Heavy metals impacted vegetables from different areas.
\r\n\tThe main goal of this book is (1) prevention and treatment of life-related diseases and metabolic syndrome, (2) mechanism of lifestyle-related diseases and metabolic syndrome, (3) effective functional compounds, foods, and diet to lifestyle-related diseases and metabolic syndrome, (4) relationship between metabolic syndrome and various diseases such as cancer, allergy, and aging. This book hopes to bring an overview of the recent advances of metabolic syndrome, and thus we welcome both review chapters and original chapters.
",isbn:"978-1-80356-780-8",printIsbn:"978-1-80356-779-2",pdfIsbn:"978-1-80356-781-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"c556d78df6bb93e8e3973ce0a9547ea8",bookSignature:"Dr. Naofumi Shiomi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11710.jpg",keywords:"Insulin Resistance, Adipokines, Obesity, Type2-diabetes, High Blood Pressure, Hyperlipidaemia, Polyphenols, DHA, Cancer, Allergy, Aging, Alzheimer's Disease",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 2022",dateEndSecondStepPublish:"April 29th 2022",dateEndThirdStepPublish:"June 28th 2022",dateEndFourthStepPublish:"September 16th 2022",dateEndFifthStepPublish:"November 15th 2022",remainingDaysToSecondStep:"24 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Shiomi is a researcher in biomedical science and biotechnology and has 27 years of educational experience with college students. He has published more than 40 papers, 10 book chapters and edited 9 books on recombinant microorganisms, bioremediation, and functional foods. His recent research focuses also on the prevention of obesity and aging.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"163777",title:"Dr.",name:"Naofumi",middleName:null,surname:"Shiomi",slug:"naofumi-shiomi",fullName:"Naofumi Shiomi",profilePictureURL:"https://mts.intechopen.com/storage/users/163777/images/system/163777.jpeg",biography:"Dr. Naofumi Shiomi studied recombinant yeast and its utilization as a researcher at the Laboratory of Production Technology of Kanena Corporation for 15 years until 1998 and earned his Ph.D. in Engineering from Kyoto University, Japan. He now works as a professor at the School of Human Sciences of Kobe College in Japan, where he teaches applied microbiology, biotechnology, and life science in his Applied Life Science laboratory. He has studied bioremediation for 24 years at Kobe College and has published more than 40 papers and several book chapters on recombinant microorganisms, bioremediation, and functional foods. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Individually, many of these conditions are rare but taken together they represent a significant mortality and morbidity affecting approximately 9% of the population worldwide with the prevalence rising [1, 2]. Given that the majority of conditions have no cure and potentially require lifelong treatment, and that most patients are diagnosed during young adulthood or in middle age, the cost to healthcare systems is particularly significant.
\nDespite the variation of organs affected and clinical presentation, many of the conditions that appear distinct will share a common theme of disease pathogenesis. Underscoring many of the conditions is a genetic susceptibility that taken in concert with an environmental trigger sets off an immune cascade resulting in the end organ damage and clinical signs and symptoms that bring the patient to the attention of their healthcare provider, the so-called multi-hit hypothesis. As science progresses and we gain greater insight into these disease processes, it is becoming more apparent that there are similarities in many of the conditions. At present, most management strategies attempt to globally restrict the immune system, a strategy that has been shown to help control the disease but comes with a significant side effect profile. Despite the accelerating knowledge we are gaining of the underlying pathogenesis, there remains a lack of directed novel therapies for patients at present, although in many conditions there are signs that this is changing.
\nMembranous nephropathy represents a particularly interesting basis to understand this process given its clear pathological classification, strong genetic contribution, putative pathogenic antibody and evidence for the loss of tolerance that is now emerging. In this chapter, we review the current understanding of autoimmune membranous nephropathy and use it as a basis for the understanding of autoimmune disease in general.
\nMembranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults worldwide but despite this remains a rare disease. Incidence is estimated at 1.2 per 100,000 in European cohorts with a peak incidence in the fifth and sixth decades, although it can affect any age, and has a slight male preponderance [3]. The classical presentation of the disease is with nephrotic syndrome, that is, the tetrad of leg swelling, proteinuria and serum hypoalbuminemia, with or without hypercholesterolemia. A number of patients have also been known to present with venous thrombosis. This can be in the form of deep vein thrombosis (DVT) and, not uncommonly as the first presentation of the disease, with acute kidney injury (AKI) as a result of renal vein thrombosis. Hypercoagulopathy as a result of the loss of anti-thrombotic factors such as anti-thrombin III and plasminogen due to proteinuria, an increased level of factor VIII and fibrinogen, along with an increased platelet hyperaggregability has been noted in nephrotic syndrome whatever the cause. However, compared to other conditions that have a similar degree of proteinuria, MN has a relatively higher risk of venous thrombosis and its associated risks; the mechanism for this association has not been ascertained [4, 5, 6].
\nClinically there are two distinct forms of MN, but these can be histologically very similar and difficult to differentiate. Both require very different treatment strategies and therefore distinguishing them is imperative. Primary MN accounts for the majority of patients (approximately 75–80%) and has now been shown to be an autoimmune disease. Secondary MN is caused by a multitude of causes including medications, systemic disorders and toxins, and its treatment is therefore aimed at the underlying trigger or condition [7].
\nIt is one of the idiosyncrasies of MN that up to a third of patients if left untreated will achieve spontaneous remission within the first 2 years following diagnosis, and this potential for spontaneous remission has informed the current treatment options, especially for those patients without rapidly progressive renal decline [8]. The mainstay of treatment at present has a focus on the reduction of proteinuria with the use of an renin-angiotensin pathway blockade or immunosuppression if this fails [7]. It has also meant that for many studies, patients undergo three to 6 months of supportive care before they are eligible, in case any response to treatment seen is actually as a result of spontaneous remission. However, with the increasing use, understanding and monitoring of biomarkers such as anti-PLA2R, treatments are likely to be less empiric in the future.
\nIf patients do reach ESRD and receive a renal transplant, it has been well demonstrated that this can provide a dramatic improvement to not only life expectancy but also quality of life [9, 10, 11]. However, this comes with the risk of recurrence of MN following transplantation (up to 34% of patients) despite the judicial use of immunosuppression and can lead to the loss of the graft in up to 50% of these cases. There is some evidence to suggest that receiving a transplant from a living related donor increases the risk of recurrence, but this is far outweighed by the complications associated with remaining on dialysis [12]. Current practice therefore, is to attempt to match HLA antigens as closely as possible to reduce the reliance on immunosuppression to minimise rejection.
\nFor many patients, MN remains a relapsing and remitting disease, requiring lifelong follow up under the care of specialists in tertiary care. Despite being a rare condition, its chronicity, current standard treatments and their associated side-effects, the risk of ESRD, and disease recurrence means it is a disease that has a significant impact on both a patient’s quality of life and a healthcare system with finite resources.
\nRecent advances in biomarker research for MN have shown promising results but at present diagnosis requires biopsy confirmation. Histologically the disease is characterised by thickening of the glomerular basement membrane and spikes seen on silver stain. Immunofluorescence almost universally shows coarse granular immunoglobulin IgG and complement C3 deposition on the capillary wall. Electron microscopy (EM) will show sub-epithelial immune complex deposition (Figure 1). It has become apparent over the years that the dominant IgG subclass found histologically (and for antibodies to PLA2R as described below) in primary MN is IgG4 [13, 14, 15]. This appears to differ from secondary MN where IgG1 predominates [16]. IgG makes up a significant proportion of serum protein in humans contributing approximately 10–20% of circulating proteins. It can be further subdivided into four subclasses with differing effects. IgG4 is the least abundant of these subclasses and is generally found in response to allergens or in response to repeated exposure to an antigen [17].
\nHistological appearance of membranous nephropathy (a) haematoxylin and eosin stain (H&E) showing marked capillary loop thickening (b) silver staining showing spikes (c) electron microscopy of MN showing sub-epithelial immune complex deposition (d) immunofluorescence showing IgG deposition on the capillary wall. Figures courtesy of Dr. Lorna Williams, Consultant Histopathologist, Manchester University Hospitals Foundation Trust, UK.
New research findings suggest that there may be a class switch involved in primary membranous nephropathy. Here it has been shown that in early MN (stage I of the Ehrenreich and Churg scale) the predominant subclass of antibody is IgG1 but as the disease progresses this changes so that IgG4 predominates [16].
\nIn primary MN, disease activity is still measured by proteinuria level and renal excretory function despite the advances in anti-PLA2R research. Proteinuria level has been shown to be not only a marker for remission when it is low but also predicts progression to ESRD when increased. If proteinuria reduces through either spontaneous remission or with treatment, then the risk of CKD progression also falls. It is for this reason that the main focus of treatment in primary MN is concerned with control of proteinuria, with or without the use of immunosuppression, generally in the form of the Ponticelli regime (or calcineurin inhibitors if cyclophosphamide is not tolerated or is contraindicated). This regime of rotating high dose intravenous steroids and immunosuppression was first described in the mid-1980s and has been the recommended regime since [7, 18, 19, 20]. Despite its success in treating the condition, the Ponticelli regime comes with a significant side effect burden, including an increased risk of infection, osteoporosis, diabetes mellitus, weight gain, haemorrhagic cystitis, infertility and malignancy [18]. It is this that has led many researchers to search for an alternative therapy including mycophenolate mofetil and tacrolimus but with variable evidence to show an improvement in outcomes.
\nRituximab is a monoclonal antibody against CD20, found on the B-cells, which leads to a reduction in B-cell numbers and has been used extensively in cancer therapy and autoimmune diseases since its introduction in the 1990s. A number of case series and studies have shown the potential that Rituximab can have for primary MN, but so far there has only been one randomised controlled trial (RCT) [21, 22, 23, 24]. Here it has been shown that compared to standard anti-proteinuric therapy, patients treated with rituximab show a greater reduction in anti-PLA2R levels at month 3, followed by a later reduction in proteinuria, increase in serum albumin and are more likely to enter remission [24]. Combined with the high cost of the medication itself, its widespread use has been restricted in resource-limited, evidence-based healthcare systems, such as the NHS in UK [25]. The use of Rituximab therapy is currently under investigation in the MENTOR study in North America and via the Commissioning through Evaluation pathway run under the auspices of the National Institute for Health and Care Excellence (NICE) in the UK. It is possible that based on these two studies the use of Rituximab will become more ubiquitous in the near future.
\nThe use of many of these medications comes with side effects that can be unpalatable to the patient and physician and the search for treatments with a reduced side-effect profile is on-going. Treatments such as immunoadsorption (IA) allow for the controlled removal of antibodies without the side effects associated with immunosuppression. Immunoadsorption RCTs in MN though, are non-existent and certainly not in the anti-PLA2R era. Immunoadsorption is a method of removing specific circulating immunoglobulins from the blood and has been shown to remove over 80% of circulating IgG with a single session adsorption of 2.5 plasma volumes, with albumin and antithrombin III almost unaffected [26]. With multiple sessions, this can rise to over 98% [27]. These are removed in the absorber through binding Peptide-GAM. Using two columns per machine, one regenerating whilst the other is removing antibodies; the process can occur indefinitely until the required level of antibody has been removed.
\nPost IA it appears that autoantibodies can be slow to re-emerge. Use in dilated cardiomyopathy for the removal of β1-adreno-receptor autoantibodies (β1-AAB) has shown that only a small minority of patients (0% in the first year and 15% by 3 years) will show an increase in significant β1-AAB autoantibodies [28, 29].
\nTo our knowledge, there has only been one publication using immunoadsorption for the treatment of MN [30]. In 1999, Esnault et al. successfully used IA for the treatment of various aetiologies of Nephrotic syndrome including four patients with MN [31]. Here they showed that not only is the procedure safe but that there was a significant improvement in proteinuria in all patients with membranous nephropathy. The main side effect in this group of patients was headache, which resolved without sequelae. Since that time the treatment has been used in numerous other autoimmune conditions including Focal Segmental Glomerulosclerosis (FSGS) [32], systemic lupus nephritis (SLE) [33, 34], ANCA-associated small vessel vasculitides [35, 36], Anti-glomerular basement membrane antibody disease [37] and in renal transplantation [38, 39, 40].
\nIn conditions such as SLE, the use of immunoadsorption can dramatically reduce the level of circulating immune complexes and autoantibodies leading to clinical improvement in even severe life-threatening SLE. These results have been shown with as little as two sessions within 3 days and repeated every 3 weeks if patients remain with active disease [33]. With the current understanding of primary MN’s autoimmune process, the use of IA could provide the ability to rapidly remove the pathogenic antibodies leading to remission. Current IA machines can remove the different classes such as IgG4 with an increased specificity but cannot differentiate further than that. If IA is proved to work for primary MN, it may be possible to develop an IA column that is specific only for anti-PLA2R, therefore allowing for an even more targeted and personalised treatment.
\nUntil recently autoimmune (or primary) MN was known as idiopathic MN as its cause remained unclear. It was generally a diagnosis of exclusion, once a patient had biopsy confirmation of MN and all causes of secondary MN had been ruled out. It was for a long time postulated to be an autoimmune disease, but the target antigen in humans remained elusive. In the late 1970s, work on the Heymann Nephritis rat model of experimental MN showed that circulating IgG antibodies could bind to the podocytes [41, 42, 43]. The target antigen was found to be megalin, but this was not present on human podocytes, so the search for the target antigen continued. It was not until 2009, almost 40 years later that this was discovered. Here Beck et al. used western blotting with MN patient sera, to show that antibodies bound to a 185 kDa protein band from glomerular extracts. This band was only seen in the primary MN group and not seen in normal patients or other proteinuric conditions including patients with secondary MN. Using mass spectrometry this band was found to contain the M-type phospholipase A2 receptor 1 (PLA2R) [15]. Since then, the increased interest and research into MN has led to the discovery of a second minor target antigen in thrombospondin type-1 domain containing 7A (THSD7A) [44].
\nThe landmark paper by Beck et al. describing the discovery of autoantibodies to PLA2R found on human podocytes transformed our understanding of the MN disease process. Here was evidence that for the majority of patients with MN, the condition was, as had been postulated, an autoimmune disease [15].
\nPLA2R is a transmembrane receptor for Phospholipase A2, a protein from the mannose receptor family, one of four described in humans; Endo180, DEC205, Mannose Receptor (MR) and PLA2R [45, 46, 47]. As with all the mannose receptor family, the transmembrane glycoprotein has an extracellular component, in the case of PLA2R, this is made up of an N-terminal ricin rich domain, a fibronectin type II domain and 8 C-type lectin domains (CTLDs) [48]. In the kidney, it is found almost exclusively on the podocytes, but it has also been found on neutrophils and in the lung [49, 50]. Its function in the kidney remains unknown, however, and how the anti-PLA2R antibodies alter its normal function leading to proteinuria, if indeed that is what is part of the process, also remains unknown [15, 51].
\nThe predominant antibody to PLA2R is IgG and in particular IgG4, which is the major component of immune complex deposition in primary MN [13, 14]. These immune complexes appear to form in the kidney with the IgG4 antibodies and the PLA2R antigen being co-localised, giving further evidence for the role of PLA2R in the disease process [52, 53]. The fact that the complexes form in situ in the kidney may explain why some patients with biopsy-proven MN and clinical evidence for the disease are serum anti-PLA2R negative. Debiec and Ronco showed in 2011 that there were a number of patients who were serum anti-PLA2R negative but had detectable PLA2R in glomerular deposits. They did also find a few patients with no PLA2R in the glomerular deposits but who were serologically positive [54]. We know that anti-PLA2R antibodies have a high affinity for PLA2R in the podocytes and it may be that a certain level of deposition is required to overload the system before the anti-PLA2R antibodies become serologically detectable [48].
\nMuch of the excitement surrounding anti-PLA2R is due to its apparent pathogenicity with the resultant potential for use as a biomarker and as a treatment target. Several studies have provided evidence for its pathogenicity showing that a high titre correlates with disease activity. For patients who go into remission either spontaneously or through the use of immunosuppression, the anti-PLA2R level falls months before this becomes clinically apparent with a fall in proteinuria. If a patient relapses, this again is predated by a rise in antibody titres [55, 56, 57, 58, 59, 60].
\nOutcomes can also be predicted with high titres predicting a worse outcome in regards to renal function and an improved outcome with low titres [55]. If treatment does not result in antibody negativity, then they are left with a high risk of relapse [51, 57]. Ruggenenti et al. have shown similar results with a reduction in anti-PLA2R levels strongly predicting remission and increasing titres following this, predicting relapse [59].
\nWith the increasingly strong evidence for the involvement of anti-PLA2R antibodies in the pathogenesis of primary MN, the focus has now shifted to trying to understand the antigen and its interaction with the autoantibody. Work carried out in Manchester has now determined the major epitope on the PLA2R antigen that is recognised by the anti-PLA2R antibodies. Four different sized fragments of extracellular PLA2R (full-length N-C8, N-terminus to C-type lectin domain (CTLD) 3 (N-C3), N-terminus to CTLD2 (N-C2) and a ricin rich domain) were used to investigate the reactivity of human anti-PLA2R autoantibodies. It was found that the major epitope was located in the N-C3 region of the receptor. The antibodies were also found to bind with an equal affinity to the four different fragments, confirming the existence of a single epitope. The epitope itself is a 31-mer peptide made up of the beta-1 and beta-3 strands and encompassing the beta-2 strand [48].
\nLeading on from this the Manchester team also constructed a 3D model of the structure of the immune complex incorporating the extracellular N-C8 PLA2R and the autoantibody with the binding site [48]. This work has been further confirmed by Kao et al. who found that the dominant epitope is in the N-terminal region as well, in particular in the region from the ricin rich domain through the fibronectin-like type to the CTLD1 [61].
\nThe fact that anti-PLA2R antibodies are found in up to 80% of patients with primary MN raises a number of possibilities. It is known that some patients with secondary membranous can develop malignancies years after the diagnosis of MN and it may be that these patients fall into this category. Whether these patients represent a cohort who have two separate conditions and it is coincidental that one is known to cause the other is still up for debate. A second possibility is that there are more pathogenic antigens leading to the formation of autoantibodies than previously thought. In fact, for a small number of patients with primary MN, this seems to be the case.
\nUsing western blotting, Thomas et al. discovered a glomerular protein of 250 kDa in patients with anti-PLA2R negative biopsy-proven membranous nephropathy. This corresponded to THSD7A, a protein found in the podocyte foot processes [44].
\nThey went on to show that the predominant antibody to this antigen was IgG4 in keeping with a diagnosis of primary MN, and on histological staining, in a similar fashion to anti-PLA2R, the immune complexes were co-localised with the antigen. Levels of the antibody were shown to correlate with disease activity, being higher in active disease and lower as the clinical manifestations of the disease improved. Interestingly, there appeared to be no statistical significance in the clinical presentation or demographics between the anti-PLA2R positive and the anti-THSD7A positive patients, except for a slightly higher number of women in the anti-THSD7A group, although this is believed to be due to the small numbers involved.
\nThis evidence suggests that for a minority of primary MN patients, approximately 2.5–5% in this study, a second unrelated and discrete antigen is involved with the pathogenesis of the disease [44]. Whether this all represents a separate disease and whether there are other minor antigens still to be discovered remains unknown as does the major epitope in THSD7A. However, for PLA2R, in addition to the major epitope in the CysR domain, evidence from the work of Fresquet et al. on the identification of the major epitope of PLA2R, showed that 10% of anti-PLA2R positive sera reacted with an epitope at CTLD4-8. This suggests that there may be a further, as yet unidentified, antibody to this minor epitope [48]. This idea of epitope spreading has been suggested by Lambeau et al. who have defined additional epitopes in CTLD1 and CTLD7 domains [62].
\nWhy some patients develop an autoantibody to PLA2R is still an unknown, but it does appear to have a strong genetic component. The first clue to the genetic basis of the disease was the discovery of the association with Human Leucocyte Antigen (HLA)—DR3 followed closely by the identification of familial clustering in 1984 [30, 63, 64]. Following the discovery of the PLA2R antigen, researchers studying Korean and Chinese populations investigated the association of a number of single nucleotide polymorphisms (SNPs) known to be associated with PLA2R. They both found that a polymorphism at rs35771982 was significantly associated with primary MN. Interestingly, this polymorphism is located on CTLD1, in the region that was later found to contain an epitope in the antigen [48, 65, 66].
\nThe major Genome-Wide Association Study (GWAS) in MN of 556 patients (French, Dutch and British) revealed two major loci of allelic association. The first is not unexpectedly on chromosome 6p21 within HLA-DQA1 gene, and the second is on chromosome 2q24 containing PLA2R1. For patients who were homozygous for these alleles, their odds ratio for having primary membranous nephropathy was 78.5 [67]. This work has recently been validated in a study using genotype and HLA imputation alongside a GWAS in 323 patients with primary MN. Here the association of HLA-DQA1 and PLA2R1 with primary MN was confirmed, without detecting any other novel signals [68].
\nHow these genetic markers modulate the risk of developing MN is unknown. The idea that the genetically restricted class II presentation of PLA2R peptides to affect the class switch to high-affinity IgG anti-PLA2R is a theory that remains to be tested.
\nIndicative of the rapid pace of research into primary MN since the discovery of the PLA2R antigen, we now have not only the clinical correlation of the antibody with disease activity but also the major epitope on the antigen and evidence for the genetic polymorphism located in the antigen itself. This, however, does not completely explain the development of the disease. The polymorphisms described in these studies are actually variants that are common to the general population. It seems likely that, similar to other autoimmune diseases such as IgA nephropathy, primary MN is a multi-hit disease. A patient with the polymorphism has a genetic predisposition but to develop the disease needs an external trigger.
\nFresquet et al. have shown that an amino acid sequence which is part of the dominant epitope in the CysR region of the PLA2R antigen is also found in the cell wall of some species of clostridia [48]. Further searches using the Basic Local Alignment Search Tool (BLAST) [69] has shown this peptide sequence is found in a number of other common pathogens such as Pseudomonas and
There is now also emerging evidence implicating air pollution in the development of autoimmune MN. A recent large study in China investigating the emerging trends of glomerulopathy based on renal biopsies in relation to air pollution noted a rise in the incidence of MN in all age ranges and in all regions, this is in contrast to other glomerular disease investigated which all remained the same. It was more prevalent in areas with the highest air pollution and the long-term average was found to be associated with a significantly increased risk of autoimmune MN.
\nWhat is not known at present is the risk of developing autoimmune MN if you have the genetic predisposition, only that you are more likely to have the risk alleles if you have autoimmune MN. What remains elusive is how a patient’s immune system converts from an advantageous defence against common pathogens to a pathogenic entity in itself. A characteristic of autoimmune MN is the heterogeneity shown in prognosis and its waxing and waning nature over time. A proportion of patients will undergo a phenomenon of spontaneous remission, and in patients with a more severe phenotype, it is not unusual for them to follow a relapsing and remitting course. Many patients, when they first come to medical attention, will describe self-limiting episodes many months or years prior to their diagnosis that is likely to be nephrotic states and the first signs of the disease. This suggests that far from being a continuously progressive immunological process, particularly in light of the pathogenicity of the autoantibody, that there may be natural mechanisms at play attempting to maintain a balance. Work in other autoimmune diseases such as autoimmune thyroiditis has proven the existence of antigens capable of maintaining a population of natural T Regs and thereby keeping pathogenic antibodies suppressed [70].
\nAs the technology evolves, flow cytometry is becoming an ever more powerful tool for the study of the immune system. A recent study using patients enrolled in the GEMRITUX trial showed that patients had lower proportions of IgD− and IgD+ memory B cells, T Regs and a higher proportion of naïve B cells at baseline compared to healthy donors [71]. In this study by Rosenzwajg et al., patients who responded to treatment were observed to have a lower proportion of T Regs at baseline compared to those who did not respond to treatment. They also noted that in patients with no response to treatment, there was no increase in T Regs following treatment, however in patients who went on to respond, there was a significantly higher proportion of T Regs at day 8 compared to baseline [71].
\nThis is similar to work currently being undertaken in our lab (unpublished) in which flow cytometry was used to model the immune system following treatment with immunoadsorption [72]. In our cohort, we also found that there was a lower proportion of IgD+ memory B cells in the patient group but a similar level of IgD− memory B cells albeit with a much larger range. For the Naïve B cells and T Regs, the medians were very similar between the patients and control group but with a much larger range in the patient cohort. One of the striking differences between our patient group and the control group at baseline is that there does not seem to be any statistical difference in PLA2R positive B cells, with a number of volunteers in the control group showing a relatively high proportion of these cells. This seemingly counterintuitive result, in fact, appears to add weight to the importance of loss of tolerance in the disease process.
\nGiven the shared sequence of amino acids (SVLTLENC), it could be expected during the development of normal natural immunity to a range of pathogens, developing IgM antibodies to this linear peptide sequence is common, entirely normal and beneficial to the host. The risk of developing an autoimmune pathology only arises then, if a patient has the genetic makeup (pathological alleles of DQA1 and PLA2R) required to present PLA2R T cell peptides to their immune system. Only with the permissive genetic background and continued exposure to the pathogen or environmental trigger, causing immune processing of PLA2R, will class switching occur from IgM to IgG, and therefore allowing the development of pathogenic high-affinity antibodies. In our PLA2R panel, the healthy control group showed a significant level of PLA2R positive B cells. A current on-going and unpublished project being carried out in our lab is the development of an IgM anti-PLA2R ELISA. Although it cannot be proven in the current flow cytometry experiment, it would appear to suggest that there is a high likelihood that the B cells seen in the healthy population may, in fact, be IgM positive B cells as opposed to being IgG positive.
\nA further interesting dimension to immune regulation and loss of tolerance that needs further study is the role that T reg cells play and how they are a potential mechanism for the suppression of pathogenic antibodies. The relapsing and remitting nature of autoimmune membranous nephropathy and the phenomenon of spontaneous remission indicates that at some level there must be an immune mechanism capable of suppressing the anti-PLA2R antibodies, much like that found in autoimmune thyroiditis. Another on-going study, again unpublished, in our lab has identified a number of healthy controls without the prerequisite HLA-DQA1 or PLA2R1 genes needed to develop autoimmune MN, who have a detectable level of circulating soluble PLA2R using mouse anti-PLA2R as the capture antibody. There is the potential that these circulating soluble-PLA2R antigens are active in maintaining a functioning level of T Regs to suppress class switching and downregulate the pathogenic antibody level. If natural T Regs did indeed have a role in keeping the pathogenic IgG anti-PLA2R antibodies suppressed, the expectation would be that in times of active disease the levels would be low. The opposite would also be true with high levels in times of remission or just before remission or response to treatment. The T cell panel used for the patient cohort does start to show a pattern of T Regs change over time, a pattern that appears to support the theory above, especially when taken in the context of antibody level. At week 4 follow up, the T Regs level has dropped to their lowest point, this is also at the same time point at which the anti-PLA2R is at its highest. The proportion of T Regs then show an increase at both week 10 and week 16 follow up, just as the antibody level is decreasing.
\nAutoimmune MN has experienced a step change in our understanding of the disease pathogenesis since the discovery of the anti-PLA2R autoantibody in 2009 [15], however, there is much that still remains unknown. Despite the advances seen over the last decade, the management of the disease remains an empirical treatment based on a regimen first introduced over two decades ago. There is as yet no disease-specific therapy or alternative to glucocorticoids and immunosuppression in mainstream use.
\nAs with all autoimmune diseases, the eventual clinically apparent symptoms are the end result in a journey of multiple steps, the so-called multi-hit hypothesis. We know that there is a strong genetic component in the development of the disease, with patients homozygous for both the HLA-DQA1 and PLA2R1 genes are almost 80 times more likely to develop the disease than patients who do not [67]. What we still do not know is whether the possession of these genes in itself guarantees the development of the disease. It is likely that a further trigger (likely environmental) is required to progress to the disease state.
\nDevelopment of the normal natural immunity requires the production of antibodies, including IgM, to linear peptides in a whole range of epitopes. With this beneficial protective immunity, circulating IgM antibodies to the PLA2R p28mer peptide can, in fact, be a normal occurrence. The presence of these antibodies in patients without the genetic predisposition to the disease would just be an expected variant of normal. It is in those patients who do have the genetic predisposition to developing the disease, that the presence of IgM antibodies with the ability to recognise the p28mer will have the potential to progress to the disease state to generate a high-affinity IgG response. Once this occurs, and there is recognition of the podocyte PLA2R epitope there begins a positive reinforcement with ever-increasing affinity. The exact nature of how patients eventually develop a pathogenic IgG antibody remains elusive. However, there is now tentative emerging evidence showing that in a control group of healthy volunteers and a patient group with active disease there is a PLA2R antigen positive B cell population in both. This is coupled with an on-going unpublished study showing a level of circulating anti-PLA2R IgM antibodies in these normal healthy patients. This requires further work, but it is the first evidence for an antibody class switch in autoimmune MN.
\nThere is also data showing that as the anti-PLA2R antibody rises in the weeks following treatment, there is a reduction in the natural T Regs. Following this, as the level of T Regs starts to rise there is a corresponding fall in the antibody level. Taken in tandem with unpublished work that is on-going showing a measurable level of circulating soluble PLA2R in healthy controls, this would appear to show that a similar process to autoimmune thyroiditis is taking place in autoimmune MN.
\nThere do remain a number of important questions in relation to the disease pathogenesis though; how does the anti-PLA2R attaching to the epitope causes the damage we see? Despite strong circumstantial evidence suggesting its pathogenicity, direct evidence is currently lacking. Can the antibody titre supplant the need for a renal biopsy? How many patients who have the genetic predisposition eventually go on to develop the disease and is there a way to predict which patient does? And are there more autoantibodies associated with the development of autoimmune membranous nephropathy.
\nCurrent understanding of the role anti-PLA2R plays in the pathogenesis has now led many to envisage a greater role for its use in clinical practice. Not only is it increasingly being used for disease monitoring and for prognosticating treatment response but it is also becoming a necessary tool for diagnosis. This has the distinct prospect of drastically altering the current diagnostic pathway and ultimately a patients quality of life. A number of groups are now actively investigating the feasibility of serum anti-PLA2R negating the need for a renal biopsy, not only reducing time to diagnosis but also avoiding the need for an invasive procedure.
\nThe hope is that by understanding the pathway of disease in this and other autoimmune conditions, new safer and more efficacious treatment options will be available for patients in the future. This is particularly pertinent given the increasing incidence of autoimmune diseases worldwide and the increased burden on patients and healthcare systems.
\nHeavy metals, which are a major environmental problem, have a natural residency in the continental mantle. In general, a heavy metal is nothing but any chemical element which is metallic with a comparatively higher density that is poisonous above a tolerable range, such as mercury (Hg), cadmium (Cd), chromium (Cr), nickel (Ni), lead (Pb), and so on [1, 2, 3]. Contaminated heavy metal is a key cause of pollution and a possible increasing environmental and human health hazard all over the world, resulting in disorders in people and animals by consuming polluted vegetables. Heavy metals have damaged soil and water eco-systems worldwide. Heavy metals have been discharging into the environment through a variety of practises, including irrigation with polluted water, the use of chemical-based fertilisers, the dumping of industrial effluents into bodies of water, volcanic eruptions, forest fires, and so on [4]. Metals may seep into the ground, ground water, and eventually agricultural plants. Heavy metals can have serious consequences for human health when vegetables polluted with these metals are ingested. Although trace levels of copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), and zinc (Zn) are needed in plants, excessive quantities of these metals can be hazardous [5, 6]. Metals including aluminium (Al), arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg) are not essential for regular human function and can cause toxicity promptly [7].
Vegetables are an integral portion of the normal diet because they contain nutritionally vital substances that are necessary for human existence. They also act as protective foods by contributing in the avoidance of disorders in people. Vegetables grown in areas polluted with dangerous metals or nearby sources of heavy metal pollution may gather greater amounts of heavy metals than other vegetables. Heavy metals are taken through the roots of plants from polluted soils and environmental wastes, entering the edible sections of plant tissues or accumulating on the surface of vegetables. Protracted irrigation of heavy metals with polluted garbage water raises heavy metal concentrations over the allowable limit [8].
The sensitivity, supplementation, potential dangers, and heavy metals sources grown in soil are all reviewed in this review study. Vegetables absorbed both essential and toxic chemicals from the soil. The consumption of heavy metal-contaminated vegetables has been related to potential human health issues such as cancer and kidney impairment (HMs). Heavy metals including Cr, Mn, Fe, Ni, Cu, Zn, Cd, Pb, and Hg were discovered in high amounts in common vegetables such
Mechanical, biochemical, and biological processes, as well as doings of human, could releases heavy metal into the environment and may cause heavy metal contaminants to accumulate inside living creatures in the food chain [9, 10]. HMs diffuse into the soil, air, as well as water bodies, wherever they could be had or eaten by crops/plants, bio-accumulating into upper consumers, and then biomagnified [11, 12, 13]. HMs cannot be easily removed from the top of the food chain once they have entered it, and they are thus cycled throughout the entire food web. Numerous hyperaccumulated plants provide nourishment for both humans as well as animals. As a result, the rotation from soil to humans thru plants and back into the soil following the expiry of upper consumers provides a pathway for HMs to persist in the environment for extended time periods, causing a variety of negative impacts. Ingestion vegetables containing HMs may provide potentially harmful health risks to lifeforms [14, 15] (Figure 1).
Vegetables get contaminated through various ways.
Heavy metals come in the food chain from a variety of sources. Cd, for example, took up from the soil by the roots and transferred to the body of plant. In the instance of Pb, the heavy metal is absorbing by plants through air pollution, whereas As and Hg can be received from dirt water. Some heavy metals having a capacity to accumulate in the tissues (liver, feathers, muscles, kidney, and other organs) of upper customers during the transit from one segment of the food chain to the next. Metal are liberated into the soil, water, and air from their parental material. These HMs are found in soil in decipherable, non-soluble, and moderately soluble forms, with the soluble forms being most harmful since they are quickly captivated by plants through roots before spreading all over the whole plant organs. Metal toxicity is caused through the disruption of cellular metabolic processes [16, 17, 18, 19]. Hazardous metals are changed to persistent oxidation states in the acid standard and combine with particular proteins and enzymes when they reach the stomach from contaminated foods. The stabilised metal compounds interact with cysteine’s sulphydryl groups (-SH) as well as methionine’s sulphur atoms (-SCH3), causing protein molecules to breakdown [18, 20].
Vegetation sensitivity to nutrition and metal concentrations varies, and their reactions can be seen in variations in stain concentration, liquid content, dehydrated weight, as well as development [28, 29, 30]. All of these variations in plant properties lead to different light absorption as well as reflectivity characteristics, which can be utilised to determine soil pollution and plant physiological condition. A few research findings have shown that metal and nutritional anxiety in plants contribute to differences in the supernatural reflectivity of the undergrowth [31, 32, 33], which may end up causing numerous biological effects in the plants and thus contribute to nutritional availability in veggies increasing or decreasing. Toxicity of metals in plants causes high germination inhibition, significant reductions in rates of growth, variations in photosynthetic efficiency, respiration, and transpiration, as well as changes in nutrient homeostasis and Mn, K, Mg. [34, 35] discovered distinctive leaf symptoms in Raphanus and Phaseolus, as well as a decrease in the root: shoot ratio and ratio of biomass. Higher levels of HM as well as cytochemical localization of Zn in
Sr. No. | Heavy metals | Vegetables | Observations | Area | References |
---|---|---|---|---|---|
1 | Pb, Cd | The concentration of the HMs increased than allowable limit | Amba nalla in Amravati city, Maharashtra | [21] | |
2 | Pb, Cd, Cu, Zn, and As | Observing health problems | Shizhuyuan area in China | [22] | |
3 | Cr, Ni, Cu, Zn, As, Cd, and Pb | Health risks of Cr, Cu, As, Cd, and Pb should be of great concern | Dhaka city, Bangladesh | [23] | |
4 | As, Cd, Cr, Pb and Zn | Pb and Cd levels exceeded the maximum permissible limits set by FAO/WHO for human consumption | Market sites of Kathmandu | [24] | |
5 | Cd, Cu, Pb and Zn | Cd and Pb levels exceeding the maximum level (ML) set by the Australian and New Zealand Food Authority | Port Kembla and Boolaroo, Australia | [25] | |
6 | Fe, Zn, Cu, Pb, Cd, Mn, and Cr | High level of pollution along cement factories of Rewa, India | J.P. Cement (Rewa) | [26] | |
7 | Cu, Cd, Zn and Pb | The concentration of the HMs increased than allowable limit | Market sites of India | [27] |
Heavy metals impacted vegetables from different areas.
Growth of plant was inhibited in both treatments of Cd, i.e. leaf chlorosis symptoms at 10 M Cd and necrotic patches at 100 M Cd, according to [36, 37], and browning of root was detected in both dealings. In root abstracts of Cd-exposed plants, the action of phosphoenolpyruvate carboxylase, which is involving in the anaplerotic fixation of CO2 into organic acids, increased. At 100 M Cd, citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities increased significantly in leaf extracts, although fumarase activity declined. Membrane damage, electron transport disturbances, enzyme inhibition/activation, and interactions with nucleic acids are among known effects of metal toxicity [38, 39]. The production of oxidative stress and the substitution of critical cofactors of numerous enzymes, like Zn, Fe, and Mn, are two plausible causes for the development of these illnesses. Various researchers have associated oxidative stress with introduction to high heavy metal concentrations [40, 41]. Heavy metals’ influence on plants, according to [42, 43, 44], growth suppression, physical harm, and a decay in physical, biological, and plant function are all consequences. Heavy metal toxicity disrupts cell and organelle membrane integrity by blocking enzymes, polynucleotides, and important nutrient and ion transport systems, displacing and/or substituting essential ions from cellular locations, denaturing and inactivating enzymes, and denaturing and inactivating enzymes. At supra-optimal absorptions, heavy metals as Cd, Pb, Hg, Cu, Zn, and Ni impede plant development, growth, and yield.
Interspecies distinctions in metal and nutrient uptake, as well as differences caused by therapeutic interventions within the similar plant, are minor and could be due to plant biomass and root exudes into the soils. The availability of metals and nutrients for plant absorption will be affected when plants develop and roots grow in soil due to biogeochemical interactions of organic acids generated by root oozes. This method may explain why tomato (
Cu had a negative effect on seed germination in Chinese cabbage, according to [47]. (
[40] find that under higher Cd concentrations, the content of protein of desolate carrot (Daucus carota) and common sunflower (
The industries are growing day by day in our country. The waste chemical contaminated water from these industries is directly thrown in river, sea, etc. Also the wastes, garbage from city is thrown in the water. This is the major reason behind the contamination of water. This water is used in many purposes like drinking, agriculture, etc. The contaminated water used in agriculture is absorbed by various vegetables. Resulting the vegetables become contaminated. We the humans use these contaminated vegetables in eating purpose. Once it is ingested in digestive system, it shows poisonous effects on the body as described in Figure 2. Heavy metal exposure typically follows this outline: from industries to air, soil, water, and foods, and then to people [55, 56, 57, 58, 59]. This heavy metals are existing in a amount of formats. Heavy metals like lead, cadmium, manganese, as well as arsenic could arrive the body by the gastrointestinal system or the entrance of digestive system while eating, drinking, or eating fruits and vegetables. The bulk of bodily heavy metals are transferred from blood to tissues [60, 61]. Red blood cells passes lead to not only the liver but also kidneys, where it is subsequently re-assigned as phosphate salt to the teeth, bone as well as hair [62, 63, 64]. Cadmium firstly fixes to blood cells & albumin, formerly to metallothionein in the kidney as well as liver. Later being carried through the blood to the lungs, vapour of manganese disperses over the membrane of lung to the central nervous system (CNS). Water solvable inorganic manganese ions are dispersed in the plasma as well as kidney for renal removal, whereas fat solvable manganese salts are diffused in the colon for faecal removal. Accumulation of Arsenic in the heart, lungs, liver, kidney, muscle, and neural tissues, as well as the skin, nails, and hair, afterward being passed by the circulation.
Cyclic explanation of how vegetables contaminated and its toxic effects on humans.
Free radicals are known to be produced by some heavy metals, which can cause oxidative stressing as well as other cellular damaging. The method by which free radicals are generated is unique to heavy metal. Heavy metals are acetified by the acid medium of stomach when they are consumed through food or drink. They oxidised to several oxidative states (Zn2+, Cd2+, Pb2+, As2+, As3+, Ag+, Hg2+, etc.) in this acidic media, which can quickly fix to biological molecules like proteins as well as enzymes to create persistent and strong connections. The thio groups are the most prevalent functional groups that heavy metals fixes to (SH group of cysteine and SCH3 group of methionine). Cadmium had shown to bind to cysteine remains in the catalytic surface of human thiol transfers in vitro, consisting thioredoxin reductase, glutathione reductase, as well as thioredoxin [65, 66, 67, 68, 69, 70].
Heavy metal-bounded proteins might be able to be useful as a substratum by some enzymes. The heavy metal-bounded protein has an enzyme-substrate complex in a specific pattern, which prevents the enzyme through absorbing any more substrates till it is release. Resulting of the enzyme being inhibited, the product of substratum is not formed, and the heavy metal becomes embedded in the tissue, producing dysfunctions, abnormalities, and damage. Constraining thiol transferases reasons an rise in oxidative pressure and cell damaging. Poisonous arsenic, which can be there in fungicides, herbicides, and insecticides, can damage enzymes’ –SH groups, preventing them from catalysing reactions.
As arsenite-inducing protein clustering was found and proved to be concentration-dependending, heavy metals may cause proteins to aggregate. The clusters also comprised a diverse ranging of proteins with roles linked to metabolism, protein portable, synthesis of protein, and protein stability [71, 72, 73, 74, 75]. After exposing to equi-toxic quantities of cadmium, arsenite, as well as chromium (Cr(VI)), Saccharomyces cerevisiae (budding yeast) cells gathered aggregated proteins, and the outcome of heavy metals on protein aggregation was altered in this direction: arsenic > cadmium > chromium [76, 77, 78, 79, 80]. The effectiveness of this agents’ cellular uptake/export, as well as their different modalities of biological action, are likely to determine their in vivo potency to cause protein aggregation.
Heavy metals in soil, air, as well as water are a severe concerned since they will have a detrimental impact on food sustainability and human health. Eating of heavy metal-contaminating vegetables can result in a variety of ailments in consumers. Vegetable eating is the primary route for heavy metals to infect humans. Heavy metal pollution in food may produce heavy metal buildup in humans’ kidneys and livers, disrupting a variety of biochemical processes that can lead to cardiovascular, neurological, renal, and bone illnesses [27, 81, 82, 83, 84]. The biotoxic effects of high are determined by their concentrations and oxidation states, deposition mechanism, chemical composition of plants, physical characterisation, and rate of intake (Table 2) [1].
Heavy metal | Applications | Health effects | References |
---|---|---|---|
Chromium | paints pigment, fungicide, Pesticide | Cancer, nephritis and ulceration | [16] |
Lead | Plastic, batteries, Auto exhaust, gasoline | Risk of cardiovascular disease and neurotoxic diseases | [85] |
Cadmium | Pigments Fertiliser, plastic | Endocrine disrupter Carcinogenic, Alter calcium regulation in biological systems mutagenic, lung damage, fragile bones | [86, 87] |
Zinc | Fertilisers | Dizziness, fatigue, vomiting, renal damage, decreased Immune function | [88, 89] |
Nickle | Electroplating | Lung cancer, Immuno-toxic Allergic disease, neurotoxic, genotoxic, Infertility | [90] |
Copper | Electronics, wood preservative, Architecture | Brain damage, Chronic anaemia, Kidney damage, Intestine irritation, Liver cirrhosis, Spontaneous abortions and gestational diabetes | [91] |
Arsenic | Pesticides, Wood products & herbicides | Immunological, Reproductive and Developmental alterations and causing cancer | [92] |
Mercury | Catalysts, Electric Switches, rectifiers, CFLs | Neurological and immune disorders, fatal to kidney and lungs | [34] |
Various heavy metals, their application areas/industries, and probable harmful health consequences on humans produced by these heavy metals are shown.
Cd had being discovered to have deleterious effects on a number of essential enzymes. The negative repercussions might include everything from a painful bone condition called ostemalacia to red blood cell disintegration and renal issues. High lead in the blood can induce hypertension, nephritis, and cardiovascular illness, as well as affecting children’s cognitive development [61, 93, 94]. Cu as well as Zn can lead to acute stomach and bowel issues as well as liver damage [95, 96, 97]. Arsenic exposurance is linked to angiosarcoma and skin cancer [98, 99]. Zn, on the different side, can impair immunological function and raise stages of higher-density lipoproteins [99].
Due to higher heavy metal concentrations in the soil, fruit, as well as vegetables, the Vanregion of Turkey has a higher incidence of greater gastrointestinal cancer rates. Eating of heavymetal-contaminating food can depletes some vital bodily nutrients, resulting in lowered immune defences, altered physico-social behaviour, intrauterine growing retardation, and problems linked with malnourishment [100, 101]. Metal poisoning has also been linked to neurotoxic, carcinogenic, mutagenic, or teratogenic consequences, which might be acute, chronic, or sub-chronic. Some employees also stated having problems with their kidneys [102, 103].
The link between heavy metal exposure during pregnancy and foetal development has been widely established. Heavy metals have the potential to harm the reproductive system of female by causing damage to the ovary and hormone production and release [104, 105]. [106] found that heavy metals can causing alterations in the structure and role of the ovary, as well as embryonic development, when they were researched on the female reproductive system. In vivo and in vitro investigations have confirmed the deposing of heavy metals in the ovary. Pb in the body of the host has been linked to lower birth weightiness, preterm birthing, stillbirths, spontaneous abortions, as well as hypertension [107], while Ar in the body of the host has been linked to foetal loss, stillbirths, spontaneous abortions, and impaired growth as well as development [107, 108]. While Cd exposure is linked to low birth weight, AS exposure has been linked to spontaneous abortions and neurotoxic consequences. Cu poisoning is linked to lower birth weightiness, spontaneous abortions, and gestational diabetes [109]. [110] found women who had miscarriages had high methylmercury levels, albeit the link among methyl mercury exposure and spontaneous abortion has yet to be shown [110]. Stillbirths, miscarriages, and foetal development problems have described as a effect of mercury toxicity.
Pollutants in the environment, food safety and security, and human health are all intricately intertwined. Heavy metal concentrations in the environment have risen rapidly in recent years. Heavy metal sources in vegetables differ across the developing and industrialised worlds. The principal contamination causes in soil–crop systems in industrialised nations are the deposition of PM on food plants and the usege of industrial effluents and sewage sludge as fertilisers. However, in underdeveloped nations, irrigation with untreated sewage or sludge is the primary cause of contamination for food crops. Heavy metal transmission from soil to crop systems is complicated and employs a variety of methods. To establish the true metal toxicity of multi-metal toxicity in vegetables, special care must be used. Human health hazards have been extensively investigated on a universal basis, but only a handful of these findings employed suitable epidemiological methodology. Existing control methods focus on decreasing heavy metal concentrations in soil and the food chain to decrease health hazards. To minimise the passage of metallic pollutants into the food chain and to develop appropriate remediation techniques, soil pollution must be mapped quickly and precisely. For temperately contaminating soils, biological remediation, such as phytoremediation and PGPR, could be a cost-effective and environmentally friendly alternative. With specific financial assurances, eco-friendly technical advancements such as nano-tools and farmer knowledge might benefit local economies and livelihoods.
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These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"66619",doi:"10.5772/intechopen.85692",title:"Contribution of the Microbiome as a Tool for Estimating Wine’s Fermentation Output and Authentication",slug:"contribution-of-the-microbiome-as-a-tool-for-estimating-wine-s-fermentation-output-and-authenticatio",totalDownloads:1094,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Wine is the alcoholic beverage which is the product of alcoholic fermentation, usually, of fresh grape must. Grape microbiome is the source of a vastly diverse pool of filamentous fungi, yeast, and bacteria, the combination of which plays a crucial role for the quality of the final product of any grape must fermentation. In recent times, the significance of this pool of microorganisms has been acknowledged by several studies analyzing the microbial ecology of grape berries of different geographical origins, cultural practices, grape varieties, and climatic conditions. Furthermore, the microbial evolution of must during fermentation process has been overstudied. The combination of the microbial evolution along with metabolic and sensorial characterizations of the produced wines could lead to the suggestion of the microbial terroir. These aspects are today leading to open a new horizon for products such as wines, especially in the case of PDO-PGI products. The aims of this review is to describe (a) how the microbiome communities are dynamically differentiated during the process of fermentation from grape to ready-to-drink wine, in order to finalize each wine’s unique sensorial characteristics, and (b) whether the microbiome could be used as a fingerprinting tool for geographical indication, based on high-throughput sequencing (HTS) technologies. Nowadays, it has been strongly indicated that microbiome analysis of grapes and fermenting musts using next-generation sequencing (NGS) could open a new horizon for wine, in the case of protected designation of origin (PDO) and protected geographical indication (PGI) determination.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Dimitrios A. Anagnostopoulos, Eleni Kamilari and Dimitrios Tsaltas",authors:[{id:"180885",title:"Associate Prof.",name:"Dimitris",middleName:null,surname:"Tsaltas",slug:"dimitris-tsaltas",fullName:"Dimitris Tsaltas"},{id:"203761",title:"MSc.",name:"Dimitris",middleName:null,surname:"Anagnostopoulos",slug:"dimitris-anagnostopoulos",fullName:"Dimitris Anagnostopoulos"},{id:"271801",title:"Ms.",name:"Elena",middleName:null,surname:"Kamilari",slug:"elena-kamilari",fullName:"Elena Kamilari"}]},{id:"67444",doi:"10.5772/intechopen.86443",title:"Somatic Variation and Cultivar Innovation in Grapevine",slug:"somatic-variation-and-cultivar-innovation-in-grapevine",totalDownloads:1036,totalCrossrefCites:4,totalDimensionsCites:9,abstract:"Paradoxically, continuous vegetative multiplication of traditional grapevine cultivars aimed to maintain cultivar attributes in this highly heterozygous species ends in the accumulation of considerable somatic variation. This variation has long contributed to cultivar adaptation and evolution under changing environmental and cultivation conditions and has also been a source of novel traits. Understanding how this somatic variation originates provides tools for genetics-assisted tracking of selected variants and breeding. Potentially, the identification of the mutations causing the observed phenotypic variation can now help to direct genome editing approaches to improve the genotype of elite traditional cultivars. Molecular characterization of somatic variants can also generate basic information helping to understand gene biological function. In this chapter, we review the state of the art on somatic variation in grapevine at phenotypic and genome sequence levels, present possible strategies for the study of this variation, and describe a few examples in which the genetic and molecular basis or very relevant grapevine traits were successfully identified.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Pablo Carbonell-Bejerano, Carolina Royo, Nuria Mauri, Javier Ibáñez and José Miguel Martínez Zapater",authors:[{id:"287215",title:"Prof.",name:"Jose Miguel",middleName:null,surname:"Martinez Zapater",slug:"jose-miguel-martinez-zapater",fullName:"Jose Miguel Martinez Zapater"},{id:"287226",title:"Dr.",name:"Javier",middleName:null,surname:"Ibáñez",slug:"javier-ibanez",fullName:"Javier Ibáñez"},{id:"300441",title:"Dr.",name:"Pablo",middleName:null,surname:"Carbonell-Bejerano",slug:"pablo-carbonell-bejerano",fullName:"Pablo Carbonell-Bejerano"},{id:"300442",title:"Dr.",name:"Carolina",middleName:null,surname:"Royo",slug:"carolina-royo",fullName:"Carolina Royo"},{id:"300444",title:"Dr.",name:"Nuria",middleName:null,surname:"Mauri",slug:"nuria-mauri",fullName:"Nuria Mauri"}]},{id:"57946",doi:"10.5772/intechopen.71627",title:"Microbiological, Physical, and Chemical Procedures to Elaborate High-Quality SO2-Free Wines",slug:"microbiological-physical-and-chemical-procedures-to-elaborate-high-quality-so2-free-wines",totalDownloads:1616,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Sulfur dioxide (SO2) is the most preservative used in the wine industry and has been widely applied, as antioxidant and antibacterial agent. However, the use of sulfur dioxide implicates a range of adverse clinical effects. Therefore, the replacement of the SO2 content in wines is one of the most important challenges for scientist and winemakers. This book chapter gives an overview regarding different microbiological, physical, and chemical alternatives to elaborate high-quality SO2-free wines. In the present chapter, original research articles as well as review articles and results obtained by the research group of the Wine Technology Center (VITEC) are shown. This study provides useful information related to this novel and healthy type of wines, highlighting the development of winemaking strategies and procedures.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Raúl Ferrer-Gallego, Miquel Puxeu, Laura Martín, Enric Nart, Claudio\nHidalgo and Imma Andorrà",authors:[{id:"207221",title:"Dr.",name:"Raúl",middleName:null,surname:"Ferrer-Gallego",slug:"raul-ferrer-gallego",fullName:"Raúl Ferrer-Gallego"},{id:"208597",title:"Dr.",name:"Miquel",middleName:null,surname:"Puxeu",slug:"miquel-puxeu",fullName:"Miquel Puxeu"},{id:"208598",title:"Dr.",name:"Laura",middleName:null,surname:"Martín",slug:"laura-martin",fullName:"Laura Martín"},{id:"208599",title:"Mr.",name:"Enric",middleName:null,surname:"Nart",slug:"enric-nart",fullName:"Enric Nart"},{id:"208600",title:"Dr.",name:"Claudio",middleName:null,surname:"Hidalgo",slug:"claudio-hidalgo",fullName:"Claudio Hidalgo"},{id:"208601",title:"Dr.",name:"Imma",middleName:null,surname:"Andorrà",slug:"imma-andorra",fullName:"Imma Andorrà"}]}],mostDownloadedChaptersLast30Days:[{id:"58638",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1953,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"57497",title:"Recovering Ancient Grapevine Varieties: From Genetic Variability to In Vitro Conservation, A Case Study",slug:"recovering-ancient-grapevine-varieties-from-genetic-variability-to-in-vitro-conservation-a-case-stud",totalDownloads:1768,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"A great number of varieties have been described in grapevine; however, few of them are currently in use. The increasing concern on varietal diversity loss has encouraged actions for recovering and preserving grapevine germplasm, which represents valuable resources for breeding as well as for diversification in grapevine-derived products. On the other hand, it is expected that this important crop, which is distributed in warm areas worldwide, will suffer the climate changes. Therefore, it is also convenient the identification of intravarietal variability and the recovery of accessions well adapted to particular environments. In this chapter, we will contribute to highlight the importance of recovering ancient materials, the usefulness of SSR markers to determine their molecular profile, the importance to analyze their virus status, and the possibilities that offer biotechnological tools for virus sanitation and in vitro storage as a complement of field preservation. In this context, we have evaluated different grapevine accessions and developed in vitro culture protocols for micropropagation, sanitation, and storage grapevine cultivars. In this work, we report the results obtained for the historic variety “Valencí Blanc” (or “Beba”) and the historic and endangered variety “Esclafagerres” (“Esclafacherres” or “Esclafacherris”).",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Carmina Gisbert, Rosa Peiró, Tania San Pedro, Antonio Olmos,\nCarles Jiménez and Julio García",authors:[{id:"207745",title:"Dr.",name:"Carmina",middleName:null,surname:"Gisbert",slug:"carmina-gisbert",fullName:"Carmina Gisbert"},{id:"207748",title:"Dr.",name:"Rosa María",middleName:null,surname:"Peiró",slug:"rosa-maria-peiro",fullName:"Rosa María Peiró"},{id:"207749",title:"Ms.",name:"Tania",middleName:null,surname:"San Pedro Galán",slug:"tania-san-pedro-galan",fullName:"Tania San Pedro Galán"},{id:"207750",title:"Dr.",name:"Antonio",middleName:null,surname:"Olmos",slug:"antonio-olmos",fullName:"Antonio Olmos"}]},{id:"58633",title:"The Evolution of Polyphenols from Grapes to Wines",slug:"the-evolution-of-polyphenols-from-grapes-to-wines",totalDownloads:2023,totalCrossrefCites:5,totalDimensionsCites:13,abstract:"Polyphenols play an important role in the quality of wines, due to their contribution to the wine sensory properties: color, astringency and bitterness. They act as antioxidants, having positive role in human health. They can be divided into non-flavonoid (hydroxybenzoic and hydroxycinnamic acids and stilbenes) and flavonoid compounds (anthocyanins, flavan-3-ols and flavonols). Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"67760",title:"Production and Marketing of Low-Alcohol Wine",slug:"production-and-marketing-of-low-alcohol-wine",totalDownloads:1300,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Moderate wine consumption may be associated with specific health benefits and a healthy lifestyle. However, increased amounts of ethanol are cytotoxic and associated with adverse health outcomes. Alcohol reduction in wine might be an avenue to reduce alcohol related harm without forcing consumers to compromise on lifestyle and benefit from positive aspects of moderate consumption. The aim of this review is to give an overview of viticultural and pre and post fermentation methods to produce low-alcohol wine, and to summarize the current evidence on the consumer acceptance and behaviour related to low-alcohol wine. Strategies for the labelling and marketing of wines with reduced alcohol content are discussed.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Tamara Bucher, Kristine Deroover and Creina Stockley",authors:[{id:"289140",title:"Dr.",name:"Creina",middleName:null,surname:"Stockley",slug:"creina-stockley",fullName:"Creina Stockley"},{id:"289141",title:"Dr.",name:"Tamara",middleName:null,surname:"Bucher",slug:"tamara-bucher",fullName:"Tamara Bucher"},{id:"289142",title:"Ms.",name:"Kristine",middleName:null,surname:"Deroover",slug:"kristine-deroover",fullName:"Kristine Deroover"}]},{id:"57946",title:"Microbiological, Physical, and Chemical Procedures to Elaborate High-Quality SO2-Free Wines",slug:"microbiological-physical-and-chemical-procedures-to-elaborate-high-quality-so2-free-wines",totalDownloads:1613,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Sulfur dioxide (SO2) is the most preservative used in the wine industry and has been widely applied, as antioxidant and antibacterial agent. However, the use of sulfur dioxide implicates a range of adverse clinical effects. Therefore, the replacement of the SO2 content in wines is one of the most important challenges for scientist and winemakers. This book chapter gives an overview regarding different microbiological, physical, and chemical alternatives to elaborate high-quality SO2-free wines. In the present chapter, original research articles as well as review articles and results obtained by the research group of the Wine Technology Center (VITEC) are shown. This study provides useful information related to this novel and healthy type of wines, highlighting the development of winemaking strategies and procedures.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Raúl Ferrer-Gallego, Miquel Puxeu, Laura Martín, Enric Nart, Claudio\nHidalgo and Imma Andorrà",authors:[{id:"207221",title:"Dr.",name:"Raúl",middleName:null,surname:"Ferrer-Gallego",slug:"raul-ferrer-gallego",fullName:"Raúl Ferrer-Gallego"},{id:"208597",title:"Dr.",name:"Miquel",middleName:null,surname:"Puxeu",slug:"miquel-puxeu",fullName:"Miquel Puxeu"},{id:"208598",title:"Dr.",name:"Laura",middleName:null,surname:"Martín",slug:"laura-martin",fullName:"Laura Martín"},{id:"208599",title:"Mr.",name:"Enric",middleName:null,surname:"Nart",slug:"enric-nart",fullName:"Enric Nart"},{id:"208600",title:"Dr.",name:"Claudio",middleName:null,surname:"Hidalgo",slug:"claudio-hidalgo",fullName:"Claudio Hidalgo"},{id:"208601",title:"Dr.",name:"Imma",middleName:null,surname:"Andorrà",slug:"imma-andorra",fullName:"Imma Andorrà"}]}],onlineFirstChaptersFilter:{topicId:"1411",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81659",title:"State-of-the-Art Knowledge about 2,4,6-Trichloroanisole (TCA) and Strategies to Avoid Cork Taint in Wine",slug:"state-of-the-art-knowledge-about-2-4-6-trichloroanisole-tca-and-strategies-to-avoid-cork-taint-in-wi",totalDownloads:27,totalDimensionsCites:0,doi:"10.5772/intechopen.103709",abstract:"Cork stoppers have been used for many centuries to seal wine in various vessels. Therefore, corks have become a traditional part of wine packaging in many countries and still play an important role for the entire wine industry. Nowadays, there is a wide option of bottle cork stoppers on the market, such as natural corks, agglomerated and technical stoppers (1 + 1), etc. These cork closures have a number of advantages, including positive sustainable and ecological aspects. Natural cork material can also be responsible for cork taint, which imparts musty/moldy or wet cardboard off-odors to the wine. However, corks are not the only source of cork taint in wine, as will be shown in the present chapter. Over the past decades, a number of compounds have been detected that can contribute to the cork taint. Among them, haloanisoles play a major role, in particular 2,4,6-trichloroanisole (TCA), which has been shown to be responsible for 50–80% or more of musty defect cases in wine. Currently, the cork and wine industries have developed a number of tools and technologies to effectively prevent cork tait in wine or to remove it if the wine is already contaminated. These practical as well as analytical questions about the TCA defects are the subject of the actual chapter.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Andrii Tarasov, Miguel Cabral, Christophe Loisel, Paulo Lopes, Christoph Schuessler and Rainer Jung"},{id:"78620",title:"Table Grapes: There Is More to Vitiviniculture than Wine…",slug:"table-grapes-there-is-more-to-vitiviniculture-than-wine",totalDownloads:141,totalDimensionsCites:0,doi:"10.5772/intechopen.99986",abstract:"Table grapes are fruits intended for fresh human consumption due to their sensory attributes and nutritional value. The objective of this chapter is to review the existing knowledge about table grapes, including a description of different varieties, with particular emphasis on the new highly appreciated seedless varieties. Following an introductory note on the world distribution and production of table grapes, also considering the impact of climate change, selected varieties of table grapes will be characterized in terms of their physiology, postharvest features, and consumer preferences. A morphological description of each variety, with emphasis on grape skin, grape rachis and grape cluster will be included. A final note on the drying of table grapes into raisins, and the most appropriate varieties for drying, will be given. The major changes occurring throughout the growth, development, and ripening phases of table grapes production will be discussed, regarding both physical (skin color and skin and pulp texture) and chemical (phenolic compounds, sugar content and acidity) parameters, as well as growth regulators.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Ana Cristina Agulheiro-Santos, Marta Laranjo and Sara Ricardo-Rodrigues"},{id:"79500",title:"New Insights about the Influence of Yeasts Autolysis on Sparkling Wines Composition and Quality",slug:"new-insights-about-the-influence-of-yeasts-autolysis-on-sparkling-wines-composition-and-quality",totalDownloads:94,totalDimensionsCites:0,doi:"10.5772/intechopen.101314",abstract:"Sparkling wines elaborated using the traditional method undergo a second fermentation in the bottle. This process involves an aging time in contact with the lees, which enriches the wine in various substances, especially proteins, mannoproteins and polysaccharides, thanks to the autolysis of the yeasts. As a result of this yeast autolysis, sparkling wines benefit from better integration of carbon dioxide and a clear sensory improvement, especially in the case of long aging. This chapter synthetizes the main results that our research group has obtained about the influence of yeasts autolysis on sparkling wines composition and quality during last years, making special emphasis on the capacity of the lees to release proteins and polysaccharides as well as on their capacity to consume oxygen and thus protect the sparkling wines from oxidation.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Pere Pons-Mercadé, Pol Giménez, Glòria Vilomara, Marta Conde, Antoni Cantos, Nicolas Rozès, Sergi Ferrer, Joan Miquel Canals and Fernando Zamora"},{id:"79110",title:"Microbial Decontamination by Pulsed Electric Fields (PEF) in Winemaking",slug:"microbial-decontamination-by-pulsed-electric-fields-pef-in-winemaking",totalDownloads:81,totalDimensionsCites:0,doi:"10.5772/intechopen.101112",abstract:"Pulsed Electric Fields (PEF) is a non-thermal technique that causes electroporation of cell membranes by applying very short pulses (μs) of a high-intensity electric field (kV/cm). Irreversible electroporation leads to the formation of permanent conductive channels in the cytoplasmic membrane of cells, resulting in the loss of cell viability. This effect is achieved with low energy requirements and minimal deterioration of quality. This chapter reviews the studies hitherto conducted to evaluate the potential of PEF as a technology for microbial decontamination in the winemaking process for reducing or replacing the use of SO2, for guaranteeing reproducible fermentations or for wine stabilization.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Carlota Delso, Alejandro Berzosa, Jorge Sanz, Ignacio Álvarez and Javier Raso"},{id:"78993",title:"pH Control and Aroma Improvement Using the Non-Saccharomyces Lachancea thermotolerans and Hanseniaspora spp. Yeasts to Improve Wine Freshness in Warm Areas",slug:"ph-control-and-aroma-improvement-using-the-non-saccharomyces-lachancea-thermotolerans-and-hanseniasp",totalDownloads:90,totalDimensionsCites:0,doi:"10.5772/intechopen.100538",abstract:"Lachancea thermotolerans is a yeast species that works as a powerful bio tool capable of metabolizing grape sugars into lactic acid via lactate dehydrogenase enzymes. The enological impact is an increase in total acidity and a decrease in pH levels (sometimes >0.5 pH units) with a concomitant slight reduction in alcohol (0.2–0.4% vol.), which helps balance freshness in wines from warm areas. In addition, higher levels of molecular SO2 are favored, which helps to decrease SO2 total content and achieve better antioxidant and antimicrobial performance. The simultaneous use with some apiculate yeast species of the genus Hanseniaspora helps to improve the aromatic profile through the production of acetyl esters and, in some cases, terpenes, which makes the wine aroma more complex, enhancing floral and fruity scents and making more complex and fresh wines. Furthermore, many species of Hanseniaspora increase the structure of wines, thus improving their body and palatability. Ternary fermentations with Lachancea thermotolerans and Hanseniaspora spp. sequentially followed by Saccharomyces cerevisiae are a useful bio tool for producing fresher wines from neutral varieties in warm areas.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Antonio Morata, Carlos Escott, Iris Loira, Juan Manuel Del Fresno, Cristian Vaquero, María Antonia Bañuelos, Felipe Palomero, Carmen López and Carmen González"},{id:"78970",title:"Alternatives to CU Applications in Viticulture. How R&D Projects Can Provide Applied Solutions, Helping to Establish Legislation Limits",slug:"alternatives-to-cu-applications-in-viticulture-how-r-d-projects-can-provide-applied-solutions-helpin",totalDownloads:180,totalDimensionsCites:2,doi:"10.5772/intechopen.100500",abstract:"Copper (Cu) and its based preparations have been used for over 200 years to control fungi and bacterial diseases in cultivated plants. Downy mildew caused by the obligate biotrophic oomycete Plasmopara viticola is one of the most relevant and recurrent diseases of grapevines. Recently, the use of Cu is being limited by some regulations because of its high impact at different levels (health and environmental problems). Due to its accumulation in soil, this metal causes a little controversy with the principles of sustainable production. Therefore, international legislation and initiatives have recently been arisen to start limiting its use, with the main goal to replace it. In this framework, some alternatives have been tested and others are recently being developed to replace, at least partially, the use of Cu in viticulture. Many of them, are being developed and tested under the scope of research and development EU funded projects. To not compromise sustainability targets in viticulture, results from these R&D projects need to be considered to assess the present risks of using Cu in viticulture and to better support establishing limits for its applications, considering soils vulnerability, while no sustainable alternatives are available in the market.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Mario De La Fuente, David Fernández-Calviño, Bartosz Tylkowski, Josep M. 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He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"24",type:"subseries",title:"Computer Vision",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR",scope:"The scope of this topic is to disseminate the recent advances in the rapidly growing field of computer vision from both the theoretical and practical points of view. Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"1177",title:"Prof.",name:"Antonio",middleName:"J. 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