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Today, narrow-field and wide-field total laryngectomy are combined with partial pharyngectomy and neck dissection to obtain good results following surgery – regarding disease-free survival of patients as well as a good quality-of-life (especially when it comes to speech and swallowing) [1, 2, 3].
After the larynx is removed, in the anterior part of the hypopharynx, there is always a resulting defect. This lack of substance is caused by the shared anatomy of the larynx and pharynx. Because most laryngeal neoplasia that warrants a total laryngectomy is usually a locally advanced disease, and the glottis and supraglottic regions are the most frequent regions involved in the disease process, there is often an extension of the neoplasia to the adjacent hypopharynx. This requires an extended resection of the diseased pharynx – a total laryngectomy with a partial pharyngectomy.
After completing the resection, reconstruction of the area uses the principle of separation of the respiratory and digestive tracts. Thus, a permanent tracheostomy is performed by anchoring the subglottic tracheal end to the skin in the suprasternal notch and the remaining pharynx is sutured around a naso-gastric feeding tube and usually covered with the prelaryngeal muscle layers (when available). This is called a three-layer closure – with the pharynx being the first layer, the prelaryngeal strap muscles the second layer and the cervical skin the third [4]. Depending on the size and shape of the resulting pharyngeal defect, primary closure by suturing of the pharyngeal margins may be done in a horizontal pattern or by a T shape pattern (Figure 1). The horizontal closure, when feasible, offers the best healing chance and has the lowest risk of development of a pharyngeal fistula. The T shape closure has more stitching, and the tips of the 2 vertical pharyngeal tranches which form the upper part of the T have the least vascularization, which make them more susceptible to necrosis and therefore a salivary leak, which may progress towards fistula formation.
Pharyngeal closure following total laryngectomy – Left (a): before suturing; Right (b): T-shaped pharyngoraphy on a naso-gastric feeding tube. Legend: F – pharynx, Tr. – trachea, Thy. – thyroid lobes, Oe – Oesophagus.
There are multiple types of suturing techniques used to close the pharynx. Choosing a closure type often depends on the size of the defect to be closed, as well as the surgeon’s personal preference. The only recommendation, which every student in Otorhinolaryngology learns from compulsory surgery textbooks is that an inverting suture should be used, similar to sutures used in digestive surgery [4]. The most frequent type of suture used is the Connell suture, which is a continuous (running) inverting suture. The needle is passed parallel to the incision line, through all the layers of the pharynx, and out on the same side, after which it runs perpendicular to the incision line to the opposite side, where it passes in similar fashion. Some authors use variations of this suture, but there is not a consensus yet on a superior technique of suturing [5].
In cases of locally advanced tumours, where surgical excision extends to the pharynx, the resulting pharyngeal defect often makes primary closure impossible (Figure 2). Such cases warrant a second, reconstructive step to obtain surgical healing, such as using a local miocutaneous pedicled flap (pectoralis major or latissimus dorsi).
Resulting defect following total laryngectomy “en bloc” with right thyroid lobe, large segment of pharynx as well as right side prelaryngeal muscle and skin. The resulting defect made primary reconstruction impossible – a local pedicled miocutaneous flap was used.
After wound healing – deglution is possible by oral intake, and respiration will always remain through the tracheostomy. Advances in speech rehabilitation made tracheoesophageal fistulisation with vocal prosthesis placement the gold-standard for vocal rehabilitation after total laryngectomy, assuring the possibility for adequate communication even without the larynx.
As with most tissue injuries, after sectioning the pharyngeal wall through all three layers and then reapproximating them to close the resulting pharyngostoma, the healing mechanism is activated by way of inflammation, angiogenesis, migration and proliferation of fibroblasts, scar formation and subsequent connective tissue remodelling [6]. Following the surgeon’s cut, the surface of the resected pharynx forms blood clots. These contain trapped red blood cells, as well as fibrin, fibronectin and complement components. Clots not only act a bleeding preventing mechanism, but also as a matrix for cells that are attracted by cytokines, chemokines and growth factors released in the area. Release of VEGF (vascular endothelial growth factor) permits increased blood vessel permeability – with subsequent inflammation and oedema. Within 24 hours from the injury, neutrophils migrate to the area and enter the local injury site by way of the blood clot matrix, to contribute to healing by releasing proteolytic enzymes. These enzymes clear debris and destroy bacteria. Between 24 and 72 hours after injury, granulation tissue is formed, by proliferating fibroblasts and vascular endothelial cells. This type of tissue has special properties, because of the high vascular permeability of new endothelial cells. This granulation tissue progressively fills all the injury space, and by 5 to 7 days the entire wound area is filled by this new tissue and neovascularization is maximal [7, 8]. Chemokines and different growth factors that are released by macrophages and neutrophils attract fibroblasts, which usually colonize the wound area in the first two days after injury. Macrophages stimulate the fibroblasts to produce IL-6 as well as epithelial growth factors, which in turn leads to epithelial cell proliferation and subsequent epithelization of the wound. During the second week after injury, the oedema, vascularity and lymphocytic infiltrate subside, and the granulation tissue scaffolding is replaced by dense collagen fibres, spindle-cell fibroblasts and other extracellular matrix components [6]. These collagen fibres are responsible for the tensile strength of the repaired wound. Shear resistance is only about 10% of normal tissue at 7 days following injury. It increases at a fast pace during the following 4 weeks, only to plateau around 70-80% of the normal tissue strength. It is of great importance to note that a repaired wound never acquires the same resistance as normal tissue [6].
One of the most important aspects in pharyngocutaneous fistulas is the lack of understanding on how the different risk factors affect and potentially cause this complications. Several factors are widely accepted as risk factors in developing a pharyngocutaneous fistula like concomitant or preexisting radiotherapy or chemotherapy, the extension and localization of the tumor – which invariably affects how large the resulting pharyngeal excision will be, the surgical technique (if a deficient surgical closure is performed – either by incorrect approximation of the tissues or improper suturing) used or septic complications of the wound (rarely encountered currently due to antibiotic therapy preoperatively as well as postoperatively) (Figure 3). Other lesser-known risk factors include preexisting comorbidities like diabetes, low hemoglobin and albumin levels, liver conditions and malnutrition as well as GERD (gastro-esophageal reflux disease).
Large midline pharyngocutaneous and pharyngotracheal fistula following total laryngectomy and radiation therapy. A nasogastric feeding tube is visibile through the fistula orifice, just above the tracheostomy (Tr.)
What is highly specific about the pharyngeal segment following total laryngectomy is that it is permanently, since day 1 of surgery, in contact with saliva as well as the microbiota of the oral cavity. The chemical composition of saliva is known for its antibacterial and mucosal protection properties, however the mucin content as well as proteases in its composition are often inefficient to prevent even dental plaque formation. Modern studies aimed to use saliva as a diagnostic tool showed however that the proteases are very active and protein cleaving is a dynamic and fast-paced process, with protein degradation being a challenge for developing reliable diagnostic tests [9]. This may factor in the decision to use a salivary bypass tube after total laryngectomy (a Montgomery tube). Some authors reported favorable results using this method [10] – but the small sample size of the study groups, as well as a lack of uniform inclusion criteria and patient distribution resulted in results that were not statistically significant [11, 12].
GERD is another factor which is demonstrated to elevate the risk of fistula formation. Studies have shown that after total laryngectomy, because of upper oesophageal sphincter impairment, patients have elevated acidity and pepsin levels at this level [13, 14]. This affects pharyngeal wound healing – with a higher incidence of fistula formation. Studies showed that postoperative antisecretory and antiacid medication lower the risk for fistula formation after total laryngectomy [15, 16].
The extent of pharyngeal resection – and consequent pharyngeal tissue remaining for pharyngeal closure is one of the factors influencing the rate of postoperative fistula formation. This is probably due to tension around the suture lines, as well as postoperative tension generated by swallowing when resuming oral feeding [17]. Another factor, this time linked to the quality of remaining pharyngeal tissues, is radiation therapy. Salvage surgery, a term coined to describe surgery following other therapies of curative intent that failed (in cases of larynx cancer usually radiation therapy and conservative surgery), has a much higher rate of postoperative complications, including pharyngocutaneous fistulas [18]. In this aspect, radiation therapy is considered the main risk factor for complications because of the changes it produces in the irradiated tissues, and as important is the interval between radiation therapy and salvage surgery. Surgery in the first year after radiation therapy presents a significant higher risk for fistula formation, risk that decreases yearly after the first one [19]. Also demonstrated to present a higher risk of pharyngocutaneous fistula formation is concomitant bilateral neck dissection [20].
Systemic factors that influence wound healing, with regard to pharyngocutaneous fistula formation following total laryngectomy are linked to malnutrition and protein deficit (Figure 4). Studies showed that laryngeal cancer in itself negatively influences the nutritional status of patients, oftentimes patients presenting with malnutrition on diagnosis of laryngeal or pharyngo-laryngeal neoplasia [21]. Regarding pharyngocutaneous fistula formation after total laryngectomy, available data demonstrates that malnutrition (Figure 6) and protein deficiency (measured by albumin and prealbumin levels), is an independent risk factor. Current medical thought process encourages correcting malnutrition in the perioperative period to lower the risk of fistula formation [22].
Malnourished patient suffering from neoplasia of the larynx and hypopharynx. Left (a): Tracheostomy and gastrostomy – before surgical treatment. Right (b): Postoperative lateral cervical fistula – intraoperative aspect showing the diameter of the fistula, as well as the metaplasia of the epithelium of the fistula tract.
If present, managing pharyngo-cutaneous fistulas is important because their persistence can lead to increased hospital visits, a longer hospital stay and increased time for the surgical wound to heal and can prolong the time from surgery to oncological treatment. It can also have severe complication like aspiration pneumonia or carotid blowout. Although self limiting in most cases, it poses some important complications and sequelae like vessel ruptures or aspirative pneumonia if it is not resolved [23].
Conservative treatment is usually considered the first option for pharyngocutaneous fistulas. The first step in assuring a chance for spontaneous healing of the fistula is to bypass the fistula by ceasing oral feeding. This is done by either placing a naso-gastric feeding tube (which is usually kept for a limited time) or by parenteral feeding. Conservative measures consist of medical therapy with antibiotics and anti-inflammatory drugs. Daily wound care is also an important aspect with the need for fluid drainage from the fistula, local cleaning and the removal of necrotic tissues if they are present. In the same time the comorbidities of the patient must be addressed for example diabetes and hemodynamic parameters of the patient must be optimized [3] especially hemoglobin and albumin levels [4]. Applying pressure dressing above the fistula has also been seen traditionally as an important routine for daily management of the pharyngocutaneous fistula. However, traditional simple dressings are not suited for fistulas due to high output of saliva and exudate. They act more as a stopgap, so that the saliva and exudate does not come out, rather it stagnates along the fistula canal. The current concept is to move away from the simple wound dressing and use modern dressings like hydrocolloid, hydrogel or silver coated dressings [24, 25]. Sterilizing the fistula from within has also been used by different authors with substances like 0,25% acetic acid by mouth [26]. Another important aspect is the nutritional status of the patient prior and after surgery. Usually head and neck cancer patient are malnourished long time before surgery is even considered and this nutritional status is seen as a risk factor for developing complications like fistulas. Immunonutrition is a process that can modulate the immune system with certain nutrients like arginine, glutamine, omega 3 fatty acids and nucleotides, that can lead to an improvement of protein synthesis. Although not universally accepted, there is evidence that preoperative immunonutrition may lower the risk of developing fistulas [27]. Literature reviews demonstrated decreased hospital stay by an average of at least 3.5 days, but the mechanism by which this was achieved is still unclear [28]. Casas-Rodero et al. demonstrated that immunonutrition by itself did not improve fistula rate, but in the group where nutritional support was administered concomitant with immunoenhanced products the best results were obtained [29].
Negative pressure wound therapy represents a dressing process in which subatmospheric pressure is applied to the wound in a continuous or intermittent way. By decreasing local tissue swelling, improving blood flow and removing excess fluid it can trigger intracellular signals that may increase the rate of cell division and promotes the formation of granulation tissue transforming the wound into a closed controlled environment with a better management of secretions [30]. In recent years this method of wound dressing has been increasingly used by head and neck surgeons to manage pharyngocutaneous fistulas with good results. It can be used even on large size fistulas and can reduce the size and even heal the fistula. It comes with some contraindications like the presence of necrotic tissues and important wound infection that cannot be controlled. Another important aspect is the cost of this system and the accessibility of it for the patient that develop fistulas [31].
Despite being a complicated site with the presence of the tracheostomy tube which can make it difficult to maintain everything airtight negative wound pressure therapy has proven to be an effective alternative treatment for pharyngocutaneous fistula as a first line or in cases where fistulas persist after surgical revisions [32].
Hyperbaric oxygen therapy involves breathing 100% oxygen in a pressurized environment with increased atmospheric pressure. Initially used for treating decompression sickness and carbon monoxide poisoning it has proven to be also effective in treating gangrene and wounds. This therapy promotes angiogenesis and cellular synthesis. The literature available on the use of hyperbaric oxygen therapy consists mostly of studies on chronic wounds such as diabetic ulcers and venous ulcers. A Cochrane database literature review demonstrated that a large part of studies had bias issues, but most had similar results, positive short-term impact on wound healing, with statistically non-significant long-term improvement [33] Published data regarding its use in treating pharyncocutaneous fistulas is scarce. Some results look promising ranging from 87,5% -100% fistula closure [34]. The drawbacks of this therapy despite the promising results are the high cost and the availability of such pressurized rooms.
All pharyngo-cutaneous fistulas should be promptly treated, but the urgency as well as aggressiveness of the therapeutic response should be adapted to the size of the fistula, the potential for complications (e.g.: carotid blowout by salivary erosion), the underlying conditions of the patient, and the impact the fistula has on the patient’s quality of life. For example: a small, midline fistula orifice, with little to no exudate that appeared during or immediately after radiation therapy in an otherwise healthy individual poses no immediate risk for complications and is easily tolerated by the patient with little to no impact on his quality of life, and has a large chance for spontaneous healing, which makes it ideal for conservative treatment. Unfortunately, in head and neck cancer surgery most cases of fistulas developing after laryngectomy are not so straightforward to treat and require surgical interventions. A universal set of recommendations does not exist, but basic surgical principles should be tailored and applied to each case depending on each patient’s characteristics and the surgeon’s preference and experience. These principles state that for small diameter orifices, closure by margin resection and two plane suturing is usually sufficient (Figure 5).
(Up - a) Midline submandibular fistula following total laryngectomy. (Right - b) Closure of the fistula after resections of margins and 3 plane suturing – pharyngeal mucosa, platysma muscle, skin.
Larger defects require interposition of a muscle layer – usually from a local source by way of a pedicled flap. One of the closest available flaps is the sternocleidomastoid muscle, however oftentimes the skin or even the muscle has modifications following neck dissection or/and radiation, which make it not ideal for dissection and manipulation. When available, the SCM pedicled flap is an ideal solution to close small to medium midline or paramedian fistulas (Figures 6 and 7).
Midline medium diameter (12 mm) pharyngocutaneous fistula following total laryngectomy and radiation therapy.
Surgical closure using two opposing miocutaneous rotation flaps from the sternocleidomastoid muscle and overlying skin. 2 safety sutures placed to prevent head extension and tensioning of the wound.
The workhorse of cervical defect reconstructions, therefore including pharyngocutaneous fistula closure, is the pectoralis major miocutaneous pedicled flap. Because of the size of the muscle, the arterial supply (the pectoral artery is situated in the upper-lateral quadrant of the muscle, ideal for translation towards superior and medial) as well as the subcutaneous fatty tissue, this is ideal for closing large and deep fistulas or pharyngostomas [35] (Figure 8). Unbiased data regarding surgical closure methods is hard to obtain, because there is a great deal of variation between surgeons and centres, however some studies shown that use of the pectoralis major flap is the most morbidity prone technique, with a high rate of complications (bleeding, flap dehiscence, recurrent fistula, carotid blowout), but it remains the most used method (Figures 9 and 10) [36].
Closure of a large midline pharyngocutaneous fistula after total laryngectomy. Translation of a miocutaneous pectoralis major flap to cover de defect.
Final postoperative aspect of closure of an anterior pharyngocutaneous fistula using a pectoral miocutaneous flap. Notice the hair follicules on the flap skin – different from normal cervical skin.
Postoperative aspect of patient with necrosis of the miocutaneous pectoral flap. After muscle tissue necrosis – large pharyngostomy, with abundant salivary leakage, as well as exposure of the underlying carotid vessels (whitish contour parallel to the NG feeding tube) with great risk of carotid blowout.
Temporoparietal fascia flap is a new addition to the increasing techniques of fistula repair and is based on the temporoparietal branch of the superficial temporalis artery. One advantage of this flap is that the pedicle is safe from radiotherapy damage but its disadvantages of pedicle length and size of flap can limit its use [37].
In recent years the need for minimal invasive surgeries has grown and endoscopic techniques have been developed to lower comorbidities, complications and try to lower hospital stay. Endoscopic techniques for fistula repair have been developed but have some limitations depending on the size of the fistula and the condition of the surrounding tissues (like the platysma muscle and the accessibility of the fistula transorally) [38].
Free flaps are used when proximal tissues are unavailable or cannot offer epithelial surface for the repair of the fistula. The advantages of free flaps are that the donor site is far from the primary wound and therefore safe from infection and have not been irradiated. The important limitation of using free flaps is the availability of neck vessels for anastomosis (especially in cases of previous radical neck dissection with ligation of internal jugular vein) [39]. The most common free flap used is the radial forearm flap and anterior thigh flap. Other free flaps that can be used are jejunal flap and latissimus dorsi flap. Another relative disadvantage of using free flaps is the significant longer operating time needed – with harvesting and implantation taking longer than using local pedicled flaps, as well as sometimes requiring two surgical teams [39].
One particular situation of fistula formation is in cases of vocal rehabilitation using tracheo-esophageal fistulization with vocal prosthesis implant. In these cases, a fistula is made by the surgeon, between the trachea and the upper cervical esophagus through the posterior tracheal wall right at the level of the tracheostomy. In this iatrogenic fistula the surgeon inserts a vocal prosthesis – basically a two-flanged device with a lumen that has a unidirectional valve. This is placed so as to permit air from the trachea to pass through towards the pharynx, but not so as to allow food and liquids to pass from the pharynx. This method permits a higher quality esophageal speech and is currently the gold-standard method for vocal rehabilitation following total laryngectomy and has been for the last 30 years [40]. However, long term studies showed that a number of complications may arise in these patients. The hardest to treat is enlargement of the fistula. This is currently linked to local factors, such as acid reflux in the upper esophageal and pharyngeal areas [41], as well as inflammation of the tissues surrounding the prosthesis – inflammation which in turn is caused by the biofilm that forms on the body and flanges of the device [42]. Once enlargement begins (Figure 11), one of the first signs will be leakage around the prosthesis, with coughing especially during drinking. Salivary leakage and micro aspiration are potentially very harmful, because of the risk of aspiration pneumonia, which may endanger the patient’s life. Methods to treat fistula enlargement vary from using larger and larger diameter flanges, to surgically closing the fistula using a local muscle flap (usually sternocleidomastoid) and after surgical healing refistulization in a different site. Some patients however after such complications abandon this technique of vocal rehabilitation altogether and opt for other methods of communication (esophageal speech or an electric larynx) [43, 44].
Tracheoesophageal puncture orifice – enlarged, with spontaneous expulsion of vocal prosthesis. Small granulation tissue visible through opening.
Following total laryngectomy, some anatomical and functional modifications of the cervical region and especially of the pharynx and upper cervical esophagus are important for the consequent evolution of the laryngectomee. Wound healing follows the same basic principles as everywhere else in the human body, but this region presents a series of particular elements. Understanding the importance of not just the quantity of the remaining pharyngeal tissue and the pharyngeal closure technique but equally the quality of said tissues (affected by recent previous radiation therapy and malnutrition) and the intrinsic factors that influence local healing (bacterial colonization, gastro-esophageal acid reflux) – is paramount to micromanaging each total laryngectomy case, in order to decrease the risk of developing a pharyngo-cutaneous fistula. Once formed, fistulas are treated by a multitude of techniques, from conservative to radical surgical plastic reconstructions using local or distant free miocutaneous flaps. Either way, treatment of fistulas is always a more expensive and higher-risk procedure than preventing fistula formation. A particular case is vocal rehabilitation of the laryngectomees, by way of iatrogenic tracheo-esophageal fistula formation with vocal prosthesis placement. In this case, managing the fistula orifice presents another set of challenges, the goal being to maintain fistula patency without granulation tissue formation and without orifice enlargement, so as to maintain patency and prevent leakage or expulsion/aspiration of the prosthesis. The same intrinsic factors – biofilm formation and GERD have been established as risk factors for complications regarding the size of the fistula orifice.
The authors declare that there are no conflicts of interests among them. All authors have contributed equally and would like to thank their colleagues for the considerable work and support.
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\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
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\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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However, some of these heavy metals in high doses can be harmful to the body while others such as cadmium, mercury, lead, chromium, silver, and arsenic in minute quantities have delirious effects in the body causing acute and chronic toxicities in humans. The focus of this chapter is to describe the various mechanism of intoxication of some selected heavy metals in humans along with their health effects. Therefore it aims to highlight on biochemical mechanisms of heavy metal intoxication which involves binding to proteins and enzymes, altering their activity and causing damage. More so, the mechanism by which heavy metals cause neurotoxicity, generate free radical which promotes oxidative stress damaging lipids, proteins and DNA molecules and how these free radicals propagate carcinogenesis are discussed. Alongside these mechanisms, the noxious health effects of these heavy metals are discussed.",book:{id:"7111",slug:"poisoning-in-the-modern-world-new-tricks-for-an-old-dog-",title:"Poisoning in the Modern World",fullTitle:"Poisoning in the Modern World - New Tricks for an Old Dog?"},signatures:"Godwill Azeh Engwa, Paschaline Udoka Ferdinand, Friday Nweke Nwalo and Marian N. Unachukwu",authors:[{id:"241837",title:"Mr.",name:"Godwill Azeh",middleName:null,surname:"Engwa",slug:"godwill-azeh-engwa",fullName:"Godwill Azeh Engwa"},{id:"274194",title:"BSc.",name:"Paschaline Ferdinand",middleName:null,surname:"Okeke",slug:"paschaline-ferdinand-okeke",fullName:"Paschaline Ferdinand Okeke"},{id:"286975",title:"Dr.",name:"Friday",middleName:null,surname:"Nweke Nwalo",slug:"friday-nweke-nwalo",fullName:"Friday Nweke Nwalo"},{id:"286976",title:"Dr.",name:"Marian",middleName:null,surname:"Unachukwu",slug:"marian-unachukwu",fullName:"Marian Unachukwu"}]},{id:"57717",doi:"10.5772/intechopen.71923",title:"In Vitro Cytotoxicity and Cell Viability Assays: Principles, Advantages, and Disadvantages",slug:"in-vitro-cytotoxicity-and-cell-viability-assays-principles-advantages-and-disadvantages",totalDownloads:14818,totalCrossrefCites:78,totalDimensionsCites:157,abstract:"Cytotoxicity is one of the most important indicators for biological evaluation in vitro studies. In vitro, chemicals such as drugs and pesticides have different cytotoxicity mechanisms such as destruction of cell membranes, prevention of protein synthesis, irreversible binding to receptors etc. In order to determine the cell death caused by these damages, there is a need for cheap, reliable and reproducible short-term cytotoxicity and cell viability assays. Cytotoxicity and cell viability assays are based on various cell functions. A broad spectrum of cytotoxicity assays is currently used in the fields of toxicology and pharmacology. There are different classifications for these assays: (i) dye exclusion assays; (ii) colorimetric assays; (iii) fluorometric assays; and (iv) luminometric assays. Choosing the appropriate method among these assays is important for obtaining accurate and reliable results. When selecting the cytotoxicity and cell viability assays to be used in the study, different parameters have to be considered such as the availability in the laboratory where the study is to be performed, test compounds, detection mechanism, specificity, and sensitivity. In this chapter, information will be given about in vitro cytotoxicity and viability assays, these assays will be classified and their advantages and disadvantages will be emphasized. The aim of this chapter is to guide the researcher interested in this subject to select the appropriate assay for their study.",book:{id:"6310",slug:"genotoxicity-a-predictable-risk-to-our-actual-world",title:"Genotoxicity",fullTitle:"Genotoxicity - A Predictable Risk to Our Actual World"},signatures:"Özlem Sultan Aslantürk",authors:[{id:"211212",title:"Dr.",name:"Özlem Sultan",middleName:null,surname:"Aslantürk",slug:"ozlem-sultan-aslanturk",fullName:"Özlem Sultan Aslantürk"}]},{id:"66259",doi:"10.5772/intechopen.85270",title:"Antioxidant Compounds and Their Antioxidant Mechanism",slug:"antioxidant-compounds-and-their-antioxidant-mechanism",totalDownloads:7594,totalCrossrefCites:58,totalDimensionsCites:152,abstract:"An antioxidant is a substance that at low concentrations delays or prevents oxidation of a substrate. Antioxidant compounds act through several chemical mechanisms: hydrogen atom transfer (HAT), single electron transfer (SET), and the ability to chelate transition metals. The importance of antioxidant mechanisms is to understand the biological meaning of antioxidants, their possible uses, their production by organic synthesis or biotechnological methods, or for the standardization of the determination of antioxidant activity. In general, antioxidant molecules can react either by multiple mechanisms or by a predominant mechanism. The chemical structure of the antioxidant substance allows understanding of the antioxidant reaction mechanism. This chapter reviews the in vitro antioxidant reaction mechanisms of organic compounds polyphenols, carotenoids, and vitamins C against free radicals (FR) and prooxidant compounds under diverse conditions, as well as the most commonly used methods to evaluate the antioxidant activity of these compounds according to the mechanism involved in the reaction with free radicals and the methods of in vitro antioxidant evaluation that are used frequently depending on the reaction mechanism of the antioxidant.",book:{id:"8008",slug:"antioxidants",title:"Antioxidants",fullTitle:"Antioxidants"},signatures:"Norma Francenia Santos-Sánchez, Raúl Salas-Coronado, Claudia Villanueva-Cañongo and Beatriz Hernández-Carlos",authors:[{id:"143354",title:"Dr.",name:"Raúl",middleName:null,surname:"Salas-Coronado",slug:"raul-salas-coronado",fullName:"Raúl Salas-Coronado"},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez"},{id:"193718",title:"Dr.",name:"Beatriz",middleName:null,surname:"Hernández-Carlos",slug:"beatriz-hernandez-carlos",fullName:"Beatriz Hernández-Carlos"},{id:"278133",title:"Dr.",name:"Claudia",middleName:null,surname:"Villanueva-Cañongo",slug:"claudia-villanueva-canongo",fullName:"Claudia Villanueva-Cañongo"}]},{id:"40253",doi:"10.5772/50486",title:"Lipid Nanoparticulate Drug Delivery Systems: A Revolution in Dosage Form Design and Development",slug:"lipid-nanoparticulate-drug-delivery-systems-a-revolution-in-dosage-form-design-and-development",totalDownloads:11293,totalCrossrefCites:22,totalDimensionsCites:105,abstract:null,book:{id:"2509",slug:"recent-advances-in-novel-drug-carrier-systems",title:"Recent Advances in Novel Drug Carrier Systems",fullTitle:"Recent Advances in Novel Drug Carrier Systems"},signatures:"Anthony A. 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Among these heavy metals, a few have direct or indirect impact on the human body. Some of these heavy metals such as copper, cobalt, iron, nickel, magnesium, molybdenum, chromium, selenium, manganese and zinc have functional roles which are essential for various diverse physiological and biochemical activities in the body. However, some of these heavy metals in high doses can be harmful to the body while others such as cadmium, mercury, lead, chromium, silver, and arsenic in minute quantities have delirious effects in the body causing acute and chronic toxicities in humans. The focus of this chapter is to describe the various mechanism of intoxication of some selected heavy metals in humans along with their health effects. Therefore it aims to highlight on biochemical mechanisms of heavy metal intoxication which involves binding to proteins and enzymes, altering their activity and causing damage. More so, the mechanism by which heavy metals cause neurotoxicity, generate free radical which promotes oxidative stress damaging lipids, proteins and DNA molecules and how these free radicals propagate carcinogenesis are discussed. Alongside these mechanisms, the noxious health effects of these heavy metals are discussed.",book:{id:"7111",slug:"poisoning-in-the-modern-world-new-tricks-for-an-old-dog-",title:"Poisoning in the Modern World",fullTitle:"Poisoning in the Modern World - New Tricks for an Old Dog?"},signatures:"Godwill Azeh Engwa, Paschaline Udoka Ferdinand, Friday Nweke Nwalo and Marian N. Unachukwu",authors:[{id:"241837",title:"Mr.",name:"Godwill Azeh",middleName:null,surname:"Engwa",slug:"godwill-azeh-engwa",fullName:"Godwill Azeh Engwa"},{id:"274194",title:"BSc.",name:"Paschaline Ferdinand",middleName:null,surname:"Okeke",slug:"paschaline-ferdinand-okeke",fullName:"Paschaline Ferdinand Okeke"},{id:"286975",title:"Dr.",name:"Friday",middleName:null,surname:"Nweke Nwalo",slug:"friday-nweke-nwalo",fullName:"Friday Nweke Nwalo"},{id:"286976",title:"Dr.",name:"Marian",middleName:null,surname:"Unachukwu",slug:"marian-unachukwu",fullName:"Marian Unachukwu"}]},{id:"49459",title:"Pharmacokinetics of Drugs Following IV Bolus, IV Infusion, and Oral Administration",slug:"pharmacokinetics-of-drugs-following-iv-bolus-iv-infusion-and-oral-administration",totalDownloads:15480,totalCrossrefCites:16,totalDimensionsCites:24,abstract:null,book:{id:"4491",slug:"basic-pharmacokinetic-concepts-and-some-clinical-applications",title:"Basic Pharmacokinetic Concepts and Some Clinical Applications",fullTitle:"Basic Pharmacokinetic Concepts and Some Clinical Applications"},signatures:"Tarek A. Ahmed",authors:[{id:"175649",title:"Dr.",name:"Tarek A",middleName:null,surname:"Ahmed",slug:"tarek-a-ahmed",fullName:"Tarek A Ahmed"}]},{id:"29240",title:"Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability",slug:"oral-absorption-intestinal-metabolism-and-human-oral-bioavailability-",totalDownloads:27175,totalCrossrefCites:28,totalDimensionsCites:58,abstract:null,book:{id:"672",slug:"topics-on-drug-metabolism",title:"Topics on Drug Metabolism",fullTitle:"Topics on Drug Metabolism"},signatures:"Ayman El-Kattan and Manthena Varma",authors:[{id:"85539",title:"Dr.",name:"Ayman",middleName:null,surname:"El-Kattan",slug:"ayman-el-kattan",fullName:"Ayman El-Kattan"},{id:"88221",title:"Dr.",name:"Manthena",middleName:null,surname:"Varma",slug:"manthena-varma",fullName:"Manthena Varma"}]},{id:"66259",title:"Antioxidant Compounds and Their Antioxidant Mechanism",slug:"antioxidant-compounds-and-their-antioxidant-mechanism",totalDownloads:7587,totalCrossrefCites:58,totalDimensionsCites:152,abstract:"An antioxidant is a substance that at low concentrations delays or prevents oxidation of a substrate. Antioxidant compounds act through several chemical mechanisms: hydrogen atom transfer (HAT), single electron transfer (SET), and the ability to chelate transition metals. The importance of antioxidant mechanisms is to understand the biological meaning of antioxidants, their possible uses, their production by organic synthesis or biotechnological methods, or for the standardization of the determination of antioxidant activity. In general, antioxidant molecules can react either by multiple mechanisms or by a predominant mechanism. The chemical structure of the antioxidant substance allows understanding of the antioxidant reaction mechanism. This chapter reviews the in vitro antioxidant reaction mechanisms of organic compounds polyphenols, carotenoids, and vitamins C against free radicals (FR) and prooxidant compounds under diverse conditions, as well as the most commonly used methods to evaluate the antioxidant activity of these compounds according to the mechanism involved in the reaction with free radicals and the methods of in vitro antioxidant evaluation that are used frequently depending on the reaction mechanism of the antioxidant.",book:{id:"8008",slug:"antioxidants",title:"Antioxidants",fullTitle:"Antioxidants"},signatures:"Norma Francenia Santos-Sánchez, Raúl Salas-Coronado, Claudia Villanueva-Cañongo and Beatriz Hernández-Carlos",authors:[{id:"143354",title:"Dr.",name:"Raúl",middleName:null,surname:"Salas-Coronado",slug:"raul-salas-coronado",fullName:"Raúl Salas-Coronado"},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez"},{id:"193718",title:"Dr.",name:"Beatriz",middleName:null,surname:"Hernández-Carlos",slug:"beatriz-hernandez-carlos",fullName:"Beatriz Hernández-Carlos"},{id:"278133",title:"Dr.",name:"Claudia",middleName:null,surname:"Villanueva-Cañongo",slug:"claudia-villanueva-canongo",fullName:"Claudia Villanueva-Cañongo"}]},{id:"66742",title:"Introductory Chapter: Alkaloids - Their Importance in Nature and for Human Life",slug:"introductory-chapter-alkaloids-their-importance-in-nature-and-for-human-life",totalDownloads:4130,totalCrossrefCites:16,totalDimensionsCites:32,abstract:null,book:{id:"6828",slug:"alkaloids-their-importance-in-nature-and-human-life",title:"Alkaloids",fullTitle:"Alkaloids - Their Importance in Nature and Human Life"},signatures:"Joanna Kurek",authors:[{id:"214632",title:"Dr.",name:"Joanna",middleName:null,surname:"Kurek",slug:"joanna-kurek",fullName:"Joanna Kurek"}]}],onlineFirstChaptersFilter:{topicId:"19",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83076",title:"Treatments for the Infection by SARS-CoV-2",slug:"treatments-for-the-infection-by-sars-cov-2",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.106232",abstract:"In late 2019, pneumonia cases from unknown origin were detected in Wuhan, China. The cause was a new coronavirus. The World Health Organization (WHO) named the virus SARS-CoV-2 and COVID-19 the associated disease. In the first months of 2020, this disease became a pandemic with a high lethality reported. Since then, the search for treatments began. We started by searching among treatments previously approved for human use that were not designed for COVID-19 and were considered to treat this condition. We continued searching on the therapeutics guidelines published by the WHO for the management of infection by SARS-CoV-2. Based on these results, we searched for the literature in PubMed to obtain further evidence on the drugs against SARS-CoV-2. The treatments presented in this chapter are Ivermectin, Hydroxychloroquine, Nitazoxanide, Azithromycin, Molnupiravir, Casirivimab-Imdevimab, Ritonavir-Nirmatrelvir, Ritonavir-Lopinavir, Remdesivir, and Favipiravir. Two years ahead of the start of the COVID-19 pandemic, a plenty of options for treatment have been investigated. Only a few of them have been shown to be efficient and safe. According to the WHO, Ritonavir-Nirmatrelvir outperforms other proposed therapeutics.",book:{id:"11690",title:"COVID-19 Drug Development - Recent Advances, New Perspectives, and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11690.jpg"},signatures:"Nicolás Padilla-Raygoza, Gilberto Flores-Vargas, María de Jesús Gallardo-Luna, Efraín Navarro-Olivos, Francisco Javier Magos-Vázquez and Daniel Alberto Díaz-Martínez"},{id:"83054",title:"Pulsatory Liposome: A Possible Biotechnological Device",slug:"pulsatory-liposome-a-possible-biotechnological-device",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.106347",abstract:"A unilamellar liposome filled with an osmotic solution is introduced into a hypotonic aqueous environment. Because of the mechanical tension induced by the osmotic flow, the vesicle swells up to a critical size, when suddenly a transbilayer pore appears and the vesicle relaxing stage starts. A part of the intracellular material leaks out through this pore, and the liposome membrane relaxes and finally recovers. The swelling begins again and the liposome experiences a periodical process. For this reason, we have named it a pulsatory liposome. The swelling of the liposome is described by a differential equation. All the processes which contribute to the vesicle relaxing and its coming back to the initial size are described by three differential equations. The pulsatory liposome can be programmed to work a number of cycles, established before. The activity of a pulsatory liposome can be characterized by the following parameters: (a) number of cycles, the length time of each cycle, and liposome activity life; (b) the length time of the swelling stage and the relaxation stage for each cycle; (c) the amount of solute leaked out through the pore in each cycle. The pulsatory liposome may be regarded as a two-stroke engine.",book:{id:"11814",title:"Liposomes - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11814.jpg"},signatures:"Dumitru Popescu and Alin Gabriel Popescu"},{id:"82962",title:"Pluralism Medical Treatment, Prevention, and Control of COVID-19 Infection and Its Long-Sufferings among the Older Adults in the Northeast of Thailand from 2019 to 2022",slug:"pluralism-medical-treatment-prevention-and-control-of-covid-19-infection-and-its-long-sufferings-amo",totalDownloads:48,totalDimensionsCites:0,doi:"10.5772/intechopen.106339",abstract:"COVID-19 in 2019 has brought both changes and challenges to the world. This global pandemic has an impact on people of all age levels, especially older adults. In Thailand, older persons are at high risk of COVID-19 infection. They are included in the so-called 608 groups. The objective of this review article was to synthesize and present medical pluralism, the development of drugs from herbs, and projects conducted to treat, prevent, and control the infection and long sufferings of COVID-19. The review covers 10 studies, three projects produced at Mahasarakham University, Chaiyaphum Rajabhat University, and Khon Kaen University that were reviewed, synthesized, and analyzed. The results of the synthesis indicate that modern and Thai traditional medicine can help reduce the severity of the infection and long sufferings of COVID-19. The medical pluralism between modern and Thai traditional medicine is needed to remedy COVID-19 cases among the older adults in the Northeast of Thailand.",book:{id:"11690",title:"COVID-19 Drug Development - Recent Advances, New Perspectives, and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11690.jpg"},signatures:"Pissamai Homchampa, Khemika Napattaradechanon, Parichat Yatniyom, Thawalrat Ratanasiri, Piyaporn Sansila, Thanawan Sirisuk, Thawalwong Ratanasiri and Amornrat Ratanasiri"},{id:"82353",title:"Pharmacovigilance of Biological Drugs",slug:"pharmacovigilance-of-biological-drugs",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105520",abstract:"The use of biological drugs has significantly increased over the past decades and has allowed for the treatment of many life-threatening and chronic diseases. The patent expiration of biological innovative medicines enables copies of these drugs called biosimilars. The availability of biosimilars enhances competition, with the potential to improve patient access to biological medications and contribute to the financial sustainability of the healthcare systems. Unlike equivalent drugs, biosimilars are not identical but similar to their innovator products because of the differences in the manufacturing process, which is a biological process. However, they are considered comparable to their originators in safety, quality characteristics, biological activity, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars, so they are subjected to rigorous characterization as well as comparative clinical studies. Since they are highly complex molecules produced from living cells, even small change in the production process can have major implications on their safety and effectiveness profile, causing a potential risk of immune-based adverse reactions. For all these reasons, for biological drugs, a robust long-term pharmacovigilance system is necessary. It is desirable that in the future, there are further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, pharmacovigilance and interchangeability/substitution, to ensure the appropriate use of these drugs in clinical practice.",book:{id:"11679",title:"Pharmacovigilance and Regulations",coverURL:"https://cdn.intechopen.com/books/images_new/11679.jpg"},signatures:"Simona Guerzoni, Flavia Lo Castro, Carlo Baraldi, Giuliana Colella and Luca Pani"},{id:"82868",title:"Recent Strategies for Ocular Drug Delivery: Promises and Challenges",slug:"recent-strategies-for-ocular-drug-delivery-promises-and-challenges",totalDownloads:9,totalDimensionsCites:0,doi:"10.5772/intechopen.106335",abstract:"Ocular diseases include various anterior and posterior segment diseases. Due to the unique anatomy and physiology of the eye, efficient ocular drug delivery is a great challenge to researchers. The emerging nanoscience is playing an important role in the development of novel strategies for ocular disease management. Various active molecules have been designed to associate with nanocarriers to overcome ocular barriers and interact with certain ocular tissues. In this chapter, highlights will be made on barrier to intraocular delivery, general pathways for ocular absorption, and factors affecting intraocular bioavailability. The recent attempts of nanotechnology for treating anterior and posterior ocular diseases will be explored. This will include nanomicelles, nanoparticles, nanosuspensions, vesicular systems, in situ gel, dendrimers, contact lenses, implants, microneedles, and cell-based delivery systems. In addition, gene-based ocular delivery systems will be discussed. In this chapter, we will also provide a comprehensive overview of drug-device combinations used for ocular diseases such as glaucoma, dry eye disease, infections, and inflammations. Furthermore, drug delivery devices for ocular surgeries are discussed. Finally, challenges and future prospective of ocular delivery systems will be explored.",book:{id:"11688",title:"Advances in Drug Delivery Methods",coverURL:"https://cdn.intechopen.com/books/images_new/11688.jpg"},signatures:"Amal H. El-Kamel and Asmaa A. Ashour"},{id:"82727",title:"Mesoporous Silica Based Cancer Theranostic: A Modern Approach in Upcoming Medicine",slug:"mesoporous-silica-based-cancer-theranostic-a-modern-approach-in-upcoming-medicine",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.105447",abstract:"In case cancers are located deep inside the body and are very tough to diagnose, diagnostic tools like MRI/CT scans can be employed to detect these cancers. The major challenge in such cases is the delivery of MRI active agents or visualizing agents to the target site. In this context we will discuss different mesoporous nanoparticles that can be employed to target the tissue at a specific location, its functionalization to reach the target site (Folic acid), different simple dyes as well as specific dyes which offer theranostic functionality. The nanoparticles like mesoporous silica nanoparticles offer the possibility to load therapeutic and diagnostic agents. Its surface allow multiple functionalization and conjugations which offer target specific delivery of these agents. Moreover we will also overview different modern drug delivery inventions for offering theranostic application.",book:{id:"11688",title:"Advances in Drug Delivery Methods",coverURL:"https://cdn.intechopen.com/books/images_new/11688.jpg"},signatures:"Ajinkya Pote, Vikas Ahirrao and Vishal Pande"}],onlineFirstChaptersTotal:57},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. Barderas",slug:"oxidative-stress-in-cardiovascular-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}}]},overviewPagePublishedBooks:{paginationCount:33,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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