sensitising, anti-fibrogenic and anti-inflammatory properties by acting on hepatocytes, liver stellate cells and hepatic macrophages (Kupffer cells), respectively. Adiponectin suppresses the transportation of free fatty acids to the liver as well as gluconeogenesis and de novo synthesis of fats but enhances oxidisation of FFAs [21]. The adiponectin-induced suppression of aldehyde oxidase and transforming growth factor has net anti-fibrotic effect [21], while decreased release of pro-inflammatory cytokines including TNF-α reduces inflammation [1]. Decreased levels of adiponectin result in loss of these protective metabolic, anti-fibrotic and anti-inflammatory effects.
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Together, these abnormalities accentuate fat loss from adipocytes and promote ectopic fat accumulation [19].
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2.2. Insulin resistance
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Obesity and type 2 diabetes mellitus, both conditions associated with peripheral insulin resistance, are frequently diagnosed in patients affected by non-alcoholic fatty liver disease [12]. Evaluating patients suffering from diabetes mellitus, NAFLD was found in 74% of them in North American study, 70% in Italian population and 35–56% in Eastern countries. In Mexico, prevalence of NASH in diabetics was 18.5%. The prevalence of NAFLD in obese patients is 57–90% in Western and 10–80% in Eastern populations. NASH is present in 15–20% patients affected by obesity. The frequency of NASH is higher in those undergoing bariatric surgery and can reach 48–60% in USA men, 20–31% in USA females and up to 80% in Taiwan patients [9, 10, 12].
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Insulin resistance has also been observed in NASH patients who are not obese and those who have normal glucose tolerance [1]; however, not all people with NAFLD have increased insulin resistance. NAFLD also cannot be considered as a cause for insulin resistance but rather as a consequence [19].
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Resistance to the action of insulin results in important metabolic changes, including the turnover of lipids. It is characterised not only by increased circulating insulin levels but also by increased hepatic gluconeogenesis, impaired glucose uptake by muscle, enhanced peripheral lipolysis, increased triglyceride synthesis and increased hepatic uptake of fatty acids, as well as increased release of inflammatory cytokines from peripheral adipose tissues, which are the key factors promoting accumulation of liver fat and progression of hepatic steatosis [1, 19].
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2.3. Lipotoxicity
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The term “lipotoxicity” describes the deleterious effects of excess FFA and ectopic fat accumulation resulting in organ dysfunction and/or cellular death. In obesity, excessive food intake combined with high FFA output from insulin-resistant adipose tissue surpasses the storage and oxidative capacity of tissues such as skeletal muscle, liver, or pancreatic β-cells [22]. Long-chain saturated fatty acids, as well as free cholesterol derived from de novo synthesis can be harmful to hepatocytes. Free cholesterol accumulation leads to liver injury through the activation of intracellular signalling pathways in Kupffer cells, liver stellate cells, and hepatocytes [19], ultimately promoting inflammation and fibrosis [23]. FFAs are redirected into noxious pathways of nonoxidative metabolism with intracellular accumulation of toxic metabolites. It is not TG accumulation per se that is uniquely hazardous, but rather the lipid-derived metabolites that trigger the development of reactive oxygen species (ROS) and activation of inflammatory pathways [22], including up-regulation of nuclear factor kappaB, production of TNF-α and IL-6 [24], and the subsequent inflammatory reaction in the liver [1].
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2.4. Oxidative stress
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In the context of increased supply of fatty acids to hepatocytes, oxidative stress can occur. It is attributable to the raised levels of reactive oxygen/nitrogen species and lipid peroxidation that are generated during free fatty acid metabolism in microsomes, peroxisomes, and mitochondria [19]. NAFLD and NASH-induced oxidative stress is partly regulated through cytochrome P450 2E1 (CYP2E1) as it metabolises C10–C20 fatty acids [14] that in turn produce hepatotoxic free oxygen radical species [1]. Peroxidation of plasma and intracellular membranes may cause direct cell necrosis/apoptosis and development of megamitochondria, while ROS-induced expression of Fas-ligand on hepatocytes may induce fratricidal cell death [19]. Recent studies support the idea that oxidative stress may be a primary cause of liver fat accumulation and subsequent liver injury [25], as well as ROS may play a part in fibrosis development. Lipid peroxidation and free oxygen radical species can also deplete antioxidant stores such as glutathione, vitamin E, beta-carotene, and vitamin C, rendering the liver susceptible to oxidative injury [1].
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2.5. Increased hepatic iron concentration
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The degree of liver fibrosis in nonalcoholic steatohepatitis shows correlation with the concentration of iron compounds in the hepatocytes. The underlying mechanism might involve the ferric-to-ferrous reduction (switch of trivalent Fe(III) to divalent Fe(II) compounds), resulting in simultaneous production of free oxygen radicals [1]. In addition, sinusoidal iron accumulation might also have a pathogenetic role in the progression of chronic liver diseases and development of hepatocellular carcinoma [26]. However, at least in Eastern populations, disturbances of iron metabolism are rarely observed in NAFLD patients [12]. In patients without iron overload, increased ferritin level in the blood may still be associated with insulin resistance and fatty liver [27].
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2.6. MicroRNAs in NAFLD
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MicroRNAs are small molecules of non-coding RNA that act as large-scale molecular switches. The pathogenetic chain of events in the transition to NAFL, NASH, and liver cirrhosis is richly regulated by miRNA network: it has been estimated that approximately 54 miRNAs regulate 107 genes involved in the development of NAFLD. The up-regulation of miR-26b and down-regulation of miR-26a decrease insulin sensitivity, while lower levels of miR-451 are associated with pro-inflammatory background. The up-regulation of miR-155 and miR-107 promotes fat accumulation in liver cells. Enhanced fibrosis is mediated by miR-21. Assessing patients with NAFLD-associated liver fibrosis, at least 9 miRNAs are expressed in modified levels, including higher expression of miR-31, miR-182, miR-183, miR-224, and miR-150 as well as down-regulated levels of miR-17, miR-378i, miR-219a, and miR-590. In the progression of liver fibrosis, the normally high levels of miR-22 and miR-125b are suppressed. The miR-29 family showing anti-fibrotic action in many organs is also suppressed [20].
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3. NASH-induced liver cirrhosis
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Liver cirrhosis develops (Table 1) when simple steatosis progresses to steatohepatitis and then fibrosis [11]. The composition of the hepatic fibrosis is similar regardless of the cause of injury as it follows the paradigm for wound healing in other tissues, including skin, lung and kidney. Fibrosis occurs first in regions of most severe injury over several months to years of ongoing tissue damage [23, 28, 29].
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Targets
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Involved cells or molecules
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Result
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Stellate cells
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Activated stellated cells are transformed to proliferating, fibrogenic and contractile myofibroblasts
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Remodelling of the matrix
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Macromolecules in the extracellular matrix
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Collagens: the total collagen content increases 3- to 10-fold including an increase in fibril-forming collagens (i.e., types I, III, and IV) and some non-fibril forming collagens (types IV and VI).
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The extracellular matrix switches from the normal low-density basement membrane-like matrix to the interstitial type
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Glycoproteins: fibronectin, laminin, SPARC, osteonectin, tenascin, and von Willebrand factor
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Matrix-bound growth factors
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Glycosaminoglycans: perlecan, decorin, aggrecan, lumican, and fibromodulin
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Proteoglycans: shift from heparan sulphate-containing proteoglycans to those containing chondroitin and dermatan sulphates
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Degradation of extracellular matrix
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Matrix metalloproteinase 2
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Disruption of normal matrix facilitates replacement by desmoplastic matrix
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Matrix metalloproteinase 9
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Membrane-type metalloproteinase 1 and/or 2
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Stromelysin 1
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Table 1.
The key structures in the development of liver cirrhosis.
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Cryptogenic cirrhosis is the end stage of a chronic liver disease in which the underlying aetiology remains unknown after extensive clinical, serological and pathological evaluation [30, 31]. In different studies, 3–30% of liver cirrhosis cases have been attributed to the cryptogenic group [9]. Naturally, occasionally the diagnosis of cryptogenic cirrhosis is issued just due to lack of information despite the definition demanding complete investigation. Studying explanted livers of cirrhotic patients undergoing liver transplantation and having preoperative diagnosis of cryptogenic cirrhosis, specific cause was identified in 28.6% of cases. The relevant diagnoses included autoimmune hepatitis, sarcoidosis, primary biliary cirrhosis, sclerosing cholangitis, congenital hepatic fibrosis and Wilson’s disease [32]. Other data/investigational methods can yield significant information as well. For instance, a significant fraction of cases initially diagnosed as cryptogenic liver cirrhosis can be associated with occult hepatitis B infection [33].
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Recent evidence suggests that cryptogenic cirrhosis is strongly associated with development of HCC, while in a varying percentage (6.9–50%) of HCC, the underlying aetiology of liver disease cannot be determined. In a retrospective study of 641 HCC patients, cryptogenic cirrhosis was found in 44 (6.9%) cases, characterised also by more frequent occurrence of obesity and diabetes mellitus than in patients having history of chronic viral hepatitis and alcohol abuse. Considering the known association between obesity, diabetes and NASH, it was hypothesised that NASH is the precursor of cryptogenic cirrhosis and hepatocellular carcinoma [34].
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At present, there is strong evidence that cryptogenic cirrhosis represents the end state of NASH at least in a fraction of patients. First, the progression of fibrosis in NASH is associated with gradual loss of fat vacuoles. Thus, the specific morphological changes would be burned out when the cirrhosis develops. Second, patients diagnosed with cryptogenic cirrhosis have high prevalence of metabolic changes as type 2 diabetes mellitus, obesity, or history of those disorders. If the history of preceding diabetes mellitus or obesity or liver biopsy revealing NAFLD is considered as the diagnostic criteria, 30–75% of cryptogenic cirrhosis cases can be retrospectively associated with NASH [9]. Third, due to growing awareness of the entity of NASH-induced cirrhosis, direct evidence has been brought by data obtained in explanted livers. Cases that were clinically diagnosed as cryptogenic cirrhosis were reclassified as NAFLD (either cirrhosis or pre-cirrhotic stage) in 78.6% of cases [12, 35, 36].
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In comparison with liver cirrhosis due to other aetiologies, NASH-induced cirrhosis is diagnosed in older patients. Higher cardiovascular mortality is observed, in addition to the classic complications of liver cirrhosis attributable to portal hypertension and oesophageal variceal bleeding, infections and renal failure [9].
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In a population-based, large study, carried out in the United Kingdom, the following distribution of cirrhosis by the cause was found (in patients, diagnosed in 1987–2006): alcohol-induced, 56.1%; cryptogenic, 20.8%; attributable to viral hepatitis, 12.0%; autoimmune or metabolic (i.e., in this study—haemochromatosis or alpha-1-antitrypsin deficiency), 11.0% [37]. In a nationwide Danish study regarding 11,605 patients diagnosed with liver cirrhosis in 1977–1989, 61.7% of cases were alcohol-induced, 2.8%—attributable to primary biliary cirrhosis, 14.6%—related to chronic hepatitis (including autoimmune inflammation) and 20.9%—non-specified [38]. Regarding the cause of cirrhosis in explanted livers, 48.6% were related to chronic viral hepatitis (31.1% to HCV and 15.9% to HBV, 1.6% to HCV and HBV coinfection), 23.1% to alcohol-induced liver damage and 16.7% to NAFLD [36]. The data on explanted livers may not reflect the true incidence of NASH-induced cirrhosis as NAFLD patients are less likely to receive transplant. The probability to receive liver transplant within 1 year is 40.5% in NAFLD, contrasting with 47% for hepatitis C or alcohol-induced cirrhosis. The difference is the result of several factors: contraindications due to morbid obesity, comorbidities, older physiologic age, impaired renal function as well as slower disease progression [9].
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Thus, cryptogenic cirrhosis is a significant burden for health care systems. Patients undergoing liver transplantation for cryptogenic cirrhosis are subjected to higher postoperative mortality, lower cumulative 5- and 10-year survival and higher rate of chronic rejection [32]. NASH is the most rapidly growing indication for simultaneous liver and kidney transplantation. NASH and cryptogenic cirrhosis in patients having body mass index greater than 30 kg/m2 constituted 6.3% in the years 2002–2003 but 19.2% in the years 2010–2011 [39].
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As the liver becomes fibrotic, significant changes occur in the extracellular matrix (ECM) quantitatively and qualitatively. ECM refers to macromolecules that comprise the scaffolding of either normal or fibrotic liver. These include collagens, non-collagen glycoproteins, matrix-bound growth factors, glycosaminoglycans, proteoglycans and matricellular proteins. In case of fibrosis, the total collagen content increases 3- to 10-fold including an increase in fibril-forming collagens (i.e., types I, III and IV) and some non-fibril forming collagens (types IV and VI). Glycoproteins (fibronectin; laminin; secreted protein, acidic and rich in cysteine: SPARC; osteonectin; tenascin, and von Willebrand factor), proteoglycans and glycosaminoglycans (perlecan, decorin, aggrecan, lumican, and fibromodulin) also accumulate in cirrhotic liver. Particularly notable is the shift from heparan sulphate-containing proteoglycans to those containing chondroitin and dermatan sulphates. These processes represent a change in the type of ECM in subendothelial space from the normal low-density basement membrane-like matrix to the interstitial type.
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The replacement of the low-density matrix with the interstitial type influences the function of hepatocytes, liver stellate cells, and endothelium of blood vessels: the microvilli disappear on the surface of liver parenchymal cells, and endothelium loses fenestrations precluding effective molecule exchange between blood and liver parenchyma. In addition, stellate cells undergo activation [23].
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The hepatic stellate cell is the primary source of ECM in normal and fibrotic liver. Hepatic stellate cells, located in subendothelial space of Disse between hepatocytes and sinusoidal endothelial cells, represent one-third of the non-parenchymal population or approximately 15% of the total number of resident cells in normal liver. Stellate cells comprise a heterogeneous group of cells that are functionally and anatomically similar but differ in their expression of cytoskeletal filaments, retinoid content, and potential for activation. Stellate cells with fibrogenic potential are not confined to liver and have been identified in other organs such as the pancreas, where they contribute to desmoplasia in chronic pancreatitis and carcinoma. Hepatic stellate cell activation is the common pathway leading to hepatic fibrosis. During activation, stellate cells undergo a transition from a quiescent vitamin A-rich cell into proliferating, fibrogenic, and contractile myofibroblasts [23], which have strong ability to secrete collagen and migrate to the area of necrosis and inflammation [40]. Proliferation of stellate cells occurs predominantly in regions of greatest injury.
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Considering liver fibrosis, the balance between synthesis and degradation of extracellular matrix also is of importance as enhanced destruction of the normal matrix in the space between hepatocytes and endothelial cells leads to accumulation of dense scar tissue. Degradation occurs through the actions of at least four enzymes: matrix metalloproteinase (MMP) 2 and MMP9, which degrade type IV collagen; membrane-type metalloproteinase 1 or 2, which activate latent MMP2 and stromelysin 1, which degrades proteoglycans and glycoproteins and activates latent collagenases. Stellate cells are the principal source of MMP2 and stromelysin. Activation of latent MMP2 may require interaction with hepatocytes. Markedly increased expression of MMP2 is a characteristic of cirrhosis. MMP9 is secreted locally by Kupffer cells. Disruption of the normal liver matrix is also a prerequisite for tumour invasion and stromal desmoplasia.
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The cytochrome CYP2E1 may have an important role in the generation of reactive oxygen species that stimulate liver stellate cells. Cultured hepatic stellate cells grown in the presence of CYP2E1-expressing cells increase the production of collagen, an effect prevented by antioxidants or a CYP2E1 inhibitor. These data suggest that the CYP2E1-derived reactive oxygen species are responsible for the increased collagen production. Such findings may help to explain the pathogenesis of liver injury in alcoholic liver disease since CYP2E1 is alcohol inducible. As noted above, reactive oxygen species are generated through lipid peroxidation from hepatocytes, macrophages, stellate cells, and inflammatory cells. In alcoholic or non-alcoholic steatohepatitis, ROS generation in hepatocytes results from induction of cytochrome P450 2E1, leading to pericentral (zone 3) injury. Also, oxidase of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) mediates fibrogenic activation of hepatic stellate cells, as well as of Kupffer cells or resident liver macrophages through generation of oxidative stress. Increasing knowledge about NADPH oxidase isoforms and their cell-specific activities is leading to their emergence as a therapeutic target [23].
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Pathology of telomeres and the related molecular events represent another key mechanism that is associated both with induction of liver steatosis and progression of NAFLD [41]. Telomerase mutations can accelerate progression of chronic liver disease to cirrhosis [42]. Missense mutations in telomerase reverse transcriptase hTERT are found more frequently in cirrhosis regardless of aetiology [41]. Thus, missense mutations were observed in 7% of cirrhotic patients in USA [43]. Functional mutations were identified in 3% of German patients affected by cirrhosis [44].
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Telomeres are repeated, short DNA sequences (in humans—TTAGGG) located at the chromosome end. These structures prevent chromosomal end-to-end fusion as well as protect the coding DNA from progressive loss at mitosis. During each mitosis, the DNA polymerase complex cannot replicate the terminal 5′ end of the lagging strand. Consequently, the chromosomal end is lost. Due to the presence of telomeres, this loss is limited to telomeres. However, the telomeres shorten in each mitosis. Telomere attrition is especially marked in chronic diseases associated with increased cell loss and proliferation. When they become critically short, cellular ageing s. senescence and apoptosis follows. To ensure the unlimited proliferation of cancer, malignant cells maintain telomere length via different mechanisms. The most significant ones include telomerase reverse transcriptase hTERT, its RNA template: telomerase RNA component hTERC, the hTERC-protecting and stabilising dyskerin complex (consisting of four nucleolar proteins) and shelterin complex, including six proteins [41].
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NAFLD is characterised by telomere shortening and increased cellular senescence in comparison to healthy controls [45]. The changes in telomeres represent an important mechanism in the transition to liver cirrhosis. However, dual effects are observed. In progressing chronic liver disease, cellular senescence enhances the loss of parenchyma, limiting the replicative potential of hepatocytes. In contrast, in advanced liver damage, the ageing of stellate cells stops the remodelling and thus, the further progression of fibrosis. Still another prognostic aspect can be involved regarding HCC development: senescent stellate cells can promote carcinogenesis by secreting pro-carcinogenic mediators. These changes are described as the senescence-associated secretory program [41]. The extent of fibrosis in NAFLD is associated with p21 protein representing another molecular regulator of cellular senescence [41].
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Although shorter telomeres are considered a hallmark of liver cirrhosis regardless of aetiology [41], the telomeres in NAFLD patients are shorter than in those affected by cryptogenic cirrhosis. In NAFLD, telomere length correlates with the level of hTERT mRNA, while hTERT-independent mechanisms already start to operate in cryptogenic cirrhosis [45].
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4. NASH-induced HCC
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Although the association between NAFLD and HCC was first observed more than two decades ago, mostly through NASH-induced cirrhosis [11], the molecular events that link NAFLD and HCC are still incompletely understood. Following the general principles of cancerogenesis, HCC in cirrhotic liver develops by dysplasia—carcinoma pathway: from a dysplastic cirrhotic nodule. The process is slow and can last for several decades [34]. The genetic events that are prerequisite for malignant change develop in the background of increased cellular proliferation. Hypothetically, it is possible that the molecular portrait of HCC in DNA, mRNA, microRNA and protein level is different in accordance to the inciting factor of the underlying liver disease. If this is true, specific molecular targets may exist for the diagnostics, prevention or treatment of NASH-induced HCC or HCC arising in diabetic and/or obese patients [10].
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The course of HCC that is associated with cryptogenic cirrhosis differs from HCC developing in other clinical settings [46]. HCC also varies by epigenetic signature in accordance to the cause [47].
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The risk of hepatocellular carcinoma differs by the aetiology of cirrhosis. To estimate this, a large population-based study was carried out in the United Kingdom. All patients diagnosed with liver cirrhosis were identified, and the results were compared to national cancer registry identifying those diagnosed with HCC. The 10-year cumulative incidence of HCC was 4% in cirrhosis induced by chronic viral hepatitis, 3.2% in cirrhosis due to autoimmune or metabolic (in this study—haemochromatosis, alpha-1-antitrypsin deficiency) diseases, 1.2% in alcohol-induced cirrhosis and 1.1% in cryptogenic cirrhosis, while the same estimates at 1 year were 1.0, 0.8, 0.3 and 0.3%, respectively. This study has the significant benefit of exploring HCC risk in patients that differ by aetiology of cirrhosis but belong to the same population [37]. Considering patients referred for liver transplantation, the frequency of hepatocellular carcinoma in cryptogenic cirrhosis is lower (8%) than in cirrhosis related to chronic hepatitis B (29%) or C (19%) as reported by Alamo et al. [32]. For the epidemiological estimates of HCC in different liver pathology, see also Table 2 [37, 38].
The causal distribution of HCC shows geographic variations. Thus, in Canadian patients, 45% of cases were attributable to alcohol-induced cirrhosis, 26% to cryptogenic cirrhosis and 13% to hepatitis C. In patients from Saudi Arabia, 47% of HCC were caused by hepatitis C, 27% by cryptogeniccirrhosis and 21% to hepatitis B [48]. In USA, regarding the HCC cause, 54.9% of cases were induced by HCV, 16.4% by alcohol, 14.1% by NAFLD and 9.5% by HBV [10]. In explanted livers, 81.8% of HCC were associated with viral hepatitis, 9.1% with alcohol-induced liver damage and 9.1% with NAFLD [36].
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In the USA, the number of NAFLD-associated HCC cases is annually growing for 9%, if the time span 2004–2009 is evaluated [10]. In Europe, NAFLD-related HCC comprised 35% of all HCC cases in 2010. HCC that is not related to hepatitis B or C is becoming increasingly frequent in Japan as well; however, here, it comprises only 10% of all HCC cases [53]. NASH is responsible for higher percentage of HCC in Western than in Eastern societies [12].
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Hepatocellular carcinoma in patients affected by metabolic syndrome has distinct morphology [49]. NAFLD-associated HCC is characterised by larger size [34] and moderate or high differentiation degree [34], showing high differentiation as frequently as in 65% of cases [49]. However, the tumours lack capsule thus confirming the true malignant biological potential [34]. This is an important diagnostic trait considering the association between NAFLD, low-grade HCC [49], and liver adenomatosis [50].
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The prognostic estimates are somewhat controversial. The NAFLD-associated hepatocellular carcinomas are diagnosed as more advanced tumours in older patients showing higher cardiovascular morbidity. The patients are less likely to receive liver transplant and have higher tumour-specific mortality [10]. HCC associated with cryptogenic cirrhosis is larger than cancers related to HCV even in patients who correspond to Milan criteria [51]. However, after curative treatment, the recurrence risk and mortality are lower for HCC arising in cryptogenic cirrhosis—finding that is in accordance with the grade difference [52].
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Although previously it was considered that HCC risk is limited to cirrhotic patients, currently at least 25–30% of NAFLD-related hepatocellular carcinomas develop in the absence of cirrhosis [9]. In Japanese group, 33% of NAFLD-related HCC occurred in the background of none or mild fibrosis contrasting with only 16% in alcohol-induced HCC [53]. According to other researchers, up to 65% of NAFLD-associated HCC evolve in the absence of fibrosis [49]. The proportion of NAFLD-associated HCC developing in non-cirrhotic liver has been variably estimated as 15, 38, or 49% [54–57]. These tumours tend to be larger [57].
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The development of HCC in noncirrhotic liver has been associated with malignant transformation in liver cell adenoma [34, 49]. Malignant change in hepatic adenoma correlates with metabolic syndrome [58]. Inflammatory molecular type of liver cell adenoma shows clinical correlation with obesity. The underlying molecular basis could include either activated IL-6 signalling or hyperoestrogenemia associated with obesity. However, a controversy exists here as inflammatory type of liver adenoma is not prone to malignisation [50].
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Several pathogenetic ways account for a tumour-promoting environment in obesity and diabetes, allowing to distinguish the pathogenesis of HCC linked to NAFLD from that of viral and other aetiologies.
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Obesity has been linked to higher frequency of cancers in a variety of tissues [59, 60] including the liver (Table 3). HCC is increasingly diagnosed among obese individuals. In a prospective cohort of the Cancer Prevention Study with more than 900,000 North American subjects, the relative risk of dying from liver cancer among men with a body mass index reaching or exceeding 35 kg/m2 was remarkably higher (4.5 fold) compared to a reference group with normal body weight. In a large cohort involving 362,552 Swedish men, the relative risk of HCC in individuals with a body mass index reaching or exceeding 30 kg/m2 was 3.1 fold higher than in controls having normal weight. Studies from other parts of the world indicate that the link between obesity and increased incidence of HCC has been globally recognised [61].
Obesity has a significant tumour-promoting effect regarding HCC. This effect largely depends on the chronic general low-grade inflammatory response it induces, which involves production of TNF-α and IL-6. Both these molecular mediators are tumour-promoting cytokines [62] and major drivers of cell proliferation in NAFLD and NASH [21]. TNF-α and other mediators produced by activated inflammatory macrophages stimulate compensatory hepatocyte proliferation and expand HCC progenitors. TNF-α further reinforces the inflammatory microenvironment and induces expression of chemokines (CCL2, CCL7 and CXCL13) and growth factors/cytokines (IL-1β, IL-6, TNF–α itself and hepatocyte growth factor) both by progenitors of hepatocellular carcinoma and surrounding cells [63]. TNF-α up-regulates the cellular proliferation through the molecular pathways of nuclear factor kappaB, mTOR and wide spectrum of kinases. The proliferative and anti-apoptotic activities of IL-6 are largely mediated through the signal transducer and activator of transcription 3, STAT3 [10]. IL-6 also contributes to the metabolic background of cancer sustaining insulin resistance that can be improved by systemic neutralization of IL-6 [64].
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Another mechanism involved in the progression of NAFLD to HCC in obese individuals is the imbalance between leptin and adiponectin. Particularly, obesity is linked to increased levels of leptin [34]. Apart from its role in obesity-associated insulin resistance and inflammation, leptin is a pro-inflammatory, pro-angiogenic, and pro-fibrogenic cytokine with a growth-promoting effect by activating the Janus kinase/STAT, phosphoinositide 3-kinase (PI3K)/Akt, and extracellular signal-regulated kinase (ERK) signalling pathways [61]. The up-regulation of PI3K/Akt pathway leads to activation of downstream molecular mediator mTOR that is found in 40% of HCC cases. Leptin-induced up-regulation of mTOR also inhibits autophagy—a process that normally would limit oxidative stress by removing damaged mitochondria. Suppression of autophagy, in turn, increases oxidative tissue damage and subsequent inflammation [21]. Since leptin exerts pro-inflammatory and pro-fibrogenic effects by activating Kupffer cells and stellate cells, it has been associated to disease progression in fibrotic NAFLD [10]. Leptin can also promote invasion and migration of hepatocellular carcinoma cells [65].
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Adiponectin, another major adipokine with potent anti-inflammatory, antiangiogenic and tumour growth-limiting properties, is suppressed in obesity [15, 24]. Adiponectin activates 5′-adenosine monophosphate–activated protein kinase, which can suppress tumour growth and increase apoptosis by regulating the mTOR and c-Jun N-terminal kinase/caspase 3 pathways. Moreover, adiponectin opposes the effects of leptin by inhibiting activation of Akt and STAT3, as well as by increasing the expression of SOCS3: the suppressor of cytokine signalling 3 [61]. Thus, low adiponectin levels may be insufficient to suppress endotoxin-mediated inflammatory signalling in Kupffer cells and other macrophages, as well as control angiogenesis, a pivotal mechanism of tumour growth [10]. Microarray analysis of tissue adiponectin levels in HCC patients revealed that adiponectin expression was inversely correlated with tumour size, supporting the hypothesis that adiponectin may inhibit proliferation and dedifferentiation [66].
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HCC can show marked accumulation of fat within the neoplastic cells (Figure 4). In a study by Salomao et al., 36% of patients who developed HCC in the setting of steatohepatitis were diagnosed as having a steatohepatitic variant of HCC as compared to 1.3% of HCC patients without steatohepatitis [67]. Increased intensity of fatty acid synthesis and characteristic pattern of perilipin proteins has been demonstrated in HCC. Regarding gene expression pattern, activated lipogenesis is associated with higher cell proliferation and worse prognosis in HCC [10]. Hypothetically, HCC cells might benefit from the energetic value of fat compounds or use lipids as building blocks of new cells.
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Figure 4.
Hepatocellular carcinoma showing nuclear atypia and presence of fat in tumour cells. Haematoxylin-eosin stain, original magnification 100× and 400×.
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Lipotoxicity, defined as the cellular dysfunction caused by ectopic deposition of fat in non-adipose tissues, may contribute to the development of HCC in NAFLD. Activated oxidation of fatty acids generates high burden of free radicals and lipid peroxide compounds that oxidise and damage large molecules and cell organoids, e.g., mitochondria and endoplasmic reticulum. The damaged cells are subjected to apoptosis, leading to higher activity in liver destruction and progression towards cirrhosis that in turn is closely associated with enhanced proliferation and accumulation of genetic damage. Accumulation of fatty acids may interfere with cellular signalling and promote oncogenesis through altered regulation of gene transcription [10]. Oxidative stress can induce mutations in the tumour suppressor gene TP53 in a pattern observed in HCC [68].
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Adipose tissue expansion, release of pro-inflammatory cytokines, and lipotoxicity collectively promote systemic and hepatic insulin resistance, resulting in hyperinsulinemia [34]. The risk of HCC in patients affected by diabetes mellitus is 2.31 [57]. Insulin resistance and hyperinsulinemia are the most common metabolic features of NAFLD, which correlate with impaired hepatic clearance of insulin and have been linked to tumour development [69]. Deregulated metabolic effects of insulin result in excessive activation of proliferative signalling cascades. Hyperinsulinemia causes reduced hepatic synthesis of insulin-like growth factor (IGF)-binding protein-1 and increased bioavailability of IGF1, which further promotes cellular proliferation and inhibits apoptosis [10, 34]. It has been shown recently that elevated fasting insulin, which is inversely related to insulin sensitivity, is an independent risk factor for HCC. Baseline serum levels of C-peptide have also been found to be associated with a higher risk of HCC in the general population independently of obesity and other established liver cancer risk factors [69]. Loss of heterozygosity for IGF2 has been observed in over 60% of HCC cases. This likely coincides with IGF2 overexpression, found in HCC, which has been associated to reduced apoptosis and increased cellular proliferation [68].
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The importance of insulin resistance is illustrated by the observations that obesity and type 2 diabetes mellitus comprise increased HCC risk even regardless of the presence or cause of liver cirrhosis [9].
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A number of studies have demonstrated a critical role for phosphatase and tensin homolog (PTEN) in the progression of NASH to tumour. PTEN deletion results in PKB/Akt activation, promoting proliferation and reducing apoptosis. Insulin-like growth factor 2 mRNA binding protein p62 was reported to be a possible upstream regulator of PTEN. Aberrant microRNAs contribute to carcinogenesis. MiR-21 was found to be another upstream regulator of PTEN participating in NASH-associated cancer induction [10, 14, 70].
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The oral iron test has revealed increased absorption of iron compounds in patients affected by NASH [71]. In turn, increased amount of iron in liver tissues is associated with increased risk of HCC in patients affected by NASH-related liver cirrhosis [72]. As the reductive conversion of Fe(III) to Fe(II) necessitates increased oxidation of other compounds, oxidative DNA damage can develop and lead to the malignancy [34, 73]. Iron overload also is known to enhance insulin resistance [74] and to act in concert with other factors damaging liver. The significance of iron overload in hepatic carcinogenesis is shown in several models. The risk of HCC is increased in hereditary haemochromatosis, characterised by excessive iron accumulation in the body and caused by excessive absorption because of homozygous C282Y mutation in HFE gene. Almost 8–10% of patients with hereditary haemochromatosis develop HCC. Increased relative risk of HCC (10×) has also been demonstrated in association with long-lasting excess dietary iron intake [37, 74, 75]. Thus, there is significant evidence of the carcinogenic action of iron overload, and evidence of iron accumulation in NAFLD and especially NASH that allows drawing conclusion that iron metabolites are contributing to the development of NASH-related HCC.
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The expression profile of Wnt signalling genes in NASH strongly suggests inhibition of Wnt pathway. IHC staining of β-catenin shows predominately membrane staining with loss of nuclear staining indicating that β-catenin is not active in NASH. In contrast, 20–90% of HCC cases exhibit active Wnt pathway [76]. Thus, the long-lasting conversion of NASH into HCC hypothetically involves up-regulation of Wnt pathway either by activators or loss of inhibitors [77].
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Hepatocyte apoptosis is a prominent feature of NASH (Figure 5). The executing mechanism of apoptosis includes activation of characteristic lytic enzymes—the caspases. In an apoptotic hepatocyte, activated caspase-3 is splitting various cell structures, including cytokeratin (CK) 18—the intermediary filament that represents the specific cytoskeleton protein of hepatocytes. Consequently, blood tests can reveal increased concentration of CK18 fragments [70]. In liver tissues, CK8 and CK18-containing Mallory bodies are evident by light microscopy as large, brightly eosinophilic inclusions in liver cell cytoplasm. Although Mallory hyaline is the hallmark of alcohol-induced hepatitis, its development can also be induced by diet rich in saturated fatty acids. The molecular pathways associated with Mallory body development include IL-6, protein p62 that binds ubiquitin in cell cytoplasm, and reduced concentration of HSP72 that prevents protein misfolding. The presence of CK18 in Mallory bodies correlates with plasma CK18 levels [78]. In a longitudinal paired liver biopsy study, the change of CK18 correlated with disease progression. Patients with increased NAFLD activity score 3 years after initial evaluation had greater increase of plasma CK18 compared with those who had stable or decreased activity score [79]. El-Zefzafy et al. proved that CK18 was a sensitive indicator of the severity of liver disease and also could predict the development of HCC. In their study, the sensitivity and specificity of serum CK18 were 95 and 96.7%, respectively, with a cut-off value of 534.5 U/L for HCC diagnosis [80].
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Figure 5.
Apoptotic bodies (arrows) in non-alcoholic steatohepatitis. Haematoxylin-eosin stain, original magnification 400×.
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In a study by Salomao et al., devoted to HCC in NASH, immunohistochemically there was diffuse loss of cytoplasmic CK8/18 and an increased number of activated hepatic stellate cells within the steatohepatitic HCC, identical to the pattern seen in the surrounding non-neoplastic liver [67, 81].
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The HCC development shows complex associations with telomere shortening. The senescence-associated secretory program of liver stellate cells promotes carcinogenesis. The telomere shortening induces also genomic instability thus facilitating HCC development [41]. Indeed, HCC is characterised by significantly shorter telomeres in comparison to adjacent tissues [82]. However, cancer cells still maintain unlimited proliferation. Evidently, hepatocellular carcinoma cells develop compensatory mechanisms either for telomere extension or for cellular proliferation despite telomere shortening. The elongation of telomeres again can be ensured via diverse mechanisms, including hTERT or alternative lengthening of telomeres via telomerase-independent mechanism seen in 7% of HCC cases [41].
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Over the progression of HCC, the telomere length changes in contrary direction. Early liver carcinogenesis is associated with telomere shortening, while disease progression is associated with telomere extension, cell immortalisation and reactivation of telomerase [83]. Longer telomeres in HCC are associated with higher stage (regional or distant spread versus localised tumour) and grade (III–IV versus lower grade) as well as with worse survival [83, 84]. Telomerase promotes HCC development via several pathways, not limited to maintenance of telomeres and thus cellular proliferation. In addition, hTERT can act as a transcription factor in the Wnt molecular cascade [41]. Experimental data by HCC induction in telomerase-deficient mice have shown increased number of early tumours and reduced incidence of high-grade HCC [85].
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Interestingly, shorter telomeres are observed more frequently (telomere length ratio between HCC and surrounding tissues lower than the mean, 70.1% versus higher, 29.9%) in HCC that is not related to hepatitis B (50.0% versus 50.0%) or C (60.0% versus 40.0%), or alcohol abuse (50.0% versus 50.0%), although the difference does not reach statistical significance [83]. Telomere shortening can be detected in peripheral blood. Notably, this assay can be used to predict HCC persistence (by telomere shortening) in cases attributable to viral hepatitis B or C but not in HCC attributable to non-infectious causes despite comparable size of patient groups [86].
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Genetic predisposition has been studied in NAFLD trying to identify those patients that are at particularly increased risk of HCC. The possible candidate genes could be associated with telomere length and mechanisms involved in preserving telomeres [42]. About 10% of patients affected both by HCC and NASH have germline mutations in hTERT in comparison to complete absence of such mutations in NASH patients having cirrhosis and healthy controls [41]. In addition, PNPLA3 polymorphisms have been studied in NAFLD patients, finding twice increased risk of HCC in association with rs738409 C>G. The proposed mechanism involves retinol metabolism in hepatic stellate cells [34].
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The interaction of these pathogenetic mechanisms and genetic predisposition finally resultsin the increased incidence of HCC in NAFLD that reaches 76–201 per 100,000 contrasting with the incidence of 4.9–16 per 100,000 of the general population [57].
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5. Potential treatment strategies
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As no specific treatment is approved for NAFLD, lifestyle interventions play the leading role in NAFLD management. Weight loss due to low calorie diet in combination with physical activities is the main therapeutic approach in overweight patients with NAFLD. As hypertriglyceridemia is a frequent and promoting feature of NAFLD [87] reduction of the triglyceride level must be among therapeutic goals. In severe hypertriglyceridemia, total fat consumption should be limited to less than 30 g/day, and carbohydrate amount in daily nutrition should be strictly controlled as well [88].
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Physical activity has beneficial effect of reducing triglyceride level, even independently from diet [89]. Thus, at least 30 min of moderate activity most days of the week would be a necessary part of dyslipidemia management [90]. Loss of 5% of body weight decreases hepatic steatosis, but body weight loss of 10% could even improve inflammation and fibrosis in liver [87].
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Experimentally investigating hepatocyte-specific PTEN-deficient mouse model, Piguet et al. showed that physical activity could reduce HCC growth in fatty liver. In PTEN-deficient mice, HCC incidence was 71% of exercised mice and 100% of sedentary mice. In addition, liver tumour volume in exercised mice was significantly smaller than that of sedentary mice (444 ± 551 versus 945 ± 1007 mm3) [91]. The physiological substantiation relies on fact that regular physical activity could inhibit mTOR complex, which is engaged in cell growth and proliferation [92].
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Increased hepatic free cholesterol accumulation is typical for NASH. Statins are commonly prescribed to reduce cholesterol synthesis in the liver and thus serum levels of free cholesterol [14]. In a recent European multi-centre cohort study, statin use was associated with protection from steatosis (odds ratio, OR 0.09; 95% CI, 0.01–0.32; p = 0.004), steatohepatitis (OR, 0.25; 95% CI, 0.13–0.47; p <0.001), and fibrosis stage F2–F4 (OR, 0.42; 95% CI, 0.20–0.80; p = 0.017). The protective effect of statins on steatohepatitis was stronger in subjects not carrying the I148M PNPLA3 risk variant (p = 0.02), indicating the role of genetic predisposition [93]. Statins also have been associated with reduced risk (range, 0.46–0.79) of HCC [94].
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In a meta-analysis, including 4298 patients with HCC, statin use was associated with a 37% reduction in the risk of hepatocellular carcinoma. The effect was stronger in Asian patients but was also present in Western populations. Moreover, the reduction of cancer risk was independent of statin lipid-lowering effects [95]. Several hypotheses have been proposed, including statin ability to inhibit cell proliferation via inhibition of v-myc avian myelocytomatosis viral oncogene homolog protein phosphorylation which seems to play a role in liver carcinogenesis [96], as well as capacity to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A reductase, which activates multiple proliferative pathways [95]. Simvastatin selectively induces apoptosis in cancer, but not in healthy cells. This proapoptotic effect is maintained via RAF/MAPK1/ERK and growth-inhibitory action by suppression of angiogenesis and proteasome pathway [95, 96]. However, data about liver carcinogenesis and statin effects remain controversial. In another large meta-analysis, including 86,936 participants, no beneficial effect of statin in terms of incidence or death from cancer was observed. Even more, in 67,258 patients who received statins, 35 new liver cancers and 24 deaths from liver cancer were reported showing no significant difference from control group, comprising 67,279 patients who received placebo, and developed 33 new liver cancer (p = 0.93) cases leading to 24 deaths (p = 1.00) as analysed by Carrat [97].
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Metformin, a widely prescribed drug for treating type 2 diabetes mellitus, is one of the most extensively recognised metabolic modulators which decreases aminotransferase levels and hepatic insulin resistance. It has no beneficial effects on NAFLD histology but still retains an important anti-cancer action [87, 98]. The hypothetic antitumor mechanisms of metformin are believed to be (1) inhibition of mTOR, (2) weight loss and (3) suppressed production of ROS and the associated DNA damage, in combination with (4) reduction of hyperinsulinemia, which is known to lead to cell proliferation [99]. In meta-analysis comprising 105,495 patients with type 2 diabetes, Zhang et al. showed that metformin was associated with an estimated 70% reduction in the risk of developing HCC [98]. The risk reduction in metformin users is significant, regarding both incidence (78%) and mortality (77%) from HCC [100].
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The mammalian target of rapamycin (mTOR) promotes growth in a majority of liver cancers, including hepatocellular carcinoma. It participates in the formation of two protein complexes—mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin and has ability to activate downstream targets which regulate cellular growth and metabolism. Prolonged mTORC1 activation is related to liver steatosis and insulin resistance in obese patients [14, 101]. Due to the ability suppress mTORC1, rapamycin and its analogues Everolimus and Temsirolimus have been tested to treat HCC. Unfortunately, results have not been promising. In a phase 3 study of patients with advanced HCC, Everolimus increased the frequency of hepatic injury and showed no improvements regarding survival [14]. After 2 weeks with rapamycin treatment, the lipid droplets in the liver decreased, as well as ROS burden. However, rapamycin treatment promoted liver damage with augmented IL-6 and decreased anti-inflammatory IL-10 production, leading to increased hepatic inflammation and hepatocyte necrosis [101].
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Inflammation promotes development of complications in patients with cirrhosis contributing to mortality and to liver insufficiency mediated by pro-inflammatory cytokines. The most recognisable pro-inflammatory cytokine associated with liver damage in case of NAFLD is TNF-α that can be inhibited by pentoxifylline. Lebrec et al. performed randomised, placebo controlled, double-blind trial assessing pentoxifyline effect in 335 patients with cirrhosis. Although pentoxifylline had no effect on short-term mortality, it significantly (p = 0.04) prolonged the complication-free time span [102].
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Knowing the important role of NADPH oxidases (NOXs) and production of ROS in liver fibrosis, different strategies to prevent the oxidative damage have been developed [23]. In hepatocytes, NOX4 mediates suppressor effects on TGF-β and can inhibit hepatocyte growth and liver carcinogenesis. In turn, dual NOX4/NOX1 pharmacological inhibitor GKT137831 could decrease both the apparition of fibrogenic markers as well as hepatocyte apoptosis in vivo [103].
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Currently, multikinase inhibitor sorafenib is the only pharmacological agent that prolongs survival of HCC patients, although the median survival is improved only by 12 weeks [14]. It acts against Raf-1 and B-raf, vascular endothelial growth factor (VEGF) receptors and platelet-derived growth factor receptor kinases [104]. Sorafenib as well as VEGF inhibitors have radiosensitizing effect. However, combined regimens including sorafenib and liver stereotactic radiation or whole liver radiotherapy are characterized by poor tolerability [104]. Various beneficial effects of sorafenib have been reported in liver cirrhosis. As epithelial-mesenchymal transition and TGF-β play crucial roles in liver fibrosis, Ma et al. proved that sorafenib had ability to strikingly suppress TGF-β1 induced epithelial-mesenchymal transition, as well as apoptosis in hepatic stellate cells, in dose-dependent manner [105].
\n
Several treatment strategies might involve the telomere and telomerase complex. In cancer, telomerase inhibitors might arrest tumour growth, prevent further malignisation in surrounding cirrhotic nodules and/or enhance HCC chemosensitivity. In early liver disease, telomerase activation might prevent tissue loss if the etiologic factor cannot be removed. This could be reached via transplantation of liver cells engineered for hTERT expression, direct supply of hTERT to the patient’s cells or by small molecules enhancing telomerase activity. However, side effects and enhanced cancer risk must be considered and prevented [41]. The treatment modulating cellular senescence and proliferation control may also target p21 [106–108] and p53 [109] pathways.
\n
The p21 protein, a strong and universal inhibitor of cyclin-dependant kinases, is an important regulator of cell proliferation, apoptosis and senescence [107, 108]. Based on its intracellular location and the molecular background, it can have dual activity. Intranuclear p21 acts as tumour suppressor, as it binds cyclin-dependant kinases and thus suppresses cellular proliferation. Cytoplasmic p21 prevents apoptosis by binding caspases and promotes proliferation and migration of p53-deficient cells. The p21 pathway is also closely associated with senescence. Few small molecular inhibitors of p21 are known, including LLW10, butyrolactone and UC2288. In addition, sorafenib also exhibits anti-p21 activity. LLW10 binds to p21 and induces proteosomal degradation via ubiquitination. Despite the reliable mechanism, the high concentration that is necessary for sufficient activity as well as the instability of LLW10 prevents it from being clinically useful drug. Butyrolactone also induces proteosomal degradation of p21. UC2288 decreases p21 concentration via suppressed transcription and modified posttranscriptional modulation [107]. In turn, up-regulation of p21 can be achieved via statins or by anticancer agents including histone deacetylase inhibitors [106]. Induction of senescence would be desirable if the tumour is already present while suppressed senescence might prevent or slow down the development of liver cirrhosis. As was noted, it is possible to modulate p21 level in both directions. However, the net effects must be carefully considered and studied experimentally, knowing the bidirectional activity of p21.
\n
p21 is also an effector of p53-mediated responses in cells maintaining functional p53. In p53-deficient cell, it manifests carcinogenic effects. Thus, restoration of wild-type p53 could be attractive, either in combination with p21-targeted treatment or with other oncological approach. In liver cancer, restoration of p53 activity has resulted in senescence and increased immune response. The therapeutic approaches could include (1) restoration of wild type function to mutant p53 by low molecular weight compounds PRIMA 1 or PRIMA-1MET. The last one has progressed to phase II clinical trials; (2) stabilising p53 due to blocked interaction with MDM2 or MDM4 by nutlins, representing low molecular weight molecules, or by stapled peptides; (3) gene therapy using viral vectors that has already been tested in HCC; (4) induction of synthetic lethality [109].
\n
\n
\n
6. Conclusions
\n
Non-alcoholic steatohepatitis is recognised as the cause of NASH-induced cirrhosis. It has also been associated with a significant fraction of cases previously diagnosed as cryptogenic cirrhosis. Liver cirrhosis can become further complicated by hepatocellular carcinoma, the most frequent primary liver tumour known for serious prognosis and limited treatment options. In addition, the development of HCC in NAFLD patients can precede cirrhosis in a significant fraction of cases. NAFLD is the major hepatic manifestation of obesity and associated metabolic diseases, such as diabetes mellitus. With increasing prevalence of these conditions, NAFLD has become the most common liver disorder worldwide. It affects around 25% of general population and 90% of patients suffering from morbid obesity, i.e., having body mass index equal or greater than 40 kg/m2.
\n
The mechanisms of liver steatosis include up-regulation of inflammatory cytokines, as TNF-α,IL-6 and CCL2, released from extrahepatic adipose tissues due to prolonged low-grade inflammation triggered by hypoxia-induced death of fast-growing fat cells. Insulin resistance further contributes to NAFLD and can be aggravated by the pro-inflammatory cytokine background. Free fatty acids and cholesterol cause lipotoxicity due to released reactive oxygen species as well as toxic metabolites generated by non-oxidative biochemical pathways. Decreased level of adiponectin, exaggerated oxidative stress and hepatic iron accumulation also are among the mechanisms of NAFLD.
\n
In the pathogenesis of NAFLD, 20–30% of patients, initially affected by simple liver steatosis, develop hepatic inflammation and thus correspond to the diagnostic criteria of NASH. These cases are at risk to progress to liver cirrhosis and hepatocellular carcinoma. The standardised incidence ratio of HCC in NASH patients reaches 4.4. Regarding the epidemiological profile of hepatocellular carcinoma, the proportion of NASH-related cases is growing and has increased from 8.3 to 13.5% in the time period 2002–2012.
\n
Obesity has been linked to higher frequency of cancers in different organs including the liver. The relative risk of HCC-attributable death in obese patients (body mass index equal or greater than 35 kg/m2) can be as high as 4.5. The underlying mechanisms of carcinogenesis include chronic general low-grade inflammation characterised by elevated levels of TNF-α and IL-6, both of which are tumour-promoting cytokines and major drivers of cell proliferation in NAFLD and NASH. The increased levels of leptin and suppressed production of adiponectin represent another mechanism involved in the progression of NAFLD to HCC in obese individuals. Leptin is a pro-inflammatory, pro-angiogenic and pro-fibrogenic cytokine with a growth-promoting effect. Adiponectin has anti-inflammatory, antiangiogenic and tumour growth-limiting properties. Insulin resistance and hyperinsulinemia lead to excessive cell proliferation. Iron compound deposition has also been related to HCC development in NAFLD-related cirrhosis, possibly due to oxidative DNA damage. Thus, the same molecular pathways that induced NAFLD continue to be active until the development of HCC. These mechanisms are supplemented by critical genetic events including PTEN deletion, switch from inactivated to upregulated Wnt pathway and typical mutation pattern in TP53. Certain microRNAs, including miR-21, act as molecular switches.
\n
Pathogenetically related molecular markers, e.g., cytokeratin 18, can serve as predictive tests to detect increased risk of HCC.
\n
The molecular pathogenesis of NAFLD is closely related to the selection of treatment targets. NAFLD patients can benefit from low calorie diet, reducing hypertriglyceridemia and potentially reversing steatosis and even fibrosis; physical activity inhibiting mTOR complex; statins influencing cholesterol synthesis, RAF/MAPK1/ERK and p21 pathway; metformin acting through suppression of mTOR and ROS; pentoxyfillin lowering production of pro-inflammatory cytokines. Multikinase inhibitor sorafenib is indicated in HCC patients. Bidirectional regulation of telomere attrition, senescence, and p21 pathway could be at least theoretically considered in the future. Restoration of wild-type p53 activity becomes possible. The regulation of miRNA machinery also represents a highly attractive future treatment option.
\n
Thus, NAFLD is gaining increasing importance in nowadays medicine as a frequent condition that can lead to such grave complications as liver cirrhosis and hepatocellular carcinoma. Awareness of the molecular profile is helpful to identify the treatment targets and predictive markers.
\n
\n
Acknowledgments
\n
The team of authors gratefully acknowledges artist Ms. Sandra Ozolina for professional preparation of illustrations.
\n
\n',keywords:"non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver cirrhosis, cryptogenic cirrhosis, hepatocellular carcinoma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/55784.pdf",chapterXML:"https://mts.intechopen.com/source/xml/55784.xml",downloadPdfUrl:"/chapter/pdf-download/55784",previewPdfUrl:"/chapter/pdf-preview/55784",totalDownloads:2831,totalViews:757,totalCrossrefCites:4,totalDimensionsCites:8,totalAltmetricsMentions:0,impactScore:6,impactScorePercentile:94,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"November 30th 2016",dateReviewed:"March 24th 2017",datePrePublished:null,datePublished:"July 5th 2017",dateFinished:"June 2nd 2017",readingETA:"0",abstract:"Non-alcoholic steatohepatitis (NASH) is growing into global problem, mainly due to NASH-induced cirrhosis and hepatocellular carcinoma (HCC), that can develop either subsequently to cirrhosis or preceding it. In addition, NASH-induced cirrhosis constitutes a significant fraction of cases diagnosed as cryptogenic cirrhosis. Thus, there is a need for deeper understanding of the molecular basis, leading to liver steatosis, then—to the associated inflammation seen in NASH, loss of liver architecture and cirrhosis, followed or paralleled by carcinogenesis and HCC. Insulin resistance, increased hepatic iron level, and certain cytokines, including TNF-α and IL-6 derived from extrahepatic adipose tissues, can trigger the chain of events. The imbalance between leptin and adiponectin is important as well. These markers remain important during the whole course from NASH through liver cirrhosis to HCC. The molecular pathogenesis substantiates treatment: hypertriglyceridemia can be lowered by low calorie diet; mTOR complex can become inhibited by physical activity and metformin; cholesterol synthesis, RAF/MAPK1/ERK and p21 pathway by statins; inflammation by pentoxyfillin, and kinases (in HCC) by sorafenib. Bidirectional regulation of telomere attrition, senescence and p21 pathway, restoration of wild-type p53 activity and regulation of miRNA network represent attractive future treatment options. Focusing on relevant molecular pathways allows deeper understanding of NASH pathogenesis, leading to identification of predictive markers and treatment targets.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/55784",risUrl:"/chapter/ris/55784",book:{id:"5960",slug:"liver-cirrhosis-update-and-current-challenges"},signatures:"Dzeina Mezale, Ilze Strumfa, Andrejs Vanags, Matiss Mezals, Ilze\nFridrihsone, Boriss Strumfs and Dainis Balodis",authors:[{id:"54021",title:"Prof.",name:"Ilze",middleName:null,surname:"Strumfa",fullName:"Ilze Strumfa",slug:"ilze-strumfa",email:"ilze.strumfa@rsu.lv",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/54021/images/system/54021.jpg",institution:{name:"Riga Stradiņš University",institutionURL:null,country:{name:"Latvia"}}},{id:"174929",title:"Dr.",name:"Andrejs",middleName:null,surname:"Vanags",fullName:"Andrejs Vanags",slug:"andrejs-vanags",email:"Andrejs.Vanags@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"202253",title:"Dr.",name:"Dainis",middleName:null,surname:"Balodis",fullName:"Dainis Balodis",slug:"dainis-balodis",email:"Dainis.Balodis@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"202548",title:"Dr.",name:"Dzeina",middleName:null,surname:"Mezale",fullName:"Dzeina Mezale",slug:"dzeina-mezale",email:"Dzeina.Mezale@rsu.lv",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202548/images/5572_n.jpg",institution:null},{id:"203011",title:"Dr.",name:"Matiss",middleName:null,surname:"Mezals",fullName:"Matiss Mezals",slug:"matiss-mezals",email:"Matiss.Mezals@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"203012",title:"Dr.",name:"Ilze",middleName:null,surname:"Fridrihsone",fullName:"Ilze Fridrihsone",slug:"ilze-fridrihsone",email:"Ilze.Fridrihsone@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"205692",title:"MSc.",name:"Boriss",middleName:null,surname:"Strumfs",fullName:"Boriss Strumfs",slug:"boriss-strumfs",email:"boriss@osi.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Common pathogenetic mechanisms of NAFLD",level:"1"},{id:"sec_2_2",title:"2.1. Inflammation in peripheral adipose tissue",level:"2"},{id:"sec_3_2",title:"2.2. Insulin resistance",level:"2"},{id:"sec_4_2",title:"2.3. Lipotoxicity",level:"2"},{id:"sec_5_2",title:"2.4. Oxidative stress",level:"2"},{id:"sec_6_2",title:"2.5. Increased hepatic iron concentration",level:"2"},{id:"sec_7_2",title:"2.6. MicroRNAs in NAFLD",level:"2"},{id:"sec_9",title:"3. NASH-induced liver cirrhosis",level:"1"},{id:"sec_10",title:"4. NASH-induced HCC",level:"1"},{id:"sec_11",title:"5. Potential treatment strategies",level:"1"},{id:"sec_12",title:"6. Conclusions",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Tendler DA. Pathogenesis of nonalcoholic fatty liver disease. UpToDate [Internet] Mar 2016 [Updated: Mar 09, 2016]. 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Digestive and Liver Disease. 2015;47(12):997-1006. DOI: 10.1016/j.dld.2015.08.004\n'},{id:"B88",body:'European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, et al. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). European Heart Journal. 2011;32(14):1769-1818. DOI: 10.1093/eurheartj/ehr158\n'},{id:"B89",body:'Vanhees L, Geladas N, Hansen D, Kouidi E, Niebauer J, Reiner Z, et al. Importance of characteristics and modalities of physical activity and exercise in the management of cardiovascular health in individuals with cardiovascular risk factors: Recommendations from the EACPR. Part II. European Journal of Preventive Cardiology. 2012;19(5):1005-1033. DOI: 10.1177/1741826711430926\n'},{id:"B90",body:'Corey KE, Chalasani N. Management of dyslipidemia as a cardiovascular risk factor in individuals with nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology. 2014;12(7):1077-1084. DOI: 10.1016/j.cgh.2013.08.014\n'},{id:"B91",body:'Piguet AC, Saran U, Simillion C, Keller I, Terracciano L, Reeves HL, Dufour JF. Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis. Journal of Hepatology. 2015;62(6):1296-1303. DOI: 10.1016/j.jhep.2015.01.017\n'},{id:"B92",body:'Degasperi E, Colombo M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. The Lancet Gastroenterology & Hepatology. 2016;1(2):156-164. DOI: 10.1016/S2468-1253(16)30018-8\n'},{id:"B93",body:'Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. Journal of Hepatology. 2015;63(3):705-712. DOI: 10.1016/j.jhep.2015.05.006\n'},{id:"B94",body:'El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009;136(5):1601-1608. DOI: 10.1053/j.gastro.2009.01.053\n'},{id:"B95",body:'Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: A systematic review and meta-analysis. Gastroenterology. 2013;144(2):323-332. DOI: 10.1053/j.gastro.2012.10.005\n'},{id:"B96",body:'Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clinical Liver Disease. 2015;19(2):361-379. DOI: 10.1016/j.cld.2015.01.012\n'},{id:"B97",body:'Carrat F. Statin and aspirin for prevention of hepatocellular carcinoma: What are the levels of evidence? Clinics and Research in Hepatology and Gastroenterology. 2014;38(1):9-11. DOI: 10.1016/j.clinre.2013.09.007\n'},{id:"B98",body:'Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: A systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2012;97(7):2347-2353. DOI: 10.1210/jc.2012-1267\n'},{id:"B99",body:'Jara JA, López-Muñoz R. Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity. Pharmacological Research. 2015;101:102-108. DOI: 10.1016/j.phrs.2015.06.014\n'},{id:"B100",body:'Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: A meta-analysis. Cancer Epidemiology. 2013;37(3):207-218. DOI: 10.1016/j.canep.2012.12.009\n'},{id:"B101",body:'Umemura A, Park EJ, Taniguchi K, Lee JH, Shalapour S, Valasek MA, et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metabolism. 2014;20(1):133-144. DOI: 10.1016/j.cmet.2014.05.001\n'},{id:"B102",body:'Lebrec D, Thabut D, Oberti F, Perarnau JM, Condat B, Barraud H, et al. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology. 2010;138(5):1755-1762. DOI: 10.1053/j.gastro.2010.01.040\n'},{id:"B103",body:'Crosas-Molist E, Fabregat I. Role of NADPH oxidases in the redox biology of liver fibrosis. Redox Biology. 2015;6:106-111. DOI: 10.1016/j.redox.2015.07.005\n'},{id:"B104",body:'Goody RB, Brade AM, Wang L, Craig T, Brierley J, Dinniwell R, et al. Phase I trial of radiation therapy and sorafenib in unresectable liver metastases. Radiotherapy & Oncology. 2017;123(2):234-239. DOI: 10.1016/j.radonc.2017.01.018\n'},{id:"B105",body:'Ma R, Chen J, Liang Y, Lin S, Zhu L, Liang X, Cai X. Sorafenib: A potential therapeutic drug for hepatic fibrosis and its outcomes. Biomedicine & Pharmacotherapy. 2017;88:459-468. DOI: 10.1016/j.biopha.2017.01.107\n'},{id:"B106",body:'Abbas T, Dutta A. p21 in cancer: Intricate networks and multiple activities. Nature Reviews Cancer. 2009;9(6):400-414. DOI: 10.1038/nrc2657\n'},{id:"B107",body:'Liu R, Wettersten HI, Park SH, Weiss RH. Small-molecule inhibitors of p21 as novel therapeutics for chemotherapy-resistant kidney cancer. Future Medicinal Chemistry. 2013;5(9):991-994. DOI: 10.4155/fmc.13.56\n'},{id:"B108",body:'Georgakilas AG, Martin OA, Bonner WM. p21: A two-faced genome guardian. Trends in Molecular Medicine. 2017;23(4):310-319. DOI: 10.1016/j.molmed.2017.02.001\n'},{id:"B109",body:'Duffy MJ, Synnott NC, McGowan PM, Crown J, O’Connor D, Gallagher WM. p53 as a target for the treatment of cancer. Cancer Treatment Reviews. 2014;40(10):1153-1160. DOI: 10.1016/j.ctrv.2014.10.004\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Dzeina Mezale",address:"dzeina.mezale@rsu.lv",affiliation:'
Department of Pathology, Riga Stradins University, Riga, Latvia
Department of Pathology, Riga Stradins University, Riga, Latvia
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1. Introduction
Chiropractic Biophysics® (CBP®) technique is a full-spine and posture correcting method that incorporates engineering and mathematical principles into a unique approach in the treatment of spine disorders [1, 2, 3, 4, 5]. CBP technique is best described as a ‘structural’ rehabilitation approach as opposed to ‘functional’ rehabilitation that typically encompasses physiotherapeutic modalities, stretching and exercises to regain function. The goal in structural rehabilitation is to restore the spine alignment and posture to as near normal as possible.
CBP operates on three main premises: 1. There is a normal/ideal static spinal configuration; 2. Abnormal alterations of the spine/posture result in abnormal function disrupting homeostatic balance; 3. Altered static spine/postural alignment results in abnormal dynamics [1]. The contemporary spine literature supports all three of these premises (See Section 4). CBP technique has published research on many facets of the technique including defining what normal/ideal spine alignment is, how to measure spine alignment parameters with reliable and repeatable methods, how to correct/re-align spinal displacements, and evidence proving correcting spine and postural displacements correlates with improvements in pain, disability and quality of life (QOL) measures (These studies are detailed later).
Herein, an overview is given of the scientific approach to treating spine disorders (i.e. subluxation) by the unique approach of CBP technique. A review will be given of the historical beginnings of CBP, rotations and translations of posture, the Harrison normal spinal model, radiographic analysis, posture and spinal coupling, the CBP protocol, clinical evidence of efficacy as well as the safety of the use of X-rays (The term ‘X-rays’ imply the use of plain radiographs throughout this chapter).
2. Historical beginnings
Donald D. Harrison, who had a Master’s degree in Mechanical Engineering and a Doctorate degree in Applied Mathematics developed a devote urgency to bring contemporary science to chiropractic. In the late 1970s, Harrison was the main instructor for the chiropractic technique named ‘Pettibon.’ Dissatisfied with the failure to produce spinal correction, he often incorporated his own methods in certain cases to better attain spine and posture improvements. It was in the treatment of one particular case (circa 1980) where he discovered that the body must be treated using the principles of mathematics; the term ‘mirror image®’ adjusting he later coined to describe these new approaches [1].
A 1974 paper by Panjabi et al. describes a Cartesian coordinate system for use in the description and study of joint biomechanics (Figure 1) [6]. Harrison was the first to apply this system of analysis to upright human posture (Figures 2 and 3). Harrison began discovering the rotations and translations of human posture in 1980. During the early 1980s, the analysis system evolved to incorporate a full spine analysis of the head, rib cage and pelvis in three-dimensions. The technique methods continued to evolve with intellectual contributions from early practitioners of CBP including among others, Drs. DeGeorge, Gambale, Pope and Deed Harrison (founder’s son).
Figure 1.
A vertebra described in terms of rotations about and translations along the x, y, and z-axes on a cartesian coordinate system as proposed by Panjabi (courtesy CBP seminars).
Figure 2.
If the head, thoracic cage, and pelvis are considered rigid bodies, then the possible rotations in three-dimensions are illustrated. Flexion and extension are rotations on the x-axis, axial rotation is about the y-axis, and lateral flexion is rotation about the z-axis (courtesy CBP seminars).
Figure 3.
If the head, thoracic cage, and pelvis are considered rigid bodies, then the possible translations in three-dimensions are illustrated. Lateral translations occur along the x-axis, vertical translations occur along the y-axis, and anterior–posterior translations (protraction-retraction) occurs along the z-axis (courtesy CBP seminars).
One of the unique methods within CBP is the use of ‘extension traction’ to restore the normal cervical or lumbar lordosis (Figures 4 and 5). The first cervical extension traction was with use of an inclined bench that utilized a camlock and pulley system to hyperextend the neck by pulling on the forehead [7]. This is the traction used in the first CBP non-randomized controlled clinical trial (nRCT) that showed that no traction either by no treatment or only cervical manipulation but no traction resulted in no improved alignment, while the traction group (also receiving cervical spinal manipulation) achieved improved lordosis [7].
Further development in cervical traction involved the addition of a posterior-to-anterior (PA) pull through the mid cervical spine with simultaneous extension and distraction of the head while sitting in a chair, so-called ‘Pope’s 2-way’ traction (Figure 4) [8]. A slight modification of this traction involves the use of a chin-forehead strap to add weight directly to the patients head as an extension-compression 2-way traction (Figure 4) [9]. More recently, a cervical extension orthotic (Denneroll) has been shown to be effective at increasing cervical lordosis (Figure 4).
In the mid 1990s, Deed Harrison helped to develop precision vectors for lumbar extension traction (Figure 5), where the first nRCT showing lumbar curve restoration was published in the Archives of Physical Medicine and Rehabilitation in 2002 and concluded: “This new method of lumbar extension traction is the first nonsurgical rehabilitative procedure to show increases in lumbar lordosis in chronic LBP (low back pain) subjects with hypolordosis” [10]. A lumbar extension orthotic device by Denneroll is also used for lumbar extension traction (Figure 5).
CBP technique is one of the most scientifically based posture and spine correcting techniques. There are many randomized controlled trials (RCTs), nRCTs, and well over 100 case reports/series documenting the improvement of diverse spine deformity patterns with concomitant reduction of pain, disability and increased QOL measures [11].
3. Rotations and translations of posture
The main strength of CBP technique is its fundamental underpinnings in engineering and mathematics [1]. It is a general theorem that any object can be decomposed as a rotation, a translation and a deformation [12]. Acknowledging that deformation of living tissues occurs, as in compressing of discs, ligaments, muscles etc., we divert attention to rotations and translations of posture. The main masses of the body, namely the head, thorax and pelvis can be described in relation to the body mass below within a Cartesian coordinate system (Figures 2 and 3). That is, the head is described in relation to the thorax, the thorax in relation to the pelvis, and the pelvis in relation to the feet [1, 13].
Any rotations or translations of the body masses as seen in neutral posture via external observation or internally by X-ray is acknowledged as abnormal. Therefore, no offset of the masses equates to the normal postural alignment (i.e. un-subluxated position). It is important to note that in the assessment of a patient, it is the presence of a rotation or translation in the neutral standing position that is abnormal. When Harrison first applied this method of analysis, the treatment became apparent with the postural diagnosis. That is, for any rotation or translation apparent in neutral standing posture, the opposite position would need to be the treatment as applied during exercises, spinal traction or spinal adjustments, as this is the mathematical solution, “the exact reversing of the patient’s abnormal posture.” [1] In fact, because the soft tissues require a significant magnitude of stress and strains to attempt to correct the spinal position via mirror image methods, Harrison suggested that postural reflections (i.e. ‘mirror image’ adjustments) need to be applied in “twice the negative of the translation distances and rotation angles.” [1].
It should be noted when Harrison finally developed the full spine analysis of rotations and translations of posture in the mid 1980s, he discovered that virtually 50% of all human movements had never been studied (except forward head posture). Thus, the Harrison research group performed several studies to evaluate the normal range of motion for several translation postures including lateral head and thoracic postures as well as anterior and posterior thoracic translation postures (Discussed in Section 6). [2, 3] Clinically, the spinal coupling patterns as discovered to be associated with these common postural positions are of utmost importance in the treatment of these spinal disorders.
Importance of the study of these never previously studied translation postures can be highlighted in the distinction between true scoliosis and ‘pseudo-scoliosis’ (Figure 6) [14] Pseudo-scoliosis is a lateral thoracic translation posture that characteristically features little to no vertebral rotation (simple to correct) [15, 16], whereas, true scoliosis characteristically features significant vertebral rotation (and is typically much more difficult to treat). X-ray screening of the spine is the only way to differentiate true scoliosis from pseudo-scoliosis.
Figure 6.
Posture image and antero-posterior lumbar radiographs depicting a left lateral thoracic translation (side shift). Both patients in the radiographs have a 20 mm left lateral shift of T10 off midline. Left patient has a pure left lateral thoracic translation posture, aka ‘pseudo-scoliosis.’ Right patient has a true left lumbar scoliosis (vertebral rotation). Green line is vertical; red line highlights patient alignment (courtesy CBP seminars).
As mentioned, the absence of rotations and translations of the body masses in standing posture is normal. However, the shape of the spine position, particularly in the sagittal plane has traditionally been debated.
4. The Harrison normal spine model
In the mid 1990s to the mid 2000s, the Harrison research team performed a series of spine modeling studies of the sagittal spinal curves (Figure 7) [17, 18, 19, 20, 21, 22, 23, 24]. To this day, this seminal work serves as the treatment outcome goal (i.e. gold standard) for providing structural rehabilitation by CBP methods (Figure 8). In a series of systematic studies, elliptical shape modeling of the path of the posterior longitudinal ligament was performed as it could be easily compared to the posterior vertebral body margins on X-rays, the same anatomical region used for measuring the sagittal spinal curves (i.e. Harrison posterior tangents (Figure 9) [25, 26, 27, 28]).
Figure 7.
The Harrison normal sagittal spine model as the path of the posterior longitudinal ligament. The cervical, thoracic and lumbar curves are all portions of an elliptical curve having a unique minor-to-major axis ratio. The cervical curve is circular meaning the minor and major axes are equal (courtesy CBP seminars).
Figure 8.
Three patients demonstrating dramatically different spine alignment patterns. Left: excessive lumbar hyperlordosis, L4 anterolisthesis, and excessive anterior sagittal balance in a mid-aged female with disabling low back pain; middle: excessive thoracolumbar kyphosis and early degenerative changes in a mid-aged male; right: excessive thoracic hyperkyphosis in a young male with Scheuermann’s disease. Red line is contiguous with posterior vertebral body margins; green line represents Harrison normal spinal model (courtesy PAO).
Figure 9.
Harrison posterior tangent method involves lines drawn contiguous with the posterior vertebral body margins. Intersegmental as well as regional sagittal curves are easily quantified having a standard error of measurement within about 2° (courtesy CBP seminars).
Computer iterations of spine shape modeling were applied to determine the best-fit geometric spinal shapes by fitting ellipses of varying minor-to-major axis ratios to the digitized data points from the posterior vertebral body corners from X-ray samples for each of the three regions of the spine (cervical [17, 18, 19], thoracic [20, 21], and lumbar spine [22, 23, 24]). As shown in Figure 7, the Harrison normal spinal model features a circular cervical lordosis, an elliptical thoracic curve featuring greater curvature cephalad with a straightened thoraco-lumbar junction and an elliptical lumbar lordosis showing a greater distal lumbar curvature. The spine is assumed to be vertical in the front view.
Although some have attempted to criticize the Harrison normal spinal model, it is important to acknowledge that it has been validated in several ways. Simple analysis of alignment data on samples of normal, asymptomatic populations have been done [17, 18, 19, 20, 21, 22, 23, 24]. Comparison studies between normal samples to symptomatic samples have been performed [17, 29]. Comparisons between normal samples to theoretical ideal models have been done [17, 18, 20, 23]. Statistical differentiation of asymptomatic subjects from symptomatic pain group patients based on alignment data has been performed [19, 24].
In subsequent biomechanical modeling studies, the Harrison group used a validated postural loading model to verify that sagittal spinal balance and the sagittal curves of the spine are critical biomechanical parameters for maintaining postural load balance in healthy subjects [30]. Keller et al. [30] stated “because the pattern of [intervertebral disc] IVD postural stresses mirrored the sagittal curvatures and sagittal displacement of the spine, a failure of the IVD’s hydrostatic mechanism under these sustained loads could occur”. In a similar biomechanical modeling study, Harrison et al. determined that anterior sagittal thoracic posture (anterior thorax translation relative to the pelvis) resulted in significant increases in disc loads and stresses for all vertebral levels below T9 and that the extensor muscle loads required to maintain static equilibrium in upright anterior posture increased almost five times that of normal [31]. In another study Keller et al. [32] determined that “postural forces are responsible for initiation of osteoporotic spinal deformity in elderly subjects”.
The Harrison group also used an elliptical shell model to evaluate the loads and bending moments on the cervical vertebrae in varying cervical spine deformity alignments [33, 34]. They found that in normal lordosis the anterior and posterior vertebral body stresses are nearly uniform and minimal, whereas, in cervical deformity configurations having kyphosis (S-shape kyphosis high or low, total kyphosis), the vertebral body stresses are ‘very large’ and opposite in direction compared to normal lordosis [33]. They concluded “This analysis provides the basis for the formation of osteophytes (Wolff’s Law) on the anterior margins of vertebrae in kyphotic regions of the sagittal cervical curve. This indicates that any kyphosis is an undesirable configuration in the cervical spine” [33]. Anterior head translation and a ‘military’ neck also displayed significantly increased vertebral body stresses that are reverse in direction from C5-T1 and are also proven to be “undesirable configurations in the cervical spine” [34].
5. Radiographic analysis
All radiographs should be taken in the ‘neutral’ standing position with the feet positioned with the heels at hips width apart. This is to avoid any induced postural deviations due to foot position. Also, to ensure a reproducible neutral (i.e. natural) body position, the subject should close their eyes and nod the head back and forth a couple times to where the subject should stop in their preferred position and then open their eyes while maintaining this adopted stance. Any postural misalignments seen in the subject should not be corrected. The lower body mass on the particular view being taken should be centered to the bucky. All X-rays should be taken without footwear.
It should be mentioned that the measurement of different sagittal spinal contours including regional curves or absolute rotation angles (ARAs) (i.e. cervical/lumbar lordosis; thoracic kyphosis) and intersegmental relative rotation angles (RRAs) between adjacent vertebrae can be easily quantified by use of the Harrison posterior tangent (HPT) lines (Figure 9) [25, 26, 27, 28]. The HPT method is preferred for three main reasons, 1. The posterior margins of the vertebral bodies are less affected by osteoarthritic changes as compared to the anterior margins which makes anatomical measurements more reliable and valid; 2. The posterior tangents are contiguous with the slope of the spinal curves and represent the first derivative in an engineering analysis and therefore, their intersection accurately depicts the sagittal configuration; 3. The HPT method has a small standard error of measurement (SEM) of approximately 2° versus higher SEMs with the Cobb (4.5–10°) [25, 26, 27]. This is why the HPT method is superior to other methods of sagittal spine mensuration including the popular Cobb method.
Generally, the global curves are measured as C2-C7, T1-T12, and L1-L5, however since the inflection of the cervical lordosis to thoracic kyphosis occurs at T1, some clinicians prefer to measure the cervical curve from C1-T1, and the thoracic curve from T2-T11 or T3-T10. Anterior sagittal translation distances are simply measured by the horizontal displacement offset between comparison vertebrae such as C2-S1, C2-C7 or T1, T1-T12, etc.
The anterior-to-posterior (AP) or PA X-rays are taken using the same postural positioning. The modified Risser-Ferguson method is employed to measure coronal plane alignment (Figure 10) [28]. On the AP/PA cervicothoracic view an upper angle is created as the angle between the best fit line of the upper cervical segments and intersection with the bite line, and a lower angle is formed between the best fit lines of the upper to lower spine segments [28]. The Rz angle is the angle formed by a vertical axis line (VAL) drawn from T4 and the lower cervicothoracic best fit line. Normal upper angle, lower angle and Rz cervicothoracic angles are 90°, 0° and 0°, respectively. The AP/PA thoracic view may show an angle. The lumbo-pelvic view has an upper angle, the angle between the best fit line of the upper versus lower lumbar segments, and a lower angle, the angle between the best fit line between the lower segments and the horizontal pelvic line [28]. The upper angle and lower angle should be 0° and 90°, respectively. Any regional or full-spine coronal balance offset (i.e. imbalance) can be easily quantified as the horizontal distance between the uppermost segment to the lowermost segment (e.g. C2-T2, T1-T12, T12-S1, C2-S1).
Figure 10.
AP radiographic line drawing by modified Risser-Ferguson method.
6. Posture and spinal coupling
Postural rotations and translations as described by Harrison (Figures 2 and 3) are understood as ‘main motions’ and the corresponding spinal displacements to accommodate the postural positions are termed ‘coupled motions’ [2, 3, 35, 36, 37, 38]. In CBP, a considerable clinical significance is placed on the correlation between the patient’s three-dimensional postural presentation (posture displacement in terms of rotations and translations) and the two-dimensional X-ray coupled motion (spinal rotations and translations) [2, 3, 38].
Of prime importance is the appreciation that unless there is buckling, anomalies or ligament damage, standing neutral postural rotation and translation displacements of the head or thorax cause the vertebral spinal coupling patterns as seen on X-ray. If a patient’s rotations and/or translations of posture ‘match’ the associated spinal coupling pattern as expected (i.e. normal coupling), then it is considered an ‘easy’ or typical case and the intuitive mirror image application of CBP methods would apply. When the patient’s rotations and/or translations of posture do not match the expected spine coupling pattern (i.e. spinal coupling does not match postural displacement), then it is considered an atypical case where the clinician needs to consider alternative (i.e. more complicated) strategies for spine rehabilitation.
A classic demonstration of the ‘matching’ versus ‘mismatching’ of rotations and translations of posture and spine coupling patterns can be illustrated with forward head posture, aka, anterior head translation (AHT) (Figure 11). The natural and expected spine coupling with a forward translated head posture involves lower cervical spine flexion and upper cervical spine extension. As seen in Figure 11, many spine different vertebral coupling patterns are possible including hyperlordosis, hypolordosis, or kyphosis and accordingly, each cervical configuration requires its own unique application of CBP methods for its ideal correction.
Figure 11.
Forward head translation as shown in posture and in three unique lateral cervical radiographs. All three X-ray images have about 25 mm of forward head translation. Left: hyperlordosis; middle: hypolordosis; right: kyphosis. Green line is normal alignment; red line highlights patient alignment.
These cervical spine patterns have been termed harmonics and their presence can only be determined by radiography [2, 39]. Importantly, in CBP treatment approaches, each cervical spine coupling pattern (harmonic) requires its own unique treatment protocol. This is why many manual therapy approaches (e.g. Mackenzie head retractions) are inadequate at correcting posture and spine alignment as these are prescribed universally (i.e. ‘blackbox treatment’) resulting in many patients receiving treatment protocols that are contraindicated. A patient with a hyperlordotic cervical spine should never be prescribed neck extension exercises as this would dynamically hyperextend the cervical joints. A patient with a complete cervical kyphosis should never be prescribed head retraction exercises as this often ‘buckles’ the spine into further kyphosis.
Also, as mentioned and illustrated in Figure 6, ‘pseudo-scoliosis’ or pure lateral translations of the thorax (or head) must be distinguished from true scoliosis by examination of the spinal coupling patterns [14]. If there is minimal or no vertebral rotation then this represents a typical case requiring CBP mirror image postural correction [3]. If there is vertebral rotation then it is considered true scoliosis and a completely different application of CBP methods (i.e. non-commutative properties of finite rotation angles [40, 41]). Case examples of the special application of CBP methods in the treatment of scoliosis is described later.
7. CBP protocol
The CBP patient management protocol [2, 3, 4] involves all typical initial patient examination procedures including the consultation, examination as well as pain, disability and quality of life questionnaires (Figure 12). In addition, CBP treatment consideration requires, without exception, a full-spine posture assessment as well as full-spine AP and lateral standing radiographs. Posture needs to be either qualitatively, but ideally quantitatively assessed as rotations and translations of the head, thorax and pelvis in three-dimensions (Figures 2 and 3). The X-rays need to be digitized and quantified, ideally with the Harrison posterior tangent method for the sagittal images and with the modified Risser-Ferguson on the AP images.
Figure 12.
CBP protocol treatment algorithm.
As seen in Figure 12, if appropriate, a new patient should be treated for their acute pain that is distinct and separate from CBP methods. It is recommended that the acute ‘pain care’ treatment include spinal manipulation, stretching (e.g. proprioceptive neuromuscular facilitation (PNF), Yoga, etc.), heat/ice, soft tissue myofascial therapy (e.g. transverse friction, Nimmo-receptor tonus technique, etc.). Once the patient experiences some initial pain relief (e.g. 6–12 treatments) they can be re-assessed and graduated to CBP structural rehabilitation. The decision to first treat a new patient with ‘acute’ pain care is a clinical decision that is mainly for patients that have either never seen a chiropractor previously or they have not been previously treated for their acute condition. For patients who have received recent previous treatment without relief, CBP rehabilitation care is recommended from the start of treatment [2, 3, 4].
CBP structural rehabilitation is suggested as either three times per week for 12-weeks (36 treatments) or four times per week for 9-weeks (36 treatments), however, the controlled trial data support treatment blocks of 30–40 treatment sessions [7, 8, 9, 10, 15, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]. An initial patient who has acute or chronic pains and who has not been treated recently or at all for their current spine issue should be treated for an initial 6–12 sessions to provide pain relief. After signs of relief have occurred, a progress exam should be performed and the patient should be transitioned or ‘graduated’ to CBP corrective care.
CBP treatment occurs in ‘blocks of care.’ Numerous CBP controlled clinical trials (RCTs [43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55] and nRCTs [7, 8, 9, 10, 15, 42]) provide evidence for spine altering changes to occur in the range of 30–40 treatment sessions; thus, it is the practitioners’ choice to set their protocol within this range (i.e. treatment blocks). The end of each ‘block’ of CBP care requires a progress exam which includes all of the typical assessment procedures as well as a posture and X-ray assessment. Exam results may either dictate the need for further CBP treatment or the recommendation for ‘supportive’ or maintenance care. An initial block of CBP structural rehabilitation will include any acute care provided in the first 2–4 weeks. It is always recommended that ongoing ‘progress exams’ be performed regularly, at either 4-week or 12 treatment intervals, or as frequently as recommended by each practitioner’s regional regulatory board requirements.
CBP does not specifically support ‘long-term’ care plans. However, based on the data, an adult typically needs 6-months of corrective care (e.g. 72 treatments over 6-months at 3x/week) which is an evidence-based recommendation. Although, any given patient may require a shorted (i.e. 3-month) or longer treatment program based on their initial presenting postural parameters—approximate treatment extrapolations can be made by studying Tables 1–3. There is also support for supportive/maintenance care at a frequency of approximately 2×/month [8, 9, 10].
Study
Journal
Traction method
Traction time
Number of treatments
Change (*)
Change/txt (*)
Theoretical treatment extrapolation
Hypolordotic -20°
No curve 0°
Kyphotic +20°
RCTs
Moustafa
Sci Reports
Denneroll
20m
30
13.9
0.46
32
76
119
Moustafa
Heliyon
Denneroll
15–20m
30
13.4
0.45
34
78
123
Moustafa
J Athl Train
Denneroll
20m
30
14.7
0.49
31
71
112
Moustafa
APMR
Denneroll
20m
30
13.1
0.44
34
80
126
Moustafa
EJPRM
Denneroll
20m
30
13.7
0.46
33
77
120
Moustafa
BFPTCU
Denneroll
20m
36
12.8
0.36
42
98
155
nRCTs
Harrison
JMPT
Pope 2-way
20m
38
17.9
0.47
32
74
117
Harrison
APMR
2way
20m
35
14.2
0.41
37
86
136
Harrison
JMPT
Ext-comp
10m
60
13.2
022
68
159
250
Table 1.
Summary of cervical lordosis improvement by number of treatments, magnitude correction/treatment and the extrapolation to typical sagittal cervical curve subluxation types and the theoretical treatment number required for their correction to -35° C2-7 ARA.
*Note: Correction is estimated to achieve -35 of cervical lordosis.
Study
Journal
Traction method
Traction time
Number of treatments
Change (*)
Change/ txt (*)
Theoretical treatment extrapolation
Hypolordotic -30°
Hypolordotic -15°
No curve 0°
RCTs
Moustafa
JBMR/JMPT
LET
20m
30
6.2
0.21
48
121
194
Moustafa
Clin Rehab
LET
20m
30
8.7
0.29
34
86
138
nRCTs
Harrison
APMR
LET
20m
36
11.3
0.31
32
80
127
Table 2.
Summary of lumbar lordosis improvement by number of treatments, magnitude correction/treatment and the extrapolation to typical sagittal lumbar curve subluxation types and the theoretical treatment number required for their correction to -40° L1-5 ARA.
*Note: Correction is estimated to achieve -40 of lumbar lordosis.
Study
Journal
Traction method
Traction time
Number of treatments
Change (mm)
Change/txt (mm)
Theoretical treatment extrapolation
Mild offset ±10mm
Moderate offset ±20mm
Severe offset ±30mm
nRCTs
Head trans Harrison
JRRD
Lat trans
20 m
37
6.9
0.19
54
107
161
Thorax trans Harrison
Eur Sp J
Lat trans
20 m
36
7.7
0.21
47
94
140
Table 3.
Summary of AP head and thorax lateral translation reduction by number of treatments, magnitude correction/treatment and the extrapolation to larger coronal plane offset subluxations and the theoretical treatment number required for their correction.
Note: Correction is estimated to achieve 0mm of offset.
8. Clinical evidence of efficacy
As mentioned, CBP technique has an abundance of clinical evidence supporting its effectiveness in correcting spine deformity and posture [7, 8, 9, 10, 15, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]. Recently, systematic reviews have summarized the clinical evidence as reported in the published controlled trials on these methods [56, 57]. We summarize the evidence here in four parts: cervical lordosis, lumbar lordosis, lateral translation (pseudo-scoliosis) postures of the head and thorax, and finally, evolving evidence from case reports/series on other important spine deformities including lumbar spondylolisthesis, cervical spondylolisthesis, thoracic hyperkyphosis, thoraco-lumbar junctional kyphosis, thoracic hypokyphosis (straight back syndrome), anterior sagittal balance, lumbar kyphosis (flat back syndrome), lumbar hyperlordosis, post-surgical cervical spine fusion and scoliosis.
8.1 Cervical lordosis
A recent systematic review found that of the RCTs and nRCTs on CBP extension traction methods, a 12–18° improvement in cervical lordosis can be achieved in 10–15 weeks after 30–36 treatment sessions [57]. Most RCTs have used the cervical Denneroll [43, 44, 45, 46, 47, 49, 50], and the three nRCTs all used different CET methods (Table 1) [7, 8, 9].
Table 1 shows the improvement in degrees per treatment as well as theoretical numbers of treatments for various presenting cervical spine subluxations. On average, there appears to be just less than a half degree improvement per treatment session; obviously, there are patients that will have both more correction and less correction than this. Using this estimation as an initial guideline, evidence-based treatment numbers can be predicted. For example, a patient presenting with a cervical kyphosis of 20° would require over 100 treatments to restore the neck to a curve of 35°.
Figures 13 and 14 show the long-term outcomes in patients receiving cervical extension traction versus comparative groups not receiving the traction. The patients restoring lordosis via CBP traction methods show improved cervical alignment which is maintained at a years’ follow-up (Figure 13) whereas, comparative groups receiving various physiotherapeutic treatments less the extension traction do not experience cervical improvement (Figure 13) and also show that any initial pain relief regresses back towards baseline levels after the cessation of treatment (Figure 14). Patient’s with improved lordosis retain their initial pain relief a year later (Figure 14). This is alarming as it shows patients receiving various physiotherapeutic treatments who do not improve their cervical lordosis (in hypolordotic patients) will have a future regression of symptoms post-treatment and may be misled by ‘apparent treatment efficacy’ [5, 57].
Figure 13.
Data from five RCTs demonstrates patients achieving cervical lordosis improvement (via extension traction) as well as conventional treatments have lordosis improvements that are sustained for 1 year after stopping treatment versus the cervical curve of comparative groups (controls not achieving lordosis improvement) remain unaffected by conventional treatments (weighted averages from five RCTs [44, 45, 47, 49, 50]). * indicates a significant group difference as specified in each of the five trials; brackets represent weighted standard deviation.
Figure 14.
Data from five RCTs demonstrates patients achieving cervical lordosis improvement (via extension traction) as well as conventional treatments have pain reductions that are sustained for 1 year after stopping treatment versus comparative groups (controls not achieving lordosis improvement) who show a regression (increase) of pain intensity towards baseline after stopping treatment (weighted averages from five RCTs [45, 46, 47, 49, 50]). * indicates a significant group difference as specified in each of the five trials; brackets represent weighted standard deviation.
8.2 Lumbar lordosis
A recent systematic review found “Limited but good quality evidence substantiates that the use of extension traction methods in rehabilitation programs definitively increases lumbar hypolordosis” [56]. The authors further stated: “Preliminarily, these studies indicate these methods provide longer-term relief to patients with low back disorders versus conventional rehabilitation approaches tested” [56]. On average, a 7–11° increase in lordosis can be achieved over 10–12 weeks after 30–36 treatment sessions (Table 2).
It must be mentioned that lumbar extension traction is necessary to increase the lumbar lordosis. Importantly, using the data from published trials [10, 53, 54, 55], one can extrapolate approximate treatment duration (Table 2). As seen, a mild hypolordotic lumbar spine of 30° (L1-L5 ARA) may only require 32–48 treatments, whereas, a flat lumbar curve would require 127–194 treatments to achieve a normal 40° lordosis.
The same trend as observed in patients receiving cervical lordosis correction versus comparative groups not receiving lordosis improvement is seen in the trials on the lumbar spine [5, 56]. Lordosis increase in patients receiving lumbar extension traction is achieved and maintained at 6-months follow-up (Figure 15); these patients also retain their initial pain relief whereas, comparative patient groups not receiving lordosis improvement (Figure 15) lose their initial pain relief by 6-months after cessation of treatment (Figure 16). Again, this is alarming and shows how active low back treatment, although offering transient pain relief, will likely regress after treatment if not receiving concurrent lordosis correction in those suffering from hypolordotic-related LBP [5, 56].
Figure 15.
Data from two RCTs demonstrates patients achieving lumbar lordosis improvement (via extension traction) as well as conventional treatments have lordosis improvements that are sustained for 6-months after stopping treatment versus the lumbar curve of comparative groups (controls not achieving lordosis improvement) remain unaffected by conventional treatments (weighted averages from two RCTs [53, 54]). * indicates a significant group difference as specified in each of the two trials; brackets represent weighted standard deviation.
Figure 16.
Data from two RCTs demonstrates patients achieving lumbar lordosis improvement (via extension traction) as well as conventional treatments have pain reductions that are sustained for 6-months after stopping treatment versus comparative groups (controls not achieving lordosis improvement) who show a regression (increase) of pain intensity towards baseline after stopping treatment (weighted averages from two RCTs [53, 54]). * indicates a significant group difference as specified in each of the two trials; brackets represent weighted standard deviation.
8.3 AP head and thorax postures
Coronal plane lateral translations of the head and thorax also referred to as ‘pseudo-scoliosis’ each has an nRCT published [15, 42] and many case reports demonstrating its reduction [16, 58, 59, 60, 61, 62, 63]. As discussed earlier, the differentiation from true scoliosis is that the involved vertebrae have minimal to no rotation, whereas, true scoliosis has substantial vertebral rotation (Figure 6). Also, the spinal coupling pattern of a laterally translated body mass (head or thorax) will demonstrate the lower involved spinal region to laterally flex towards the side of the translation and the upper involved spinal region to laterally flex back towards the vertical [35, 36].
Based on the data, a laterally translated body mass can be reduced about 7–8 mm after about 35 treatments. On average, correction of a laterally translated head or thorax can be corrected at about 0.2 mm per treatment, or about 1 mm per five treatments. Extrapolations of treatment numbers to patient subluxation presentation are shown in Table 3. From the data in each of the nRCTs, an approximate 50% reduction of the initial laterally translated head and thorax postures occurred; therefore, an average patient having an approximate 15 mm translation posture (head or rib cage) requires 6-months of corrective care (approximately 72 treatments). It must also be mentioned that many case reports have demonstrated larger lateral translation postural corrections/reductions with CBP methods in similar time frames [16, 58, 59, 60, 61, 62, 63], thus, these serve as approximate treatment extrapolations.
8.4 Other spine deformities
It is known that the science for manual therapies is lacking [64]. Therefore, lesser forms of evidence must be considered when evaluating various treatment approaches used to treat various spinal conditions by manual therapists [65, 66]; this includes treatment utilizing CBP methods. We now highlight more recent case studies and series showing structural spinal correction for a variety of relatively common disorders.
8.4.1 Lumbar spondylolisthesis
Fedorchuk et al. [67] reported on an 11 mm reduction (13.3–2.4 mm) of an L4 anterolisthesis in a 69-year old suffering from LBP and leg cramping. Pain relief was achieved after 60 treatments over 45 weeks. This was the first documented report of a reduction of a Grade 2 lumbar spondylolisthesis by CBP methods, as well as any other non-surgical method.
Oakley and Harrison reported on the reduction of multiple retrolistheses from L1-L4 ranging from 4.5 to 5.9 mm in a 32-year old male with LBP [68]. These were all reduced to within normal (<4.5 mm) after approximately 36 treatments over 14-weeks. A 13-month follow-up indicated the patient remained well and reported no back pain and the corrections had remained stable.
Fedorchuk et al. [69] reported on the reduction of L1 (−6.6 to −1.7 mm) and L2 (−6.1 to −2.0 mm) retrolistheses and an L5 anterolisthesis (+6.8 to −2.5 mm) in a 63-year old female bodybuilder with severe LBP and osteoarthritis. Thirty treatments were given over 10-weeks which resulted in normalizing all spondylolistheses as well as a dramatic reduction in pain and an ability to leg press 60 more pounds in the gym.
Fedorchuk et al. reported the complete reduction of an L3 retrolisthesis and L4 anterolisthesis after 50 treatments over a 7-month period [70]. The patient was 57-years old with severe LBP and sciatica. The L3 retrolisthesis reduced from −5.3 to −1.7 and the L4 anterolisthesis reduced from +5.4 to +1.0 mm. After treatment the patient was able to return to playing hockey and experienced full resolution of the back pain which had forced him to retire from sport. A 1-year follow-up showed the patient had remained well and maintained the corrections.
8.4.2 Cervical spondylolisthesis
Recently, Fedorchuk et al. present a case series of eight female patients with concomitant cervical hypolordosis, forward head translation and spondylolistheses [71]. All were in motor vehicle collisions, each having at least one, and at most four simultaneous cervical vertebral spondylolistheses ranging in magnitude from >2 mm up to 4.5 mm. All cases experienced a reduction in translational offset of the spondylolistheses, and increase in cervical lordosis and a decrease in forward head translation as well as an increase in spinal canal diameter at the location of the spondylolisthesis after 30 treatment sessions that included cervical extension traction over a duration of 12-weeks. On average, the spondylolistheses reduced by 2.6 mm and there was an average drop in neck disability by 30%.
In another case, Fedorchuk et al. presented a single case of a 52-year old with chronic neck pain [72]. The patient had a C4 anterolisthesis of 2.4 mm which was reduced to 0.7 mm as well as an increase in cervical lordosis and reduction in forward head translation after 30 treatments over 12-weeks. The patient reported a resolution of their neck pain and stiffness.
8.4.3 Thoracic hyperkyphosis
Thoracic hyperkyphosis is a relatively common subluxation pattern in the aging. Although there is one RCT on CBP methods showing reduction of the deformity, it is yet to be formally published [52]. A systematic review of CBP methods used to reduce thoracic hyperkyphosis was published [73] and summarized the outcomes of several case reports and series [74, 75, 76, 77, 78, 79]. In Table 2 of the Oakley and Harrison review an average 12° reduction in thoracic kyphosis occurred after 32 treatments over 14.5 weeks from a total of 17 patients [52]. The improved posture correlated with reduced pain, disability and improved QOL [52]. Figures 17 and 18 show various CBP mirror image spinal exercises and traction, respectively.
Figure 17.
CBP recommended mirror image exercises for patients with thoracic hyper-kyphosis.
Figure 18.
CBP mirror image traction for patients with thoracic hyper-kyphosis.
8.4.4 Thoracolumbar junctional kyphosis
Thoracolumbar kyphosis is the forward angled spine at the junction of the thoracic and lumbar spine and is associated with chronic LBP (CLBP). Gubbels et al. presented a case of the minimization of pain in a 16-year old female after a 22° reduction of thoracolumbar kyphosis, a 48 mm reduction of posterior sagittal balance, an 11° increase in lumbar lordosis and a 10° increase in sacral inclination [80]. Twenty-four in office treatments were given over an 8-week period with daily home traction resulting in a minimization of back pains.
8.4.5 Thoracic hypokyphosis (straight back syndrome)
Thoracic spine hypolordosis is termed straight back syndrome (SBS) and is associated with back pains and exertional dyspnea. Fortner et al. [81] reported on an 18-year old male suffering from back pains and exertional dyspnea. Twenty-four treatments over a 9-week period resulted in a 15° increase in thoracic kyphosis, a decrease in pain and improved exertional dyspnea symptoms. A 4-month follow-up showed the patient remained well.
Betz et al. [82] reported the improvement in a 19-year old male who suffered from exertional dyspnea and back pain. Over 12-weeks a 14° increase in thoracic curve was achieved resulting in relief of exertional dyspnea and pain, as well as increases in both the antero-posterior thoracic diameter and the ratio of antero-posterior to transthoracic diameter, both measures critical to the wellbeing of patients with SBS. A 2.75-year follow-up showed the patient remained well.
Fedorchuk et al. [83] reported on a 13° increased thoracic curve in a 26-year old male with back pains and type 1 diabetes. Treatment over 7-weeks included 36 sessions. Back pains reduced and importantly, there was also improvement in blood glucose immediately following the onset of each visit. An improvement in blood glucose averages, percentage of time of blood glucose in a healthy target range, and glycosylated hemoglobin occurred and the patient was able to reduce their basal insulin need by approximately half after the 7-weeks of care.
Mitchel et al. [84] reported a 10° increase in thoracic curve over 16-weeks in a 33-year old male suffering from exertional dyspnea and back pains. The measured lung capacity improved by 2L, the back pain diminished and the exertional dyspnea resolved. A 7-month follow-up indicated the patient remained well.
8.4.6 Anterior sagittal balance
Anterior sagittal balance (ASB) is the forward displacement of the upper body over the pelvis. Haas et al. reported on the dramatic 110 mm reduction in ASB in an 87-year old female with CLBP and sciatica [85]. Treatment consisted of 24 in office sessions over an 8-week period. The patient achieved a dramatic reduction of symptoms, improvements in flexibility and orthopedic testing.
Anderson et al. [86] reported on a 91 mm reduction in ASB in a 59-year old male patient suffering from a variety of symptoms associated with Parkinson’s disease. Initial treatment involved 38 treatments over 5 months. The patient experienced significant improvements in multiple postural parameters, gait, balance, hand tremors, low back and knee pains and SF-36 values. A 21-month follow-up showed the patient remained essentially well and most of the initial postural improvements were maintained.
8.4.7 Lumbar kyphosis (flat back syndrome)
Flat back syndrome (FBS) is the anterior translation of the upper body and gross loss (or kyphosis) of the lumbar spine and is associated with high pain and disability. In a case series, Harrison and Oakley describe the significant restoration of lumbar lordosis in two patients suffering from debilitating CLBP from flat back syndrome [87]. One patient had a 50° lordosis improvement in 100 treatments over 20 weeks, the other had a 26° lordosis improvement in 70 treatments over 16.5 weeks. In the discussion section of the report, it was calculated that the treatment costs of the patients receiving CBP treatment versus the projected costs for the surgical procedures recommended to the two patients equated to only 1–8%; the authors stated “at first 70 or 100 treatments may be criticized as ‘over-treatment,’ however, considering the overall cost-effectiveness and positive patient outcomes, it certainly is not” [87].
8.4.8 Lumbar hyperlordosis
Although lumbar hypolordosis is the most common lumbar misalignment in those presenting with chronic LBP [10], lumbar hyperlordosis is also seen clinically. CBP methods can be directed at decreasing lumbar lordosis and its typically associated anteriorly rotated pelvis. In a recent case, Oakley et al. [88] presented a case demonstrating the relief of CLBP and hip pains after an 8° reduction in lumbar hyperlordosis, a 5° reduction in pelvic tilt and an accompanying 17 mm reduction of forward sagittal balance. This occurred over a period of 13 months and 73 total treatments.
8.4.9 Post-surgical cervical spine fusion
Post-surgical cervical spine intervertebral fusion is not a common finding in clinical practice however, it is occasionally encountered. Many of these patients continue to suffer years after the intervention. Harrison et al. [89] presented a case showing improvement in sagittal postural parameters which corresponded with improved clinical outcome in a 52-year old male. Over a 6-month period, a 6° increase in cervical lordosis was achieved as well as a 13 mm reduction in anterior head translation (AHT). These improvements were maintained at a 2.5-year follow-up.
Fedorchuk et al. [90] also presented a successful outcome in a 43-year old with a C5-6 intersegmental fusion. After 36 treatments over 3-months, there was a 13° increase in cervical lordosis, a 9 mm decrease in AHT and a 5 mm reduction in lateral head translation.
8.4.10 Scoliosis
Although too large of a topic to address in this chapter, CBP technique has a unique approach in the treatment of scoliosis [3]. CBP methods incorporates the ‘non-commutative property of finite rotation angles under addition’ to ascertain the order of postural movements to be prescribed in the mirror image treatment of this disorder. Harrison and Oakley described reductions in curve magnitude in five lumbar or thoracolumbar scoliosis patients ranging from 5° to 24° after 18–84 treatments [40]. All patients were female and ranged in age from 19 to 45 years.
Haggard et al. reported a 19° reduction in a thoracolumbar curve in a 15-year old female patient after 24 office treatments over 15-weeks. The patient also performed 45 at home spine blocking sessions as prescribed by the attending chiropractor [41]. The patients LBP and headaches were dramatically improved, and the curve was reduced to 8°.
9. Use of X-ray
Use of X-ray for spine analysis is essential for treating spine deformities, including with CBP technique methods. Historically, there has been concerns of carcinogenicity associated with X-ray use. Recently, however, new evidence has come to light showing that anti-X-ray sentiment stemming from the supposed carcinogenicity is based on flawed science [91, 92, 93]. The bottom line is the linear no-threshold (LNT) model used to support radiation risk analysis is not scientific as it is not consistent with current radiobiological data [94, 95, 96, 97, 98].
X-rays and CT scans deliver low-dose radiation doses (<200 mGy), and because of this they cannot cause cancer. This is because low-dose (versus high-dose) radiation exposures stimulate the adaptive repair systems of the body to repair any damage done [99, 100, 101]. Although this topic is important, it is a much larger issue than the scope of this chapter but many recent reviews have found that X-rays (and CT scans) are not harmful [103]. In fact, after a substantial and critical review of higher quality studies on radiation exposure, Schultz et al. concluded: “The evidence suggests that exposure to multiple CT scans and other sources of low-dose radiation with a cumulative dose up to 100 mSv (approximately 10 scans), and possibly as high as 200 mSv (approximately 20 scans), does not increase cancer risk.” Thus, there should be no hesitation or misunderstanding surrounding X-ray risks. Doctors and patients need to become updated on X-ray safety and not succumb to the traditional carcinogenicity misinformation.
10. Conclusion
CBP technique is a well-studied approach to the structural improvement of spinal disorders. Many spinal disorders with associated pain and functional syndromes have either well characterized or evolving evidence for their treatment by the mirror image approach that underpins CBP methods. The correlation of the spine alignment and postural rotations and translations of posture are of critical importance and unique in the CBP approach.
Acknowledgments
We acknowledge the pioneering work of Dr. Donald D. Harrison.
Conflict of interest
D.E.H. teaches spine rehabilitation methods and sells products related to the treatment of spine deformities; P.A.O. is a paid consultant to CBP.
Nomenclature
AHT
anterior head translation
ASB
anterior sagittal balance
AP
anterior-to-posterior
ARA
absolute rotation angle
CBP
Chiropractic BioPhysics®
CLBP
chronic low back pain
HPT
Harrison posterior tangent
IVD
intervertebral disc
LBP
low back pain
LNT
linear no-threshold
nRCT
non-randomized controlled trial
QOL
quality of life
PA
posterior-to-anterior
PNF
proprioceptive neuromuscular facilitation
RCT
randomized controlled trial
RRA
relative rotation angle
SEM
standard error of measurement
SBS
straight back syndrome
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Mirror image® postural positions and movements are utilized including spinal extension positions to improve the spine and posture towards a normal/ideal alignment. Specifically, corrective exercises, corrective traction and chiropractic adjustments are performed encompassing a multimodal rehabilitation program with the goal of improving the posture and spine alignment. CBP Rehabilitation programs are typically performed in-office with supportive at-home measures. Repeat assessment including radiographs are used to quantify and monitor structural improvements. CBP technique is an evidence-based approach to treat spine deformities and is supported by all forms of clinical evidence including systematic literature reviews, randomized controlled trials, non-randomized controlled trials, case reports/series as well as is supported by biomechanical posture-spine coupling validity, radiographic and posture analysis reliability/repeatability and use of a validated biomechanical spinal model as the outcome goal of care. CBP technique is a proven method to improve pain, disability and quality of life in those with structural deformities.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81876",risUrl:"/chapter/ris/81876",signatures:"Deed E. Harrison and Paul A. Oakley",book:{id:"11042",type:"book",title:"Complementary Therapies",subtitle:null,fullTitle:"Complementary Therapies",slug:null,publishedDate:null,bookSignature:"Prof. Mario Bernardo-Filho, Prof. Redha Taiar, Danúbia Da Cunha De Sá-Caputo and Dr. Adérito Seixas",coverURL:"https://cdn.intechopen.com/books/images_new/11042.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83969-012-9",printIsbn:"978-1-83969-011-2",pdfIsbn:"978-1-83969-013-6",isAvailableForWebshopOrdering:!0,editors:[{id:"157376",title:"Prof.",name:"Mario",middleName:null,surname:"Bernardo-Filho",slug:"mario-bernardo-filho",fullName:"Mario Bernardo-Filho"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"308067",title:"Dr.",name:"Paul A.",middleName:null,surname:"Oakley",fullName:"Paul A. Oakley",slug:"paul-a.-oakley",email:"docoakley.icc@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"308068",title:"Dr.",name:"Deed E.",middleName:null,surname:"Harrison",fullName:"Deed E. Harrison",slug:"deed-e.-harrison",email:"drdeedharrison@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Historical beginnings",level:"1"},{id:"sec_3",title:"3. Rotations and translations of posture",level:"1"},{id:"sec_4",title:"4. The Harrison normal spine model",level:"1"},{id:"sec_5",title:"5. Radiographic analysis",level:"1"},{id:"sec_6",title:"6. Posture and spinal coupling",level:"1"},{id:"sec_7",title:"7. CBP protocol",level:"1"},{id:"sec_8",title:"8. Clinical evidence of efficacy",level:"1"},{id:"sec_8_2",title:"8.1 Cervical lordosis",level:"2"},{id:"sec_9_2",title:"8.2 Lumbar lordosis",level:"2"},{id:"sec_10_2",title:"8.3 AP head and thorax postures",level:"2"},{id:"sec_11_2",title:"8.4 Other spine deformities",level:"2"},{id:"sec_11_3",title:"8.4.1 Lumbar spondylolisthesis",level:"3"},{id:"sec_12_3",title:"8.4.2 Cervical spondylolisthesis",level:"3"},{id:"sec_13_3",title:"8.4.3 Thoracic hyperkyphosis",level:"3"},{id:"sec_14_3",title:"8.4.4 Thoracolumbar junctional kyphosis",level:"3"},{id:"sec_15_3",title:"8.4.5 Thoracic hypokyphosis (straight back syndrome)",level:"3"},{id:"sec_16_3",title:"8.4.6 Anterior sagittal balance",level:"3"},{id:"sec_17_3",title:"8.4.7 Lumbar kyphosis (flat back syndrome)",level:"3"},{id:"sec_18_3",title:"8.4.8 Lumbar hyperlordosis",level:"3"},{id:"sec_19_3",title:"8.4.9 Post-surgical cervical spine fusion",level:"3"},{id:"sec_20_3",title:"8.4.10 Scoliosis",level:"3"},{id:"sec_23",title:"9. Use of X-ray",level:"1"},{id:"sec_24",title:"10. Conclusion",level:"1"},{id:"sec_25",title:"Acknowledgments",level:"1"},{id:"sec_28",title:"Conflict of interest",level:"1"},{id:"sec_27",title:"Nomenclature",level:"1"}],chapterReferences:[{id:"B1",body:'Harrison DD, Janik TJ, Harrison GR, Troyanovich S, Harrison DE, Harrison SO. Chiropractic biophysics technique: A linear algebra approach to posture in chiropractic. Journal of Manipulative and Physiological Therapeutics. 1996;19(8):525-535'},{id:"B2",body:'Harrison DE, Harrison DD, Haas JW. Structural Rehabilitation of the Cervical Spine. Evanston, WY: Harrison CBP® Seminars, Inc.; 2002'},{id:"B3",body:'Harrison DE, Betz JW, Harrison DD, et al. CBP Structural Rehabilitation of the Lumbar Spine. Eagle, ID, USA: Harrison Chiropractic Biophysics Seminars; 2007'},{id:"B4",body:'Oakley PA, Harrison DD, Harrison DE, Haas JW. Evidence-based protocol for structural rehabilitation of the spine and posture: Review of clinical biomechanics of posture (CBP) publications. Journal of the Canadian Chiropractic Association. 2005;49(4):270-296'},{id:"B5",body:'Oakley PA, Moustafa IM, Harrison DE. Restoration of Cervical and Lumbar Lordosis: CBP® Methods Overview. In: Bettany-Saltikov J, Kandasamy G, editors. Spinal Deformities in Adolescents, Adults and Older Adults [Internet]. London: IntechOpen; 2019 [cited 2022 Apr 26]. DOI: 10.5772/intechopen.90713'},{id:"B6",body:'Panjabi MM, White AA 3rd, Brand RA Jr. A note on defining body parts configurations. Journal of Biomechanics. 1974;7(4):385-387'},{id:"B7",body:'Harrison DD, Jackson BL, Troyanovich S, Robertson G, de George D, Barker WF. The efficacy of cervical extension-compression traction combined with diversified manipulation and drop table adjustments in the rehabilitation of cervical lordosis: A pilot study. Journal of Manipulative and Physiological Therapeutics. 1994;17(7):454-464'},{id:"B8",body:'Harrison DE, Cailliet R, Harrison DD, Janik TJ, Holland B. A new 3-point bending traction method for restoring cervical lordosis and cervical manipulation: A nonrandomized clinical controlled trial. Archives of Physical Medicine and Rehabilitation. 2002;83(4):447-453'},{id:"B9",body:'Harrison DE, Harrison DD, Betz JJ, Janik TJ, Holland B, Colloca CJ, et al. Increasing the cervical lordosis with chiropractic biophysics seated combined extension-compression and transverse load cervical traction with cervical manipulation: Nonrandomized clinical control trial. Journal of Manipulative and Physiological Therapeutics. 2003;26(3):139-151'},{id:"B10",body:'Harrison DE, Cailliet R, Harrison DD, Janik TJ, Holland B. Changes in sagittal lumbar configuration with a new method of extension traction: Nonrandomized clinical controlled trial. Archives of Physical Medicine and Rehabilitation. 2002;83(11):1585-1591'},{id:"B11",body:'CBP NonProfit. www.cbpnonprofit.com'},{id:"B12",body:'Beer FP, Johnston ER. Vector Mechanics for Engineers: Statics and Dynamics. 4th ed. New York: McGraw-Hill; 1984. p. 95'},{id:"B13",body:'Harrison DD. Abnormal postural permutations calculated as rotations and translations from an ideal normal upright static spine. In: Sweere J, editor. Chiropractic Family Practice. Gaitherburg, MD: Aspen Publishers; 1992'},{id:"B14",body:'Harrison DE, Betz JW, Cailliet R, Colloca CJ, Harrison DD, Haas JW, et al. Radiographic pseudoscoliosis in healthy male subjects following voluntary lateral translation (side glide) of the thoracic spine. Archives of Physical Medicine and Rehabilitation. 2006;87(1):117-122'},{id:"B15",body:'Harrison DE, Cailliet R, Betz JW, Harrison DD, Colloca CJ, Haas JW, et al. A non-randomized clinical control trial of Harrison mirror image methods for correcting trunk list (lateral translations of the thoracic cage) in patients with chronic low back pain. European Spine Journal. 2005;14(2):155-162'},{id:"B16",body:'Henshaw M, Oakley PA, Harrison DE. Correction of pseudoscoliosis (lateral thoracic translation posture) for the treatment of low back pain: A CBP® case report. Journal of Physical Therapy Science. 2018;30(9):1202-1205'},{id:"B17",body:'Harrison DD, Janik TJ, Troyanovich SJ, Holland B. Comparisons of lordotic cervical spine curvatures to a theoretical ideal model of the static sagittal cervical spine. Spine. 1996;21(6):667-675'},{id:"B18",body:'Harrison DD, Janik TJ, Troyanovich SJ, Harrison DE, Colloca CJ. Evaluations of the assumptions used to derive an ideal normal cervical spine model. Journal of Manipulative and Physiological Therapeutics. 1997;20(4):246-256'},{id:"B19",body:'Harrison DD, Harrison DE, Janik TJ, Cailliet R, Haas JW, Ferrantelli J, et al. Modeling of the sagittal cervical spine as a method to discriminate hypolordosis: Results of elliptical and circular modeling in 72 asymptomatic subjects, 52 acute neck pain subjects, and 70 chronic neck pain subjects. Spine. 2004;29:2485-2492'},{id:"B20",body:'Harrison DE, Janik TJ, Harrison DD, Cailliet R, Harmon S. Can the thoracic kyphosis be modeled with a simple geometric shape? The results of circular and elliptical modeling in 80 asymptomatic subjects. Journal of Spinal Disorders. 2002;15(3):213-220'},{id:"B21",body:'Harrison DE, Harrison DD, Janik TJ, Cailliet R, Haas JW. Do alterations in vertebral and disc dimensions affect an elliptical model of the thoracic kyphosis? Spine. 2003;28(5):463-469'},{id:"B22",body:'Troyanovich SJ, Cailliet R, Janik TJ, Harrison DD, Harrison DE. Radiographic mensuration characteristics of the sagittal lumbar spine from a normal population with a method to synthesize prior studies of lordosis. Journal of Spinal Disorders. 1997;10(5):380-386'},{id:"B23",body:'Janik TJ, Harrison DD, Cailliet R, Troyanovich SJ, Harrison DE. Can the sagittal lumbar curvature be closely approximated by an ellipse? Journal of Orthopaedic Research. 1998;16(6):766-770'},{id:"B24",body:'Harrison DD, Cailliet R, Janik TJ, Troyanovich SJ, Harrison DE, Holland B. Elliptical modeling of the sagittal lumbar lordosis and segmental rotation angles as a method to discriminate between normal and low back pain subjects. Journal of Spinal Disorders. 1998;11(5):430-439'},{id:"B25",body:'Harrison DE, Harrison DD, Cailliet R, et al. Cobb method or Harrison posterior tangent method: which to choose for lateral cervical radiographic analysis. Spine. 2000;25:2072-2078'},{id:"B26",body:'Harrison DE, Cailliet R, Harrison DD, et al. Reliability of centroid, Cobb, and Harrison posterior tangent methods: Which to choose for analysis of thoracic kyphosis. Spine. 2001;26:E227-E234'},{id:"B27",body:'Harrison DE, Harrison DD, Cailliet R, et al. Radiographic analysis of lumbar lordosis: Centroid, Cobb, TRALL, and Harrison posterior tangent methods. Spine. 2001;26:E235-E242'},{id:"B28",body:'Harrison DE, Holland B, Harrison DD, et al. Further reliability analysis of the Harrison radiographic line drawing methods: Crossed ICCs for lateral posterior tangents and AP modified-Risser Ferguson. Journal of Manipulative and Physiological Therapeutics. 2002;25:93-98'},{id:"B29",body:'McAviney J, Schulz D, Bock R, Harrison DE, Holland B. Determining the relationship between cervical lordosis and neck complaints. Journal of Manipulative and Physiological Therapeutics. 2005;28(3):187-193'},{id:"B30",body:'Keller TS, Colloca CJ, Harrison DE, Harrison DD, Janik TJ. Influence of spine morphology on intervertebral disc loads and stresses in asymptomatic adults: Implications for the ideal spine. The Spine Journal. 2005;5(3):297-309'},{id:"B31",body:'Harrison DE, Colloca CJ, Harrison DD, Janik TJ, Haas JW, Keller TS. Anterior thoracic posture increases thoracolumbar disc loading. European Spine Journal. 2005;14(3):234-242'},{id:"B32",body:'Keller TS, Harrison DE, Colloca CJ, Harrison DD, Janik TJ. Prediction of osteoporotic spinal deformity. Spine. 2003;28(5):455-462'},{id:"B33",body:'Harrison DE, Harrison DD, Janik TJ, William Jones E, Cailliet R, Normand M. Comparison of axial and flexural stresses in lordosis and three buckled configurations of the cervical spine. Clinical Biomechanics. 2001;16(4):276-284'},{id:"B34",body:'Harrison DE, Jones EW, Janik TJ, Harrison DD. Evaluation of axial and flexural stresses in the vertebral body cortex and trabecular bone in lordosis and two sagittal cervical translation configurations with an elliptical shell model. Journal of Manipulative and Physiological Therapeutics. 2002;25(6):391-401'},{id:"B35",body:'Harrison DE, Harrison DD, Cailliet R, Janik TJ, Troyanovich SJ. Cervical coupling during lateral head translations creates an S-configuration. Clinical Biomechanics (Bristol, Avon). 2000;15(6):436-440'},{id:"B36",body:'Harrison DE, Cailliet R, Harrison DD, Janik TJ, Troyanovich SJ, Coleman RR. Lumbar coupling during lateral translations of the thoracic cage relative to a fixed pelvis. Clinical Biomechanics (Bristol, Avon). 1999;14(10):704-709'},{id:"B37",body:'Harrison DE, Cailliet R, Harrison DD, Janik TJ. How do anterior/posterior translations of the thoracic cage affect the sagittal lumbar spine, pelvic tilt, and thoracic kyphosis? European Spine Journal. 2002;11(3):287-293'},{id:"B38",body:'Harrison DE, Harrison DD, Haas JW, Oakley PA. Spinal Biomechanics for Clinicians. Vol. I. Evanston, WY: Harrison Chiropractic Biophysics Seminars, Inc.; 2003'},{id:"B39",body:'Oakley PA, Cuttler JM, Harrison DE. X-ray imaging is essential for contemporary chiropractic and manual therapy spinal rehabilitation: Radiography increases benefits and reduces risks. Dose-Response. 2018;16(2):1559325818781437'},{id:"B40",body:'Harrison DE, Oakley PA. Scoliosis deformity reduction in adults: A CBP® Mirror image® case series incorporating the \'non-commutative property of finite rotation angles under addition\' in five patients with lumbar and thoraco-lumbar scoliosis. Journal of Physical Therapy Science. 2017;29(11):2044-2050'},{id:"B41",body:'Haggard JS, Haggard JB, Oakley PA, Harrison DE. Reduction of progressive thoracolumbar adolescent idiopathic scoliosis by chiropractic biophysics® (CBP®) mirror image® methods following failed traditional chiropractic treatment: A case report. Journal of Physical Therapy Science. 2017;29(11):2062-2067'},{id:"B42",body:'Harrison DE, Cailliet R, Betz J, Haas JW, Harrison DD, Janik TJ, et al. Conservative methods for reducing lateral translation postures of the head: A nonrandomized clinical control trial. Journal of Rehabilitation Research and Development. 2004;41(4):631-639'},{id:"B43",body:'Moustafa IM, Diab AA, Hegazy F, Harrison DE. Demonstration of central conduction time and neuroplastic changes after cervical lordosis rehabilitation in asymptomatic subjects: A randomized, placebo-controlled trial. Scientific Reports. 2021;11(1):15379'},{id:"B44",body:'Moustafa IM, Diab A, Shousha T, Harrison DE. Does restoration of sagittal cervical alignment improve cervicogenic headache pain and disability: A 2-year pilot randomized controlled trial. Heliyon. 2021;7(3):e06467'},{id:"B45",body:'Moustafa I, Youssef ASA, Ahbouch A, Harrison DE. Demonstration of autonomic nervous function and cervical sensorimotor control after cervical lordosis rehabilitation: A randomized controlled trial. Journal of Athletic Training. 2021;56(3):10'},{id:"B46",body:'Moustafa IM, Diab AA, Hegazy F, Harrison DE. Does improvement towards a normal cervical sagittal configuration aid in the management of cervical myofascial pain syndrome: A 1-year randomized controlled trial. BMC Musculoskeletal Disorders. 2018;19(1):396'},{id:"B47",body:'Moustafa IM, Diab AA, Harrison DE. The effect of normalizing the sagittal cervical configuration on dizziness, neck pain, and cervicocephalic kinesthetic sensibility: A 1-year randomized controlled study. European Journal of Physical and Rehabilitation Medicine. 2017;53(1):57-71'},{id:"B48",body:'Moustafa IM, Diab AAM, Hegazy FA, Harrison DE. Does rehabilitation of cervical lordosis influence sagittal cervical spine flexion extension kinematics in cervical spondylotic radiculopathy subjects? Journal of Back and Musculoskeletal Rehabilitation. 2017;30(4):937-941'},{id:"B49",body:'Moustafa IM, Diab AA, Taha S, Harrison DE. Addition of a sagittal cervical posture corrective orthotic device to a multimodal rehabilitation program improves short- and long-term outcomes in patients with discogenic cervical radiculopathy. Archives of Physical Medicine and Rehabilitation. 2016;97(12):2034-2044'},{id:"B50",body:'Moustafa IM. Does improvement towards a normal cervical configuration aid in the management of fibromyalgia. A randomized controlled trial. Bulletin of Faculty of Pharmacy, Cairo University. 2013;18(2):29-41'},{id:"B51",body:'Moustafa IM, Diab AM, Ahmed A, Harrison DE. The efficacy of cervical lordosis rehabilitation for nerve root function, pain, and segmental motion in cervical spondylotic radiculopathy. Physiotherapy. 2011;97(supplment):846-847'},{id:"B52",body:'Moustafa IM, Walton LM, Raigangir V, Shousha TM, Harrison D. Reduction of posture hyperkyphosis improves short- and long-term outcomes in patients with neck pain. Abstract: International Journal of Orthopaedic & Sports Physical Therapy. 2020;50(1):CSM143'},{id:"B53",body:'Diab AAM, Moustafa IM. The efficacy of lumbar extension traction for sagittal alignment in mechanical low back pain: A randomized trial. Journal of Back and Musculoskeletal Rehabilitation. 2013;26(2):213-220'},{id:"B54",body:'Moustafa IM, Diab AA. Extension traction treatment for patients with discogenic lumbosacral radiculopathy: A randomized controlled trial. Clinical Rehabilitation. 2012;27(1):51-62'},{id:"B55",body:'Diab AA, Moustafa IM. Lumbar lordosis rehabilitation for pain and lumbar segmental motion in chronic mechanical low back pain: A randomized trial. Journal of Manipulative and Physiological Therapeutics. 2012;35(4):246-253'},{id:"B56",body:'Oakley PA, Ehsani NN, Moustafa IM, Harrison DE. Restoring lumbar lordosis: A systematic review of controlled trials utilizing Chiropractic Bio Physics® (CBP®) non-surgical approach to increasing lumbar lordosis in the treatment of low back disorders. Journal of Physical Therapy Science. 2020;32(9):601-610'},{id:"B57",body:'Oakley PA, Ehsani NN, Moustafa IM, Harrison DE. Restoring cervical lordosis by cervical extension traction methods in the treatment of cervical spine disorders: A systematic review of controlled trials. Journal of Physical Therapy Science. 2021;33(10):784-794'},{id:"B58",body:'Haas JW, Oakley PA, Harrison DE. Cervical pseudo-scoliosis reduction and alleviation of dystonia symptoms using chiropractic BioPhysics® (CBP®) technique: A case report with a 1.5-year follow-up. The Journal of Contemporary Chiropractic. 2019;2:131-137'},{id:"B59",body:'Jaeger JO, Oakley PA, Moore RR, Ruggeroli EP, Harrison DE. Resolution of temporomandibular joint dysfunction (TMJD) by correcting a lateral head translation posture following previous failed traditional chiropractic therapy: A CBP® case report. Journal of Physical Therapy Science. 2018;30(1):103-107'},{id:"B60",body:'Oakley PA, Harrison DE. Alleviation of pain and disability in a post-surgical C4-C7 total fusion patient after reducing a lateral head translation (side shift) posture: A CBP® case report with a 14 year follow-up. Journal of Physical Therapy Science. 2018;30(7):952-957'},{id:"B61",body:'Berry RH, Oakley P, Harrison D. Alleviation of radiculopathy by structural rehabilitation of the cervical spine by correcting a lateral head translation posture (-TxH) using Berry translation traction as a part of CBP methods: A case report. The Chiropractic Journal of Australia. 2017;45(1):63-72'},{id:"B62",body:'Berry RH, Oakley PA, Harrison DE. Alleviation of chronic headaches by correcting lateral head translation posture (-TxH) using Chiropractic Biophysics & Berry Translation Traction. Annals of Vertebral Subluxation Research. 2017;(1-2):87-92'},{id:"B63",body:'Oakley PA, Berry RH, Harrison DE. A structural approach to the postsurgical laminectomy case. Journal of Vertebral Subluxation Research. 2007;(March 19):1-7'},{id:"B64",body:'Nuckols TK, Lim YW, Wynn BO, et al. Rigorous development does not ensure that guidelines are acceptable to a panel of knowledgeable providers. Journal of General Internal Medicine. 2008;23(1):37-44'},{id:"B65",body:'Rome P, Waterhouse JD. An evidence-based narrative of the evidence-base concept. Asia-Pacific Chiropractic Journal. 2020;1:004. https://doi.org/10.46323/2021004'},{id:"B66",body:'Ebrall P, Doyle M. The value of case reports as clinical evidence. The Chiropractic Journal of Australia. 2020;47(1):29-43'},{id:"B67",body:'Fedorchuk C, Lightstone DF, McRae C, Kaczor D. Correction of grade 2 spondylolisthesis following a non-surgical structural spinal rehabilitation protocol using lumbar traction: A case study and selective review of literature. Journal of Radiology Case Reports. 2017;11(5):13-26'},{id:"B68",body:'Oakley PA, Harrison DE. Correction of multilevel lumbar retrolistheses by non-surgical extension traction procedures in a patient with congenital fusion of L5-S1: A CBP® case report with a 13-month follow-up. The Journal of Contemporary Chiropractic. 2020;3(1):137-142'},{id:"B69",body:'Fedorchuk C, Haugen H. Reduction in three levels of lumbar degenerative spondylolisthesis following chiropractic care: A case report & review of the literature. Annals of Vertebral Subluxation Research. 2020;(Dec. 3):165-170'},{id:"B70",body:'Fedorchuk CA, Lightstone DF, Oakley PA, Harrison DE. Correction of a double spondylolisthesis of the lumbar spine utilizing chiropractic biophysics® technique: A case report with 1-year follow-up. Journal of Physical Therapy Science. 2021;33(1):89-93'},{id:"B71",body:'Fedorchuk C, Lightstone DF, DeVon CR, Katz E, Wilcox J. Improvements in cervical spinal canal diameter and neck disability following correction of cervical lordosis and cervical spondylolistheses using chiropractic BioPhysics technique: A case series. Journal of Radiology Case Reports. 2020;14(4):21-37'},{id:"B72",body:'Fedorchuk C, Lightstone D. Reduction in cervical anterolisthesis & pain in a 52-year-old female using chiropractic biophysics® technique: A case study and selective review of literature. Annals of Vertebral Subluxation Research. 2016;3:118-124'},{id:"B73",body:'Oakley PA, Harrison DE. Reducing thoracic Hyperkyphosis subluxation deformity: A systematic review of chiropractic BioPhysics® methods employed in its structural improvement. The Journal of Contemporary Chiropractic. 2018;1(1):59-66'},{id:"B74",body:'Fortner MO, Oakley PA, Harrison DE. Alleviation of chronic spine pain and headaches by reducing forward head posture and thoracic hyperkyphosis: A CBP® case report. Journal of Physical Therapy Science. 2018;30(8):1117-1123'},{id:"B75",body:'Oakley PA, Jaeger JO, Brown JE, Polatis TA, Clarke JG, Whittler CD, et al. The CBP® mirror image® approach to reducing thoracic hyperkyphosis: A retrospective case series of 10 patients. Journal of Physical Therapy Science. 2018;30(8):1039-1045'},{id:"B76",body:'Fortner MO, Oakley PA, Harrison DE. Treating \'slouchy\' (hyperkyphosis) posture with chiropractic biophysics®: A case report utilizing a multimodal mirror image® rehabilitation program. Journal of Physical Therapy Science. 2017;29(8):1475-1480'},{id:"B77",body:'Miller JE, Oakley PA, Levin SB, Harrison DE. Reversing thoracic hyperkyphosis: A case report featuring mirror image® thoracic extension rehabilitation. Journal of Physical Therapy Science. 2017;29(7):1264-1267'},{id:"B78",body:'Fedorchuk C, Snow E. Reduction in thoracic hyperkyphosis with increased peak expiratory flow (PEF), forced expiratory volume (FEV) and SF-36 scores following CBP protocols in asymptomatic patients: A case series. Annals of Vertebral Subluxation Research. 2017;(Oct. 12):189-200'},{id:"B79",body:'Jaeger JO, Oakley PA, Colloca CJ, et al. Non-surgical reduction of thoracic hyper-kyphosis in a 24-year old music teacher utilizing chiropractic biophysics® technique. British Journal of Medicine and Medical Research. 2016;11:1-9'},{id:"B80",body:'Gubbels CM, Werner JT, Oakley PA, Harrison DE. Reduction of thoraco-lumbar junctional kyphosis, posterior sagittal balance, and increase of lumbar lordosis and sacral inclination by chiropractic BioPhysics® methods in an adolescent with back pain: A case report. Journal of Physical Therapy Science. 2019;31(10):839-843'},{id:"B81",body:'Fortner MO, Oakley PA, Harrison DE. Chiropractic biophysics management of straight back syndrome and exertional dyspnea: A case report with follow-up. The Journal of Contemporary Chiropractic. 2019;2:115-122'},{id:"B82",body:'Betz JW, Oakley PA, Harrison DE. Relief of exertional dyspnea and spinal pains by increasing the thoracic kyphosis in straight back syndrome (thoracic hypo-kyphosis) using CBP® methods: A case report with long-term follow-up. Journal of Physical Therapy Science. 2018;30(1):185-189'},{id:"B83",body:'Fedorchuk C, Lightstone DF, Comer RD, Weiner MT, McCoy M. Improved glycosylated hemoglobin, hyperglycemia, and quality of life following thoracic hypokyphosis vertebral subluxation correction using Chiropractic BioPhysics®: A prospective case report. Journal of Diabetes & Metabolism. 2018;9(10):1-10'},{id:"B84",body:'Mitchell JR, Oakley PA, Harrison DE. Nonsurgical correction of straight back syndrome (thoracic hypokyphosis), increased lung capacity and resolution of exertional dyspnea by thoracic hyperkyphosis mirror image® traction: A CBP® case report. Journal of Physical Therapy Science. 2017;29(11):2058-2061'},{id:"B85",body:'Haas JW, Harrison DE, Oakley PA. Non-surgical reduction in anterior sagittal balance subluxation and improvement in overall posture in a geriatric suffering from low back pain and sciatica: A CBP® case report. The Journal of Contemporary Chiropractic. 2020;3(1):45-50'},{id:"B86",body:'Anderson JM, Oakley PA, Harrison DE. Improving posture to reduce the symptoms of Parkinson’s: A CBP® case report with a 21 month follow-up. Journal of Physical Therapy Science. 2019;31(2):153-158'},{id:"B87",body:'Harrison DE, Oakley PA. Non-operative correction of flat back syndrome using lumbar extension traction: A CBP® case series of two. Journal of Physical Therapy Science. 2018;30(8):1131-1137'},{id:"B88",body:'Oakley PA, Ehsani NN, Harrison DE. Non-surgical reduction of lumbar hyperlordosis, forward sagittal balance and sacral tilt to relieve low back pain by Chiropractic BioPhysics® methods: A case report. Journal of Physical Therapy Science. 2019;31(10):860-864'},{id:"B89",body:'Harrison DE, Oakley PA, Betz JW. Anterior head translation following cervical fusion-a probable cause of post-surgical pain and impairment: A CBP® case report. Journal of Physical Therapy Science. 2018;30(2):271-276'},{id:"B90",body:'Fedorchuk C, Lightstone DF, Andino H. Failed neck surgery: Improvement in neck pain, migraines, energy levels, and performance of activities of daily living following subluxation correction using Chiropractic Biophysics® Technique: A case study. Annals of Vertebral Subluxation Research. 2017;(May 18):93-100'},{id:"B91",body:'Calabrese EJ. Cancer risk assessment foundation unraveling: New historical evidence reveals that the US National Academy of Sciences (US NAS), biological effects of atomic radiation (BEAR) committee genetics panel falsified the research record to promote acceptance of the LNT. Archives of Toxicology. 2015;89(4):649-650'},{id:"B92",body:'Calabrese EJ. An abuse of risk assessment: How regulatory agencies improperly adopted LNT for cancer risk assessment. Archives of Toxicology. 2015;89(4):647-648'},{id:"B93",body:'Calabrese EJ. On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith. Environmental Research. 2015;142:432-442'},{id:"B94",body:'Scott BR, Sanders CL, Mitchel REJ, Boreham DR. CT scans may reduce rather than increase risk of cancer. The Journal of the American Physicians and Surgeons. 2008;13(1):8-11'},{id:"B95",body:'Lemon JA, Phan N, Boreham DR. Single CT scan prolongs survival by extending cancer latency in Trp53 heterozygous mice. Radiation Research. 2017;188(4.2):505-511'},{id:"B96",body:'Lemon JA, Phan N, Boreham DR. Multiple CT scans extend lifespan by delaying cancer progression in cancer-prone mice. Radiation Research. 2017;188(4.2):495-504'},{id:"B97",body:'Cuttler JM. Application of low doses of ionizing radiation in medical therapies. Dose-Response. 2020;18(1):1559325819895739'},{id:"B98",body:'Calabrese EJ, Dhawan G, Kapoor R, Kozumbo WJ. Radiotherapy treatment of human inflammatory diseases and conditions: Optimal dose. Human & Experimental Toxicology. 2019;38(8):888-898'},{id:"B99",body:'Pollycove M, Feinendegen LE. Radiation-induced versus endogenous DNA damage: Possible effect of inducible protective responses in mitigating endogenous damage. Human and Experimental Toxicology. 2003;22(6):290-306'},{id:"B100",body:'Pollycove M. Radiobiological basis of low-dose irradiation in prevention and therapy of cancer. Dose-Response. 2006;5(1):26-38'},{id:"B101",body:'Feinendegen LE, Cuttler JM. Biological effects from low doses and dose rates of ionizing radiation: Science in the service of protecting humans, a synopsis. Health Physics. 2018;114(6):623-626'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Deed E. Harrison",address:null,affiliation:'
CBP NonProfit, Inc., USA
'},{corresp:"yes",contributorFullName:"Paul A. Oakley",address:"docoakley.icc@gmail.com",affiliation:'
Private Practice, Canada
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This is the reason why the conservation of cultural heritage is of great concern. Ceramics (Greek κεράμιον Keramion) is a material obtained by shaping and firing clay. In the Romanian history, many ceramic pieces, of great diversity, have been discovered, and most of them are used in traditional households. Ceramic materials based on clay minerals in cultural heritage (ceramic heritage) involve techniques of characterization of raw materials and ceramic objects based on clays, discovered in different archaeological sites, leading to some results about the production technology, provenance, authentication, and historical appartenance on Romanian territory. The chemical composition of ancient ceramics and pigments decorating them, excavated from different Romanian archaeological sites, suggested a chemical composition of ceramic based on clay minerals (kaolinite, illite, and smectite), while the pigments belonging to them contained red pigments (hematite or ocher), manganese oxides (brown pigments), and magnetite or carbon of vegetable origin (black-pigmented layers).",signatures:"Rodica-Mariana Ion, Radu-Claudiu Fierăscu, Sofia Teodorescu, Irina\nFierăscu, Ioana-Raluca Bunghez, Daniela Ţurcanu-Caruţiu and\nMihaela-Lucia Ion",authors:[{id:"137269",title:"Dr.",name:"Radu Claudiu",surname:"Fierascu",fullName:"Radu Claudiu Fierascu",slug:"radu-claudiu-fierascu",email:"radu_claudiu_fierascu@yahoo.com"},{id:"171504",title:"Prof.",name:"Rodica-Mariana",surname:"Ion",fullName:"Rodica-Mariana Ion",slug:"rodica-mariana-ion",email:"rodica_ion2000@yahoo.co.uk"},{id:"176479",title:"Dr.",name:"Sofia",surname:"Teodorescu",fullName:"Sofia Teodorescu",slug:"sofia-teodorescu",email:"sofiateodorescu@yahoo.com"},{id:"176480",title:"Dr.",name:"Irina",surname:"Fierascu",fullName:"Irina Fierascu",slug:"irina-fierascu",email:"dumitriu.irina@yahoo.com"},{id:"176481",title:"Dr.",name:"Ioana Raluca",surname:"Bunghez",fullName:"Ioana Raluca Bunghez",slug:"ioana-raluca-bunghez",email:"raluca_bunghez@yahoo.com"},{id:"176482",title:"Prof.",name:"Daniela",surname:"Turcanu-Carutiu",fullName:"Daniela Turcanu-Carutiu",slug:"daniela-turcanu-carutiu",email:"d_turcanu2002@yahoo.com"},{id:"176483",title:"Dr.",name:"Mihaela-Lucia",surname:"Ion",fullName:"Mihaela-Lucia Ion",slug:"mihaela-lucia-ion",email:"mihaella_ion@yahoo.com"}],book:{id:"5073",title:"Clays, Clay Minerals and Ceramic Materials Based on Clay Minerals",slug:"clays-clay-minerals-and-ceramic-materials-based-on-clay-minerals",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"20955",title:"Dr.",name:"Guadalupe",surname:"Sánchez-Olivares",slug:"guadalupe-sanchez-olivares",fullName:"Guadalupe Sánchez-Olivares",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"137269",title:"Dr.",name:"Radu Claudiu",surname:"Fierascu",slug:"radu-claudiu-fierascu",fullName:"Radu Claudiu Fierascu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"171504",title:"Prof.",name:"Rodica-Mariana",surname:"Ion",slug:"rodica-mariana-ion",fullName:"Rodica-Mariana Ion",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171504/images/system/171504.jpg",biography:"Prof. Rodica-Mariana Ion, Ph.D., is Full Professor of Nanomaterials at Valahia University, Targoviste and Head of Cultural Heritage Research Group ICECHIM - Bucharest, Romania. Author of 275 publications (Hirsch index = 22 (Google Scholar), 18 (Scopus); 20 books/chapters; 20 patents on nanoparticles on conservation/restoration of mural paintings, stone surface, paintings, books, wood churches, scientific analytical investigations of artifacts, photochemical aging processes and mechanism. Research Projects: (1) Method based on nanomaterials for conservation of paper and wood artifacts - Romania-Republic of South Africa; (2) Colour and Space in Cultural Heritage - UE COST TD 1201; (3) Innovative techniques and materials for preservation/restoration of stucco and decorative elements of masonry in patrimony buildings; (4) New diagnosis and treatment technologies for the preservation and revitalization of archaeological components of the national cultural heritage.",institutionString:"Valahia University of Târgoviște",institution:{name:"Valahia University of Targoviste",institutionURL:null,country:{name:"Romania"}}},{id:"176435",title:"Dr.",name:"Nouha",surname:"Jaafar",slug:"nouha-jaafar",fullName:"Nouha Jaafar",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Carthage",institutionURL:null,country:{name:"Tunisia"}}},{id:"176480",title:"Dr.",name:"Irina",surname:"Fierascu",slug:"irina-fierascu",fullName:"Irina Fierascu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/176480/images/system/176480.png",biography:"Irina Fierascu is a scientific researcher (CS1) at INCDCP-ICECHIM Bucharest with competences in analytical chemistry (different modern analytical techniques), nanomaterials – obtaining and characterization, nanotechnology, materials science, archaeometry, superior use of natural resources (obtaining and using natural extracts), photosynthesized nanomaterials, environmental protection, etc. Her PhD is in Material Engineering, and she has followed postdoctoral programs in Industrial Biotechnology and Environmental Engineering. The habilitation thesis covers “Capitalization of autochthonous vegetal species: from biomedical applications to nanotechnology”. She has been the author/co-author of several papers published in prestigious ISI journals (more than 80) in the field of natural extracts, nanomaterials, and photosynthesized metallic nanoparticles (especially gold and silver nanoparticles), as well as author/co-author of 12 books/chapter in books. She has experience in managing projects with topics of international relevance: application of nanomaterials in different fields: environment, agriculture or conservation/restoration of cultural heritage artifacts. She has won different awards, from government institutions or other prestigious institutions in the field.",institutionString:"National Institute for Research & Development in Chemistry and Petrochemistry",institution:null},{id:"176481",title:"Dr.",name:"Ioana Raluca",surname:"Bunghez",slug:"ioana-raluca-bunghez",fullName:"Ioana Raluca Bunghez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"176482",title:"Prof.",name:"Daniela",surname:"Turcanu-Carutiu",slug:"daniela-turcanu-carutiu",fullName:"Daniela Turcanu-Carutiu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/176482/images/system/176482.png",biography:"Prof. (full) Daniela Turcanu-Carutiu, Ph.D. is the Director of Institute of Science, Culture and Spirituality, Ovidius University of Constanta, Romania, including Center of Expertise Art Works by Advanced Instrumental Methods. Her research interest is in the heritage field: in Physico-chemical investigation by advanced instrumental methods for authentication, conservation, restoration artworks, archaeology components of cultural heritage, materials: pigments-colors and chromatology. She is the author of a reference book on cultural heritage, co-author of numerous chapters and articles published in internationally prestigious journals, citations in ISI Thomson Web of Science. Her research projects include: an integrated approach for reinforcement of historical chalk monuments by means of nanomaterials based treatments, new diagnosis and treatment technologies for the preservation and revitalization of archaeological components of the national cultural heritage.",institutionString:"Ovidius University",institution:{name:"Ovidius University",institutionURL:null,country:{name:"Romania"}}},{id:"176483",title:"Dr.",name:"Mihaela-Lucia",surname:"Ion",slug:"mihaela-lucia-ion",fullName:"Mihaela-Lucia Ion",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"177584",title:"Prof.",name:"Hafsia",surname:"Ben Rhaiem",slug:"hafsia-ben-rhaiem",fullName:"Hafsia Ben Rhaiem",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"177585",title:"Prof.",name:"Abdesslem",surname:"Ben Haj Amara",slug:"abdesslem-ben-haj-amara",fullName:"Abdesslem Ben Haj Amara",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"our-story",title:"Our story",intro:"
The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
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2004
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Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
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Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
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2005
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IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
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2006
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IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
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2008
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Downloads milestone: 200,000 downloads reached
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2009
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Publishing milestone: the first 100 Open Access STM books are published
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2010
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Downloads milestone: one million downloads reached
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IntechOpen expands its book publishing into a new field: medicine.
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2011
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Publishing milestone: More than five million downloads reached
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IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
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IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
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IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
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2012
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Publishing milestone: 10 million downloads reached
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IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
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2013
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IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
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2014
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IntechOpen turns 10, with more than 30 million downloads to date.
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IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
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2015
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Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
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Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
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40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
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Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
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2016
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IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
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2017
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Downloads milestone: IntechOpen reaches more than 100 million downloads
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Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
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Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
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2005
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IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
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2006
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IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
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2008
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Downloads milestone: 200,000 downloads reached
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2009
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Publishing milestone: the first 100 Open Access STM books are published
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2010
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Downloads milestone: one million downloads reached
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IntechOpen expands its book publishing into a new field: medicine.
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2011
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Publishing milestone: More than five million downloads reached
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IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
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IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
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IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
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2012
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Publishing milestone: 10 million downloads reached
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IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
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2013
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IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
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2014
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IntechOpen turns 10, with more than 30 million downloads to date.
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IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
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2015
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Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
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Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
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40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
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Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
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2016
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IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
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2017
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Downloads milestone: IntechOpen reaches more than 100 million downloads
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Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
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Marquis, Éric Guillaume and Carine Chivas-Joly",authors:[{id:"44307",title:"Dr",name:"Damien",middleName:"Michel",surname:"Marquis",slug:"damien-marquis",fullName:"Damien Marquis"},{id:"44317",title:"Prof.",name:"Carine",middleName:null,surname:"Chivas-Joly",slug:"carine-chivas-joly",fullName:"Carine Chivas-Joly"}]},{id:"52860",doi:"10.5772/65937",title:"Cerium Oxide Nanostructures and their Applications",slug:"cerium-oxide-nanostructures-and-their-applications",totalDownloads:5365,totalCrossrefCites:23,totalDimensionsCites:55,abstract:"Due to excellent physical and chemical properties, cerium oxide (ceria, CeO2) has attracted much attention in recent years. This chapter aimed at providing some basic and fundamental properties of ceria, the importance of oxygen vacancies in this material, nano‐size effects and various synthesis strategies to form diverse structural morphologies. Finally, some key applications of ceria‐based nanostructures are reviewed. We conclude this chapter by expressing personal perspective on the probable challenges and developments of the controllable synthesis of CeO2 nanomaterials for various applications.",book:{id:"5510",slug:"functionalized-nanomaterials",title:"Functionalized Nanomaterials",fullTitle:"Functionalized Nanomaterials"},signatures:"Adnan Younis, Dewei Chu and Sean Li",authors:[{id:"191574",title:"Dr.",name:"Adnan",middleName:null,surname:"Younis",slug:"adnan-younis",fullName:"Adnan Younis"}]}],mostDownloadedChaptersLast30Days:[{id:"71103",title:"Preparation of Nanoparticles",slug:"preparation-of-nanoparticles",totalDownloads:3140,totalCrossrefCites:11,totalDimensionsCites:25,abstract:"Innovative developments of science and engineering have progressed very fast toward the synthesis of nanomaterials to achieve unique properties that are not the same as the properties of the bulk materials. The particle reveals interesting properties at the dimension below 100 nm, mostly from two physical effects. The two physical effects are the quantization of electronic states apparent leading to very sensitive size-dependent effects such as optical and magnetic properties and the high surface-to-volume ratio modifies the thermal, mechanical, and chemical properties of materials. The nanoparticles’ unique physical and chemical properties render them most appropriate for a number of specialist applications.",book:{id:"9109",slug:"engineered-nanomaterials-health-and-safety",title:"Engineered Nanomaterials",fullTitle:"Engineered Nanomaterials - Health and Safety"},signatures:"Takalani Cele",authors:[{id:"305934",title:"Dr.",name:"Takalani",middleName:null,surname:"Cele",slug:"takalani-cele",fullName:"Takalani Cele"}]},{id:"72636",title:"Nanocomposite Materials",slug:"nanocomposite-materials",totalDownloads:2139,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Nanocomposites are the heterogeneous/hybrid materials that are produced by the mixtures of polymers with inorganic solids (clays to oxides) at the nanometric scale. Their structures are found to be more complicated than that of microcomposites. They are highly influenced by the structure, composition, interfacial interactions, and components of individual property. Most popularly, nanocomposites are prepared by the process within in situ growth and polymerization of biopolymer and inorganic matrix. With the rapid estimated demand of these striking potentially advanced materials, make them very much useful in various industries ranging from small scale to large to very large manufacturing units. With a great deal to mankind with environmental friendly, these offer advanced technologies in addition to the enhanced business opportunities to several industrial sectors like automobile, construction, electronics and electrical, food packaging, and technology transfer.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Mousumi Sen",authors:[{id:"310218",title:"Dr.",name:"Mousumi",middleName:null,surname:"Sen",slug:"mousumi-sen",fullName:"Mousumi Sen"}]},{id:"38951",title:"Carbon Nanotube Transparent Electrode",slug:"carbon-nanotube-transparent-electrode",totalDownloads:3985,totalCrossrefCites:3,totalDimensionsCites:5,abstract:null,book:{id:"3077",slug:"syntheses-and-applications-of-carbon-nanotubes-and-their-composites",title:"Syntheses and Applications of Carbon Nanotubes and Their Composites",fullTitle:"Syntheses and Applications of Carbon Nanotubes and Their Composites"},signatures:"Jing Sun and Ranran Wang",authors:[{id:"153508",title:"Prof.",name:"Jing",middleName:null,surname:"Sun",slug:"jing-sun",fullName:"Jing Sun"},{id:"153596",title:"Ms.",name:"Ranran",middleName:null,surname:"Wang",slug:"ranran-wang",fullName:"Ranran Wang"}]},{id:"49413",title:"Electrodeposition of Nanostructure Materials",slug:"electrodeposition-of-nanostructure-materials",totalDownloads:3732,totalCrossrefCites:1,totalDimensionsCites:7,abstract:"We are conducting a multi-disciplinary research work that involves development of nanostructured thin films of semiconductors for different applications. Nanotechnology is widely considered to constitute the basis of the next technological revolution, following on from the first Industrial Revolution, which began around 1750 with the introduction of the steam engine and steelmaking. Nanotechnology is defined as the design, characterization, production, and application of materials, devices and systems by controlling shape and size of the nanoscale. The nanoscale itself is at present considered to cover the range from 1 to 100 nm. All samples prepared in thin film forms and the characterization revealed their nanostructure. The major exploitation of thin films has been in microelectronics, there are numerous and growing applications in communications, optical electronics, coatings of all kinds, and in energy generation. A great many sophisticated analytical instruments and techniques, largely developed to characterize thin films, have already become indispensable in virtually every scientific endeavor irrespective of discipline. Among all these techniques, electrodeposition is the most suitable technique for nanostructured thin films from aqueous solution served as samples under investigation. The electrodeposition of metallic layers from aqueous solution is based on the discharge of metal ions present in the electrolyte at a cathodic surface (the substrate or component.) The metal ions accept an electron from the electrically conducting material at the solid- electrolyte interface and then deposit as metal atoms onto the surface. The electrons necessary for this to occur are either supplied from an externally applied potential source or are surrendered by a reducing agent present in solution (electroless reduction). The metal ions themselves derive either from metal salts added to solution, or by the anodic dissolution of the so-called sacrificial anodes, made of the same metal that is to be deposited at the cathode.",book:{id:"4718",slug:"electroplating-of-nanostructures",title:"Electroplating of Nanostructures",fullTitle:"Electroplating of Nanostructures"},signatures:"Souad A. M. Al-Bat’hi",authors:[{id:"174793",title:"Dr.",name:"Mohamad",middleName:null,surname:"Souad",slug:"mohamad-souad",fullName:"Mohamad Souad"}]},{id:"71346",title:"Application of Nanomaterials in Environmental Improvement",slug:"application-of-nanomaterials-in-environmental-improvement",totalDownloads:1691,totalCrossrefCites:0,totalDimensionsCites:13,abstract:"In recent years, researchers used many scientific studies to improve modern technologies in the field of reducing the phenomenon of pollution resulting from them. In this chapter, methods to prepare nanomaterials are described, and the main properties such as mechanical, electrical, and optical properties and their relations are determined. The investigation of nanomaterials needed high technologies that depend on a range of nanomaterials from 1 to 100 nm; these are scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffractions (XRD). The applications of nanomaterials in environmental improvement are different from one another depending on the type of devices used, for example, solar cells for producing clean energy, nanotechnologies in coatings for building exterior surfaces, and sonochemical decolorization of dyes by the effect of nanocomposite.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Ali Salman Ali",authors:[{id:"313275",title:"Associate Prof.",name:"Ali",middleName:null,surname:"Salman",slug:"ali-salman",fullName:"Ali Salman"}]}],onlineFirstChaptersFilter:{topicId:"208",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81438",title:"Research Progress of Ionic Thermoelectric Materials for Energy Harvesting",slug:"research-progress-of-ionic-thermoelectric-materials-for-energy-harvesting",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.101771",abstract:"Thermoelectric material is a kind of functional material that can mutually convert heat energy and electric energy. It can convert low-grade heat energy (less than 130°C) into electric energy. Compared with traditional electronic thermoelectric materials, ionic thermoelectric materials have higher performance. The Seebeck coefficient can generate 2–3 orders of magnitude higher ionic thermoelectric potential than electronic thermoelectric materials, so it has good application prospects in small thermoelectric generators and solar power generation. According to the thermoelectric conversion mechanism, ionic thermoelectric materials can be divided into ionic thermoelectric materials based on the Soret effect and thermocouple effect. They are widely used in pyrogen batteries and ionic thermoelectric capacitors. The latest two types of ionic thermoelectric materials are in this article. The research progress is explained, and the problems and challenges of ionic thermoelectric materials and the future development direction are also put forward.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jianwei Zhang, Ying Xiao, Bowei Lei, Gengyuan Liang and Wenshu Zhao"},{id:"77670",title:"Thermoelectric Elements with Negative Temperature Factor of Resistance",slug:"thermoelectric-elements-with-negative-temperature-factor-of-resistance",totalDownloads:72,totalDimensionsCites:0,doi:"10.5772/intechopen.98860",abstract:"The method of manufacturing of ceramic materials on the basis of ferrites of nickel and cobalt by synthesis and sintering in controllable regenerative atmosphere is presented. As the generator of regenerative atmosphere the method of conversion of carbonic gas is offered. Calculation of regenerative atmosphere for simultaneous sintering of ceramic ferrites of nickel and cobalt is carried out. It is offered, methods of the dilated nonequilibrium thermodynamics to view process of distribution of a charge and heat along a thermoelement branch. The model of a thermoelement taking into account various relaxation times of a charge and warmth is constructed.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Yuri Bokhan"},{id:"79236",title:"Processing Techniques with Heating Conditions for Multiferroic Systems of BiFeO3, BaTiO3, PbTiO3, CaTiO3 Thin Films",slug:"processing-techniques-with-heating-conditions-for-multiferroic-systems-of-bifeo3-batio3-pbtio3-catio",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101122",abstract:"In this chapter, we have report a list of synthesis methods (including both synthesis steps & heating conditions) used for thin film fabrication of perovskite ABO3 (BiFeO3, BaTiO3, PbTiO3 and CaTiO3) based multiferroics (in both single-phase and composite materials). The processing of high quality multiferroic thin film have some features like epitaxial strain, physical phenomenon at atomic-level, interfacial coupling parameters to enhance device performance. Since these multiferroic thin films have ME properties such as electrical (dielectric, magnetoelectric coefficient & MC) and magnetic (ferromagnetic, magnetic susceptibility etc.) are heat sensitive, i.e. ME response at low as well as higher temperature might to enhance the device performance respect with long range ordering. The magnetoelectric coupling between ferromagnetism and ferroelectricity in multiferroic becomes suitable in the application of spintronics, memory and logic devices, and microelectronic memory or piezoelectric devices. In comparison with bulk multiferroic, the fabrication of multiferroic thin film with different structural geometries on substrate has reducible clamping effect. A brief procedure for multiferroic thin film fabrication in terms of their thermal conditions (temperature for film processing and annealing for crystallization) are described. Each synthesis methods have its own characteristic phenomenon in terms of film thickness, defects formation, crack free film, density, chip size, easier steps and availability etc. been described. A brief study towards phase structure and ME coupling for each multiferroic system of BiFeO3, BaTiO3, PbTiO3 and CaTiO3 is shown.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Kuldeep Chand Verma and Manpreet Singh"},{id:"78034",title:"Quantum Physical Interpretation of Thermoelectric Properties of Ruthenate Pyrochlores",slug:"quantum-physical-interpretation-of-thermoelectric-properties-of-ruthenate-pyrochlores",totalDownloads:78,totalDimensionsCites:0,doi:"10.5772/intechopen.99260",abstract:"Lead- and lead-yttrium ruthenate pyrochlores were synthesized and investigated for Seebeck coefficients, electrical- and thermal conductivity. Compounds A2B2O6.5+z with 0 ≤ z < 0.5 were defect pyrochlores and p-type conductors. The thermoelectric data were analyzed using quantum physical models to identify scattering mechanisms underlying electrical (σ) and thermal conductivity (κ) and to understand the temperature dependence of the Seebeck effect (S). In the metal-like lead ruthenates with different Pb:Ru ratios, σ (T) and the electronic thermal conductivity κe (T) were governed by ‘electron impurity scattering’, the lattice thermal conductivity κL (T) by the 3-phonon resistive process (Umklapp scattering). In the lead-yttrium ruthenate solid solutions (Pb(2-x)YxRu2O(6.5±z)), a metal–insulator transition occurred at 0.2 moles of yttrium. On the metallic side (<0.2 moles Y) ‘electron impurity scattering’ prevailed. On the semiconductor/insulator side between x = 0.2 and x = 1.0 several mechanisms were equally likely. At x > 1.5 the Mott Variable Range Hopping mechanism was active. S (T) was discussed for Pb-Y-Ru pyrochlores in terms of the effect of minority carrier excitation at lower- and a broadening of the Fermi distribution at higher temperatures. The figures of merit of all of these pyrochlores were still small (≤7.3 × 10−3).",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Sepideh Akhbarifar"},{id:"77635",title:"Optimization of Thermoelectric Properties Based on Rashba Spin Splitting",slug:"optimization-of-thermoelectric-properties-based-on-rashba-spin-splitting",totalDownloads:124,totalDimensionsCites:0,doi:"10.5772/intechopen.98788",abstract:"In recent years, the application of thermoelectricity has become more and more widespread. Thermoelectric materials provide a simple and environmentally friendly solution for the direct conversion of heat to electricity. The development of higher performance thermoelectric materials and their performance optimization have become more important. Generally, to improve the ZT value, electrical conductivity, Seebeck coefficient and thermal conductivity must be globally optimized as a whole object. However, due to the strong coupling among ZT parameters in many cases, it is very challenging to break the bottleneck of ZT optimization currently. Beyond the traditional optimization methods (such as inducing defects, varying temperature), the Rashba effect is expected to effectively increase the S2σ and decrease the κ, thus enhancing thermoelectric performance, which provides a new strategy to develop new-generation thermoelectric materials. Although the Rashba effect has great potential in enhancing thermoelectric performance, the underlying mechanism of Rashba-type thermoelectric materials needs further research. In addition, how to introduce Rashba spin splitting into current thermoelectric materials is also of great significance to the optimization of thermoelectricity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Zhenzhen Qin"},{id:"75364",title:"Challenges in Improving Performance of Oxide Thermoelectrics Using Defect Engineering",slug:"challenges-in-improving-performance-of-oxide-thermoelectrics-using-defect-engineering",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96278",abstract:"Oxide thermoelectric materials are considered promising for high-temperature thermoelectric applications in terms of low cost, temperature stability, reversible reaction, and so on. Oxide materials have been intensively studied to suppress the defects and electronic charge carriers for many electronic device applications, but the studies with a high concentration of defects are limited. It desires to improve thermoelectric performance by enhancing its charge transport and lowering its lattice thermal conductivity. For this purpose, here, we modified the stoichiometry of cation and anion vacancies in two different systems to regulate the carrier concentration and explored their thermoelectric properties. Both cation and anion vacancies act as a donor of charge carriers and act as phonon scattering centers, decoupling the electrical conductivity and thermal conductivity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jamil Ur Rahman, Gul Rahman and Soonil Lee"}],onlineFirstChaptersTotal:6},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:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,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:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,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:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"May 19th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. 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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"17",type:"subseries",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. 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