Risk factors for gallbladder stone diseases.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"2323",leadTitle:null,fullTitle:"Carbohydrates - Comprehensive Studies on Glycobiology and Glycotechnology",title:"Carbohydrates",subtitle:"Comprehensive Studies on Glycobiology and Glycotechnology",reviewType:"peer-reviewed",abstract:"It is my great honor and pleasure to introduce this comprehensive book to readers who are interested in carbohydrates. This book contains 23 excellent chapters written by experts from the fields of chemistry, glycobiology, microbiology, immunology, botany, zoology, as well as biotechnology. According to the topics, methods and targets, the 23 chapters are further divided into five independent sections. In addition to the basic research, this book also offers much in the way of experiences, tools, and technologies for readers who are interested in different fields of Glycobiology. I believe that readers can obtain more than anticipated from this meaningful and useful book.",isbn:null,printIsbn:"978-953-51-0864-1",pdfIsbn:"978-953-51-4264-5",doi:"10.5772/2702",price:159,priceEur:175,priceUsd:205,slug:"carbohydrates-comprehensive-studies-on-glycobiology-and-glycotechnology",numberOfPages:572,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"f7c2e6a3566eee14c9884ad0820a6416",bookSignature:"Chuan-Fa Chang",publishedDate:"November 21st 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2323.jpg",numberOfDownloads:118174,numberOfWosCitations:357,numberOfCrossrefCitations:156,numberOfCrossrefCitationsByBook:7,numberOfDimensionsCitations:418,numberOfDimensionsCitationsByBook:11,hasAltmetrics:1,numberOfTotalCitations:931,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 22nd 2011",dateEndSecondStepPublish:"December 20th 2011",dateEndThirdStepPublish:"April 18th 2012",dateEndFourthStepPublish:"July 17th 2012",dateEndFifthStepPublish:"August 16th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"145728",title:"Prof.",name:"Chuan-Fa",middleName:null,surname:"Chang",slug:"chuan-fa-chang",fullName:"Chuan-Fa Chang",profilePictureURL:"https://mts.intechopen.com/storage/users/145728/images/1226_n.jpg",biography:"Dr. Chuan-Fa Chang started his research work in Glycobiology for his doctorate at Institute of Biological Chemistry, Academia Sinica. He developed new methodologies for carbohydrate organic synthesis and accomplished series of carbohydrate analogs by using exo-glycals as building blocks. He then joined Dr. Chi-Huey Wong’s chemical biology lab as a postdoctoral fellow and worked on discovering glycosidase inhibitors by high-throughput drug screening systems. In 2007, Dr. Chang moved to National Cheng Kung University and initiated his independent research career. He is also the member of Society of Glycobiology (since 2004) and participating investigator of Consortium for Functional Glycomics (CFG, since 2011). 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"79566",title:"Pathophysiology of Gallstones",doi:"10.5772/intechopen.100553",slug:"pathophysiology-of-gallstones",body:'The gallstones (Figure 1) are hard, pebble-like pieces of material, usually made of cholesterol or bilirubin, that develop in the gallbladder [1]. These stones are formed due to various disorders. Five defects primarily play critical role in pathogenesis of cholesterol stones Viz lithogenes and genetic factors; hepatic hypersecretion of cholesterol; rapid phase transition of cholesterol in bile; impaired gallbladder motility; intestinal factors involving absorption of cholesterol, slow intestinal motility and altered gut microbiota.
Cholesterol gallstones and gallbladder after cholecystectomy.
Gallstones affect about 15% of United States population. About 10–20% of the United States population will get gallstones at some point in their life time and females are more affected than men [2].
Gallstones can cause biliary colic, cholecystitis, pancreatitis, empyema Gallbladder, perforation of gallbladder, cholangitis, bile duct obstruction [3], and cancers (gallbladder [4], colorectal [5, 6], pancreatic [7]). In 85% of patients with gallbladder cancer, gall stones are present [8]. Gallbladder cancer is a very fatal cancer with average survival of 6 months [9] and 5-year survival rate of 5% [8]. This bad prognosis is because of silent features. An increased mortality from cardiovascular disease and cancer was found to be associated with gallstones by an 18 year national study [10]. Asymptomatic cholelithiasis are present in 80% of cases and most of these are incidentally found when the patients are under investigation for other ailments [11]. In general, 10–25% of asymptomatic cases may develop symptoms during the patient’s lifetime [12]. The estimated cost for gallbladder diseases was 6.5 billion dollar annually in United States only in 2002 [13].
There are three types of gallstones; first and most common type is cholesterol stone. Black and brown pigmented stones are the other two types of gallstones. The prevalence of various types of gallstones in the western world is: 75% of gallstones are cholesterol stones, 20% are black pigment stones, and 5% or less are brown pigment stones. Cholesterol and black pigment stones are formed exclusively in gallbladder in a sterile medium, while as brown pigment stones are formed everywhere in the biliary tree owing to the anaerobic bacterial infection. Stasis of bile is an essential component in the formation of gallstone or bile duct stone formation [14]. In underdeveloped countries parasitic infection of biliary tree is associated with brown pigment stones [15].
Physical-chemical origin is the basis of pathogenesis of sterile stones (cholesterol and black pigment stones) [16]. There is an alteration in lipid and lipo-pigment composition which results in the formation of stones. In cholesterol and black pigment stones the major component is cholesterol monohydrate crystals and calcium hydrogen bilirubinate respectively. During the long stay in gallbladder, the black pigment gets degraded and polymerized by free radicals and helps in the formation of black pigment stones while as in the brown pigment stones the main mechanism is infectious where the enzymatic hydrolysis of biliary lipids by anaerobic bacterial enzymes produces supersaturated long chain fatty and deconjugated bile acids [14, 17].
Gallstone formation occurs as a result of interaction between genetic and environmental factors in which few are unmodifiable and unaltered as age and genetic makeup. The traditional risk factors for gallstones are four “F” female, fertile, fat, forty and some have added fifth “F” for fair skin [18].
Various intrinsic and extrinsic risk factors for the causation of different types of gallstones are genetic factors, advanced age, female gender, parity, ethnicity, rapid weight loss, different medications (oestrogen replacement therapy, oral contraceptive pills), total parenteral nutrition [19], obesity, westernized diet, Type 2 diabetes mellitus, metabolic syndrome [20], dyslipidaemia, hyperinsulinemia [21], increased enterohepatic circulation of bilirubin [22], defective gall bladder motility [23] as shown in Table 1.
Risk factors for gallstone diseases | |
---|---|
Intrinsic factor | Extrinsic factor |
Age | Lipid profile |
Gender | Diet |
Ethnicity | Obesity |
Defective gallbladder motility | Weight loss |
Physical activity | |
Genetics | Diseases |
Medication |
Risk factors for gallbladder stone diseases.
Age is an important factor for the stone formation, with increase in age enzyme 7 α hydroxylase (Limiting enzyme for bile acid synthesis) activity decreases which increases the saturation of cholesterol in bile and hence increasing the chances of stone formation [24].
Various genes are linked with increased susceptibility of gallstones like Lith genes identified in mouse models [25]. Two variants of ATP binding Cassette transporters ABCG5-R50C and ABCG8-D19H [26]; 3 variants of Farnesoid X Receptor gene (FXR) (rs 35724, rs 11110358, rs 11110386) [27]; polymorphism of apolipoprotein E4 allele [28]; mucin genes [29]; fibroblast growth factor receptor 4 (FGFR4) [30], polymorphism in CCK 1-R gene [31] are linked with cholelithiasis. The genetic factors are responsible for 25–30% of symptomatic gallstones as inferred from twin studies [32]. Gene expressions are affected by environmental factors and gene-environmental interactions through epigenetic mechanisms [33] also involving fat storage and insulin resistance [34]. These factors primarily include micro RNAs [35] Viz. 114 miRNA [36], miR-122 [37].
Females are having a higher risk factors due to various reasons for cholelithiasis such as higher oestrogen levels naturally [38], multiparity [39] and ingestion of oral contraceptives containing oestrogens [38]. Females also tend to undergo cholecystectomy procedure more than males [40].
Ethnicity plays an important non-modifiable role in cholelithiasis as few ethnic groups are having higher incidence of having gall stones as in North American Indians (73% among women more than 30 years old within Prima Tribe) [14], American Indians (men 29.5%, women 64.1%) [41]. Prevalence of Gallstone and Gallbladder Cancer are co-related and effects certain indigenous population like South America & North India, especially younger population [42].
Risk of deaths from gallbladder cancer and other malignancies has been observed to be seven times more in tribal members with gallstones [43].
The co-relation between lipids and cholesterol stone formation is complex, multi factorial and is dependent on other factors also as few studies are in favour and few showing inverse relationship [14]. Few studies show high LDL [44], high cholesterol [45], low HDL [46] are associated with higher gall stone formation which seems to be evident but other studies show there are having inverse relationship with gallstone formation like low HDL, high cholesterol and high LDL [14].
Cholesterol gallstones are associated with western diet [47]. Multiple studies have shown high carbohydrate intake couples with high glycemic load [48], chronic hypernutrition [49] fibre depleted diet [50] are associated with higher risk for cholelithiasis in process which are associated with decreased risk are intake of in saturated fat [51], coffee [52], fibre [53], fish oil [54], calcium [55], ascorbic acid [56], fresh fruits and vegetables [57] and nuts [51].
Obesity is itself risk factor for cholelithiasis. It has been shown that an obese women (BMI ≥ 30 kg/m2) has two fold and morbidly obese women (BMI ≥ 45 kg/m2) has seven fold higher risk for cholelithiasis as compared to lean women (BMI < 25 kg/m2) [58].
Rapid weight loss i.e., >1.5 kg/week and or loss of body weight >25% [59] are risk factors for cholelithiasis which usually occur after bariatric surgery. Weight loss has also been found to reduce risk of gallstones except when rapid loss occurs.
Physical activity decreases risk for cholelithiasis [60] as it improves hepatobiliary funtions, gut motility [61], increasing HDL [62], improves insulin release and plasma triglyceride levels [63]. An endurance exercise (cycling and running) 5 times per week for 30 minutes daily decreases risk by 34% for cholelithiasis [64] or 2–3 h/week of recreational exercise decrease risk by 20% for cholecystectomy [60]. While as reduced physical activity increases risk for cholelithiasis [64].
Various diseases increase the risk for cholelithiasis as these work by different mechanisms like causing abnormal gallbladder motility, malabsorption of bile salts, decreased bile salt synthesis [65], increasing bile cholesterol saturation [66], supersaturation of bile and increased hepatic cholesterol secretion [67]. Different diseases increasing risk for cholelithiasis viz. metabolic syndrome, dyslipidaemia, diabetes (2–3 fold [68]), insulin resistance or hyperinsulinemia [69], chronic hepatitis C virus [66], liver cirrhosis (25–30% increased risk [65] and Chron’s disease [70].
Both these habits have controversial results from various studies some favouring and others refuting association with cholelithiasis.
Men consuming alcohol 0–20 g per day have higher risk than those who consume 20–60 g per day [24]. But few studies show severe alcohol abuse in itself and also led to chronic cirrhosis (pigment stones), which is an independent risk factor for cholelithiasis [71].
Cigarette smoking is another risk factor for gallstones among woman [72], while as few studies refute these claims show no association with gallstones [73].
An imbalance between absorption and synthesis of cholesterol i.e., increased biliary cholesterol secretion from high dietary cholesterol and decreased bile acid synthesis and pool, all driving bile supersaturation [22]. High cholesterol diet and high intestinal cholesterol absorption are two independent risk factors for gallstones [74], regulated by many factors like expression of sterol transport protein [75].
In patients with cholelithiasis there is evidence of altered gut microbiota with increment of intestinal bacterial phylum proteobacteria decrement of
Defective gallbladder motility is another risk factor for cholesterol stones [78]. About one-third of patients with cholesterol gallstones display enlarged fasting and post prandial residual gallbladder volume with delayed emptying which antedates gallstone formation [79]. Sufficient time for cholesterol nucleation and gallstone growth is provided by dysfunctional gallbladder motility [80]. Various conditions are associated with dysfunctional gallbladder motility like insulin resistance, diabetes, irritable bowel syndrome, liver cirrhosis, and so on [81]. There is increase in lithogenic bile secretion to small intestine directly from liver in fasting motility defect, leading to faster recycling of bile acids and increasing bile acid pool hydrophobicity [82]. This is another predisposing factor for cholesterol crystallization and cholelithiasis [83].
Various defects occur simultaneously for the nucleation and crystallization of cholesterol monohydrate viz unphysiological supersaturation with cholesterol, accelerated nucleation and gallbladder hypomotility [16]. The mucin glycoprotein hypersecretion follows and lead to the stone formation [84].
Excessive secretion of cholesterol into bile leads to cholesterol supersaturation [85] owing to multiple biochemical defects either from increased input (de novo synthesis, lipoprotein uptake) or decreased disposition (de novo bile salt and cholesteryl ester synthesis) [84]. However single defects in hepatocellular processing of cholesterol are known viz
Increased number of apolipoprotein B/E and E receptors (constitutional/oestrogens/rapid weight loss/diet)
Increased activity of hydroxy-methyl-glutaryl-CoA reductase (obesity/hypertriglyceridemia/fibric acids)
Diminished activity of cholesterol 7α-hydroxylase (constitutional/fibric acids)
Diminished activity of Acyl CoA: cholesterol acyltransferase (constitutional/progestogens) [86]
These changes resulting in the increased levels of cholesterol in microsomes [87] and cytosol [88] of hepatocytes in patients with gallstones. Sterol carrier protein 2 concentration also increases simultaneously [89].
At puberty hypersecretion of cholesterol into bile begins [90]. In liver excess cholesterol is delivered to bile by a relay station [91]. Postprandially the cholesterol is completely micellized by bile salts and lecithin during healthy condition [92]. Cholesterol molecules are absorbed by gallbladder mucosa efficiently from micelles of supersaturated bile [93] where the activity of acyl coenzyme A: cholesterol acyl transferase esterifies the sterol [87]. But the molecules that remain free are dissolved in plasma and intercellular membranes where they become intercalated with and stiffen the phospholipid molecules [86]. Reverse diffusion when gallbladder bile become unsaturated or esterification is the only means of escape of membrane cholesterol as gallbladder mucosa does not produce cholesterol [92].
The abnormity in diurnal variation of gallbladder bile due to hypersecretion of cholesterol lead to the further trapping of excess free cholesterol molecules into gallbladder mucosa and muscle membranes [94]. There occurs the divergence of hepatic bile into gastrointestinal tract due to impaired motor and mucosal functions of gallbladder [95]. This in turn lead to increased bacterial catabolism and turnover of primary bile salts [92], which ultimately increase the production of secondary bile salts (hydrophobic bile salts) and suppress de novo bile salt synthesis [96].
Rapid recirculation and hydrophobicity are harmful for the stability of bile as these lead to the augmentation of secretion of cholesterol and hydrophobic lecithin molecules, which in turn shorten the time of nucleation of supersaturated bile [91]. The hydrophobicity of bile salt pool also increases secretion of total proteins into bile [97] and also altering the ratio of pro and anti-nucleating activities for cholesterol crystallization [97]. Multiple stimuli trigger mucin glycoprotein hypersecretion like cholesterol in itself [87], ‘cytotoxic’ filamentous cholesterol crystals [98], prostanoids [99], and hydrophobic bile salts e. g Deoxycholate and lithocholate conjugates [100]. This lead to the development of mucin gel on gallbladder wall and then as a crescent in gallbladder lumen, setting stage for accelerated nucleation. This together with hypomotility lead to its accumulation as biliary sludge, failure of complete evacuation of which lead to gallstone formation [84]. However, the end result may become inevitable by an environmental perturbation that inauspiciously tips the delicate pathophysiological and physical-chemical balance of supersaturated bile towards nucleation and stone growth [86].
Black stones occur in sterile environment [101] with increased frequency in patients of chronic haemolysis. A shift in ratio of bilirubin diconjugates to the favour of monoconjugates especially monoglucuronides occur due to hypersecretion of bilirubin conjugates in bile [102]. Bile pigment output increases by 10-fold with haemolysis [102] and predominantly becomes monoconjugates that are more hydrolysed by endogenous β glucuronidase [101]. This gives rise to very high levels of unconjugated pigment exceeding biliary solubility [101]. The insoluble acid calcium salt [Ca (HUCB)2] forms at pH values typical of gallbladder bile [103]. Unphysiological supersaturation occurs with an elevation in the ion product of calcium and monoacid species of unconjugated bilirubin [101] facilitating factors like in cholesterol stones are important for stone formation. The prevalence of pigment stones increases with age and is gender dependent; and all haemolytic patients does not develop pigment stones [101]. In experimental studies it was shown that there is no gallbladder motility defect in black pigment stone formation [104]. However, mucin hypersecretion occurs [105] in response to the high levels of unconjugated bilirubin [106] or mucosal cell cytotoxicity of earliest precipitates [107]. Nucleation is initiated at glandular crypts of gallbladder mucosa where mucin gel accumulates first [107]. Biliary supersaturation (owing to defective acidification of hepatic bile [101] with organic salts occur which is indicated by presence of crystalline calcium carbonate and phosphates in black pigment stones [101]. 3–20% of black pigment stones are composed of mucin glycoprotein [108]. Various factors came into play and through different mechanisms give rise to pigment stone formation in alcoholic cirrhosis, ileal dysfunction and in aging Viz bile salt hyposecretion, defective solubilization of unconjugated bilirubin, impaired calcium ion binding, haemolysis, defective bilirubin conjugation [101], enteric hyperbilirubinobilia [86].
Chronic anaerobic infection with functional stasis of bile ducts is necessary for brown pigment stones. Stasis in bile duct occur due to secondary stones from gallbladder, or due to sphincter of Oddi dysfunction or parasitic infections (mostly underdeveloped countries) [84]. Commencing with stasis of bile and then followed by anaerobic bacterial infection lead to accumulation of both mucin gel and bacterial cytoskeleton in bile ducts. Bacterial enzymes (phospholipase A, β glucuronidase) hydrolyse the biliary lipids that contain amide or ester linkages which results in the nucleation of cholesterol monohydrate crystals A trap is laid down in the form of culture medium for anaerobic bacteria by mucin gel and solid components making their exit difficult. This is a vicious cycle formed between growing stone, stasis of bile and bacterial infection [84, 109].
Anal fistulas, especially complex anal fistulas, still present a challenge for surgeons because of their high recurrence rate, possible postoperative risk of fecal incontinence and also the fact that nowadays we still do not have a standardized procedure of choice for treatment.
An anal fistula is defined as an abnormal communication between perianal skin and anal canal, filled with granulation and fibrotic tissue that supports chronic inflammation, disabling spontaneous healing. Most fistulas are of cryptoglandular etiology, but can also be associated with inflammatory bowel disease (Mb Crohn), malignancies, trauma, pelvic sepsis or diverticulitis. Incidence of the disease is about 10 cases per 100,000 individuals with a male to female ratio of 2:1 [1, 2].
In the past, various classifications for anal fistulas were proposed. One of the most widespread classifications was Parks’ classification which classified fistulas according to their correlation with anal sphincter complex and divided fistulas into intersphincteric, transsphincteric, suprasphincteric and extrasphincteric [3].
Surgeons noticed, using traditional surgical techniques such as fistulotomy, fistulectomy or cutting seton, frequent continence disturbance following operations, especially in cases when fistula tract passed through deeper parts of sphincter complex and internal fistula opening was positioned more proximally in the anal canal.
To simplify classification and to prevent possible postoperative continence disturbance, colorectal surgeons nowadays mostly use simple classification which divides fistulas into two groups: simple and complex, according to the relation of the proportion of the anal sphincter mechanism they pass through. The classification that distinguishes simple and complex anal fistulas helps the surgeon to avoid using traditional techniques to prevent possible continence disturbance, but does not help in the decision which operative technique is best to use in the treatment of complex fistulas. Classification by Garg is extrapolated from multiple clinical scenarios and presents a better correlation with an actual patient case (Figure 1).
Garg classification of anal fistulas (with permission of Dr. Pankaj Garg).
Simple anal fistulas have only one tract that crosses less than 30% of the anal sphincter complex and can be treated by fistulotomy or fistulectomy with very low postoperative continence disturbance incidence and high healing rate.
All other fistulas are classified as complex. These fistulas cross the anal sphincter at a point that encompasses more than 30% of the external anal sphincter. They can have multiple tracts. Complex fistulas also include those about inflamatory bowel disease (IBD), those which are anteriorly positioned in female patients or those which are recurrent. If those fistulas are treated with fistulotomy or some other traditional technique, it can result in some type of postoperative fecal incontinence. The average rate of continence disturbance, such as flatus or liquid stool leakage following fistulotomy, was observed in 20–25% cases and up to 12% cases after cutting seton treatment [4, 5]. This effect on continence has resulted in traditional surgical techniques being less favorable for complex anal fistulas treatment and the incentive to use minimally invasive sphincter sparing techniques is increasing.
In anal fistula treatment, it is important to apply an appropriate surgical approach to obtain the best postoperative results such as high primary healing rate, low postoperative pain, low risk for any type of fecal incontinence, low recurrence rate and to subsequently increase postoperative patient’s life quality.
To delve into the intricacies of anal fistulas, one must first understand hypotheses that currently exist. The most widespread hypothesis is the cryptoglandular one which states that infected or inflamed anal glands are the cause of anal abscess and fistula [6]. This could be due to the ascending inflammation originating in the anal canal or blockage of discharge. Over almost 150 years, much research was done to find out exact relationship between anal glands and anal fistula, and while some researchers found them to correlate, others weren’t even able to prove the existence of anal glands or found them to be very variable at best [7]. Nevertheless, this is the predominant theory that surgeons adhere to throughout the modern surgery era, and anal glands seem to be the likely culprit. Despite this, etiology remains uncertain or unknown, but the inflammatory process seems to play a crucial role.
From the anatomical standpoint, it was stated by Parks that anal fistula is the chronic manifestation of anal abscess that is an acute condition. Fistula forms as a consequence of the medio-lateral spread of infection that subsequently may perforate the anal sphincter complex and extend to the perianal skin, thus forming a fistula [3]. More recently, Garg has shown that intersphincteric space plays a major role in anal fistula pathology, stating that almost all complex fistulas have some degree of intersphincteric involvement and that fistula in closed intersphincteric space acts like an abscess and must be treated accordingly [8, 9].
Molecular analyses of an anal fistula are scarce. One study has shown abundant expression of pro-inflammatory cytokine IL-1b in 93 % of the cryptoglandular anal fistulas, along with increased levels of cytokines IL-8, IL-12p40 and TNF-α in anal fistulas [10]. IL-1, especially IL-1β are strong pro-inflammatory cytokines that can be stimulated by other cytokines, microbial products and even IL-1β by auto stimulation, which can play a role in the recurrence or persistence of anal fistula. Tozer et al. showed immunological differences between cryptoglandular and Crohn’s disease-associated fistula [11]. While those are undoubtedly valuable findings that advance our understanding of anal fistula pathology, they still don’t change anything in our management of this problem.
To achieve best results, accomplish a higher primary healing rate, prevent recurrence and risk of postoperative continence disturbance, it is essential to identify the entire course of fistula tract including infected anal gland in intersphincteric space, main and possible secondary tracts. In that way, one can decide which surgical option is best for the patient.
After performing DRE, additional usage of the metal probe with insertion through fistula canal should be done to identify which type of fistula patient has so one can decide which surgical option should be performed. In case of pain, this can be performed under anesthesia (EUA: examination under anesthesia) [12]. In the case of a simple anal fistula, it is usually sufficient to examine as mentioned above, but in cases of a complex anal fistula in most cases, additional diagnostic methods should be done.
Some diagnostic methods that have previously been used to verify the course of fistula tracts, have since been abandoned. One of these techniques is X-ray fistulography. This technique is not performed anymore because it does not show the correlation of the fistula tract to the anal sphincter complex, so in that way, surgeon does not know which type of anal fistula the patient has [13].
Possible options to verify the correlation of the fistula tract with anal sphincter complex are: CT fistulography, endoanal ultrasound (EUS) and MRI fistulography.
CT fistulography can be more accurate in cases associated with acute inflammations and abscesses, but it somewhat deficient in cases of mature anal fistula.
Endoanal ultrasound (EUS) is a very good option to verify fistula tract correlation with sphincter complex and possible secondary branches but it is a highly operator-dependent technique [14, 15, 16].
For now, the golden standard for anal fistula diagnosis and classification is magnetic resonance imaging (MRI). MRI helps not only to accurately demonstrate disease extension but also to predict prognosis, make therapy decisions and can be used in some cases in follow-up periods especially in the patient suffering from Crohn´s disease or recurrent fistula (Figure 2) [16, 17, 18, 19, 20, 21].
MR fistulography clearly shows horseshoe fistula on axial view.
One other possibility in the verification of main fistula tract and possible secondary branches is using fistuloscope during the diagnostic phase of VAAFT procedure (video-assisted anal fistula treatment) but the technique can also be considered as operator-dependent [22]. VAAFT procedure will be discussed later in this chapter.
It is stated that the ideal treatment for anal fistula lies on two principles. The first is the eradication of sepsis and promotion of fistula tract healing, and the second is preserving the sphincter complex and continence mechanism [23]. With simple fistulas, this can be achieved by laying open the fistulous tract with high healing rates and with no significant continence disturbance [24]. While simple fistulas have simple treatment solutions, the concept of treatment for complex fistulas is somewhat different, and while the above-mentioned principle holds, certain aspects should be explained.
Colorectal surgeons’ postulate that internal fistula openings should always be identified and closed. This was shown in a meta-analysis by Mei et al. with class I evidence for significant association between anal fistula recurrence and failure to identify and close internal fistula opening. The same meta-analysis also showed the connection between horseshoe fistula extensions and recurrence [25]. Both of these problems could be solved by applying video-assisted approach in treatment. This covers the first principle.
To achieve the second principle in complex anal fistula, sphincter preserving techniques should be used to address the anal continence problem. Currently, no study compares lay open techniques and sphincter preserving techniques for complex anal fistula treatment but other studies have shown that, in this case, lay open techniques have an unacceptably high incidence of continence disturbance, up to 25% [4]. Meanwhile, sphincter preserving techniques for complex fistulas, with the possible exception of rectal advancement flap, have shown to have no or only minor continence disturbances in up to 1.7% patients [26].
A somewhat different approach, arising from analysis of modern sphincter preserving techniques, to the ideal treatment of anal fistulas was described by Garg. He hypothesized that in order to successfully heal anal fistula, we should bear in mind three principles:
Intersphincteric fistula tract acts like an abscess in closed intersphincteric space.
Second principle follows the first: intersphincteric fistula must be drained and continuous drainage should be ensured.
Healing occurs progressively until interrupted irreversibly by a collection [9].
This may be the reason why most sphincter preserving treatment methods still do not have healing results comparable to lay open techniques.
When talking about traditional techniques in anal fistula treatment we refer to fistulotomy, fistulectomy or techniques with seton placement in the anal fistula canal. Even since Hippocrates, there have been advices and different references on how one should treat anal fistula [27]. Traditional techniques were used in the treatment of anal fistula during history, before the development of sphincter preserving techniques.
Fistulotomy as the oldest, simplest and most widely performed procedure in anal fistula treatment has its benefits and drawbacks. This procedure, with its synonym “lay open technique,” is quite a simple procedure in which the surgeon, after insertion of the metal probe, cuts (or lays open) the whole of fistula tract from the internal fistula opening which is located in the anal canal to the external opening situated on the perianal skin. Following this, the surgeon performs curettement of granulation tissue from the fistula tract remnant making, in a sense, an acute wound that should heal by secondary intention. Some surgeons perform additional marsupialization of wound edges the following fistulotomy to reduce postoperative bleeding and to speed up wound healing (Figure 3) [28].
Fistulotomy with marsupialization (shown by red arrows).
In this way, crucial postulates in anal fistula treatment are satisfied, except the preservation of anal sphincter complex to a lesser degree. Even though this procedure has a success rate of more than 90%, it is also associated with some type of postoperative continence disturbance in cases when the fistula tract crosses through deeper parts of the anal sphincter complex and when the internal fistula opening is placed more proximally in the anal canal. The incontinence rate following these procedures vary given the heterogeneity of anal fistulas, but can be up to 28% [4, 29].
In recent times, according to Garg’s classification, this technique should be only reserved for treatment of type 1 and 2 anal fistulae without risk of continence disturbance, meaning low intersphincteric and low transsphincteric fistula (simple anal fistula) [30].
Fistulectomy is performed by excising the whole of fistula tract, removing in that way the whole fistula tract from external fistula opening to internal fistula opening, without preservation of anal sphincter complex. In a meta-analysis that included 565 patients comparing fistulectomy and fistulotomy for low anal fistulas, there has been no conclusive evidence as to which procedure is better in simple anal fistula treatment [31].
Failure of treatment with fistulotomy of fistulectomy and recurrence is associated with inappropriate selection of patients with high anal fistulas or those with multiple tracts.
The seton placement technique distinguishes between “cutting” and “loose” seton.
Cutting seton technique is nowadays almost abandoned but was used to convert high anal fistula to low one which was later treated by lay open technique. Seton was made of unabsorbable material, placed through the anal fistula canal and then tightened enabling in that way slow cutting of the sphincter mechanism leaving behind a scar. The idea behind the technique was that it would prevent anal sphincter muscle to split and, in that way, to prevent serious problems with continence disturbance. It was proven however, that this technique has a high incidence of continence disturbance with high morbidity and recurrence rates [5].
When talking about the role of loose seton the situation is somewhat different. Loose seton should be placed through the fistula tract without tightening, helping in that way to reduce sepsis and to mature the fistula tract. This would be the first stage in resolving of anal fistula problem. Many surgeons advocate loose seton placement as an important step of rectal advancement flap procedure or LIFT (ligation of intersphincteric fistula tract) prior to that operation, even though there has not been clear clinical evidence [32, 33]. Seton placement before fistulotomy with sphincter reconstruction has shown its benefits in fistula treatment, namely in converting high transsphincteric to low transsphincteric fistula and also in the acute abscess stage before this procedure to reduce the risk of breakdown of sphincter repair [34].
As mentioned earlier, the high risk of postoperative continence disturbance after treatment of complex anal fistulas with traditional techniques, have led to the need for the development of new techniques, which would be dubbed “sphincter preserving techniques.” The main characteristic of such techniques is that they prevent or greatly reduce any possibility of postoperative fecal incontinence. Various sphincter preserving techniques were introduced in clinical practice in the last 10–15 years. Among these are laser treatment procedure (FiLaC®: fistula laser closure), fibrin glue treatment, anal fistula plug, VAAFT procedure (video-assisted anal fistula treatment), LIFT procedure (ligation of intersphincteric fistula tract), anal fistula treatment with platelet cells (PRP: platelet rich plasma), RAF (rectal advancement flap) and others. [22, 33, 35, 36, 37, 38, 39, 40, 41, 42].
Some sphincter preserving techniques weren’t broadly accepted given high cost, high recurrence rates or inability to reproduce similar results in other centers. Of above-mentioned sphincter preserving techniques, several gained wider acceptance, such as LIFT, VAAFT, and RAF technique.
Ligation of intersphincteric fistula tract (LIFT) is a sphincter preserving technique first performed and published by Rojanasakul [39]. This technique satisfies all goals of anal fistula treatment such as the closure of internal fistula opening, removal of infected intersphincteric fistula tract (anal gland) and eradication of remaining fistula tract. It is reserved for the treatment of complex transsphincteric anal fistulas. After identification of fistula tract using metal, probe surgeon makes a curvilinear incision on the anocutaneous border entering intersphincteric space and performs preparation of intersphincteric part of anal fistula, followed by removal of the intersphincteric portion of the fistula. Closure of remaining defect of anal fistula on internal and external anal sphincter muscle then follows. Curettement of remaining fistula tract from external fistula opening to external anal sphincter muscle should be performed. Intersphincteric space is then reconstructed and the perianal wound sutured.
According to the two available meta-analyses, this procedure gives an overall success rate of 76.4 and 78 % respectively, with a low complication rate 5.5–13.9%. The most common complication was wound dehiscence, and others were bleeding, infection, hematoma, anal discharge. Only a low grade of postoperative fecal incontinence in 1.4% of patents was recorded (Figure 4) [33, 43].
LIFT procedure: identification of fistula tract in the intersphincteric plane; red arrow showing fistula tract.
This technique is easily reproducible without the necessity of investment in potentially expensive equipment. In case of dehiscence of intersphincteric space loose seton can be inserted through the intersphincteric wound, thus making conversion of transsphincteric fistula in intersphincteric one, which can be afterward treated by fistulotomy without fear of continence disturbance.
Video-assisted anal fistula treatment (VAAFT) procedure is the only technique that enables visualization and operation of anal fistula from within fistula tract, using specially designed equipment. This sphincter preserving technique was developed by Meinero who described short and long-term results [22].
Using a special instrument (fistuloscope), the surgeon visualizes the fistula tract from inside, which helps to identify possible secondary branches of the fistula tract, abscess cavities and later destroys all chronic granulation tissue in the fistula tract making in that way an acute wound which should heal by secondary intention. The important part of this technique is also to identify the internal fistula opening inside the anal canal and to close it securely (Figures 5–9).
Intraoperative view of the fistula tract through fistuloscope.
Fulguration of the fistulous tract.
View of the debris after fulguration.
Postoperative view after VAAFT for complex horseshoe fistula.
Healed wounds in the same patient.
Many surgeons worldwide accepted this technique in their everyday practice for the treatment of complex anal fistulas [22, 38, 44, 45, 46].
The main indication for this technique is the treatment of complex anal fistulas, especially cases with multiple secondary branches which are deep in the ischioanal fossa and are not easily reached. Also, VAAFT has its benefits in treatment of patients who have anal fistula associated with Crohn’s disease, helping to ameliorate symptoms associated with chronic anal fistula such as pain and soiling, thus significantly increasing patient’s quality of life [44, 47]. VAAFT technique is comparable with other sphincter preserving techniques to healing and patient satisfaction. Diminished postoperative pain, earlier recovery after surgery and smaller postoperative perianal wounds allows for earlier return to normal activities [48].
In case of failure, this technique can be repeated because there is no risk for any continence disturbance following this procedure. The proposed mechanism whereby repeated procedures have an incremental effect is the conversion of complex fistula with multiple tracts into a more manageable, low or simple fistula, which can be called conversion of the fistula. [38]
VAAFT technique has been proven to be a safe procedure, associated with good functional outcomes and a very low incidence of complications [22, 44, 45], which was shown in a published meta-analysis [46]. It showed a recurrence rate ranging from 7.5 to 33.3% with a weighted mean recurrence rate of 17.7%. Recurrence rates varied significantly depending on the method of internal fistula opening closure (mattress suture, stapler, rectal advancement flap). No affection of anal continence was documented.
This technique is one of the oldest techniques which were and still are reserved for the treatment of complex anal fistulas especially in cases with large internal fistula opening. When discussing this technique, we can’t talk about the “pure” sphincter preserving technique because flap should be performed by dissection of anorectal mucosa and adjacent internal anal sphincter muscle, so in that way, internal anal sphincter muscle does not stay intact.
When doing this procedure surgeon should identify and excise the internal fistula opening in the anal canal. Then the U-shaped or rhomboid flap with a wider base side should be performed by dissecting anorectal mucosa and adjacent internal anal sphincter muscle. Curettement and irrigation of the whole fistula tract should be performed, followed by suture of a defect in sphincter complex left by earlier fistula tract. The site is then a covered by previously prepared flap and sutured. Even though much research has been made about optimal flap thickness, researchers found that there was a statistically higher rate of primary healing in cases with thicker flaps, but also have noticed a higher rate of mild postoperative continence disturbance which was more severe than the thicker flap was (Figure 10) [41, 49, 50].
Formed rectal advancement flap.
There have been many publications and several systematic reviews and meta-analyses on this technique where the effectiveness was shown to be 60–80%, but the same cases also reported some degree of postoperative fecal disturbance [42, 50, 51].
Factors that could affect healing after flap procedure are obesity and smoking, so patients should be advised to quit smoking and to try to reduce their weight prior to flap operation [52, 53, 54]. To increase the effectiveness of this technique one should perform bigger rhomboid or U-shape flaps using the minimally invasive approach, avoiding tissue trauma made by surgical cautery, avoiding excessive grasping as well as the too big strain of suture line.
As mentioned earlier in this chapter, there is no universal approach for anal fistula treatment. Some other possible solutions may be hybrid sphincter preserving techniques, fistulotomy with primary sphincter reconstruction, TROPIS (trans anal opening of the intersphincteric space) and use of autologous platelet rich plasma in anal fistula treatment.
Hybrid sphincter preserving techniques are combinations of two or more sphincter preserving techniques in a single procedure to increase healing rates and achieving better results.
Several reports exist with different combinations of techniques with authors trying to achieve higher healing rates, but the majority of reports are on a single institution basis or case reports with a small number of patients.
A combination of VAAFT and LIFT techniques was performed with intention of secure closure of internal fistula opening from intersphincteric space and additional exploration and eradication of remaining fistula tract from external fistula opening with identification of possible secondary branches using fistuloscope [55, 56]. VAAFT was also used in different combinations with other sphincter preserving techniques such as FiLaC® procedure and with RAF procedure in cases with large internal fistula opening [38, 44, 57].
The combination of LIFT technique with the insertion of a bioprosthetic graft in intersphincteric space was also described in a study that included 31 patients, where the success rate was 94% in a one-year follow-up period [58]. Another study combined LIFT and human acellular dermal matrix as a bioprosthetic plug with a reported success rate of 95% on a 21-patient sample [59]. Rectal advancement flap with the injection of porcine dermal collagen implant through the external opening was combined in a study which included 24 patients with a success rate of 82.5% in a 14-month follow-up period [60].
It was to be expected that surgeons started to combine two or more sphincter preserving techniques to achieve better results, but until evidence is found that one technique, or combination of techniques, has significantly better results over the others, they should be tailored individually depending on patient’s case.
This approach in the treatment of anal fistulas has the same operative philosophy as fistulotomy or fistulectomy, but is reserved for higher fistulas. In this procedure surgeon after eradication of the fistula tract and possible secondary fistula branches to prevent recurrences, makes additional anal sphincter reconstruction to try to eliminate the possibility of postoperative fecal incontinence. Ratto et al. reported a 93.2% overall success rate with a low morbidity rate using this approach. Overall postoperative fecal incontinence was 12.4% mainly post-defecation soiling, without significant changes in anorectal manometry parameters [61]. Voon et al. reported their experience in using this technique and had good outcomes with a very low rate of continence disturbance in follow-up period [34]. Even though this technique has been implemented in guidelines for anal fistula treatment by several surgical societies, it wasn’t accepted worldwide as the standardized procedure [62]. In case of abscess formation as the initial presentation, it is crucial to place seton drainage to give enough time for maturing of the fistula and to prevent continence disturbance following fistulotomy.
This technique was described and published by Garg, who used this approach in the treatment of high complex anal fistulas with a high primary healing rate and very low incidence of morbidities [8]. It is well known that high intersphincteric parts of anal fistula and abscesses are difficult to reach through intersphincteric approach or probing from external fistula opening, as well as that they are usually branching.
TROPIS approach also satisfies golden principles in the treatment of anal fistula such as identification and resolving internal fistula opening problem, as well as intersphincteric fistula tract with the accompanying anal gland, and also eradication of remaining fistulous tract by curettement.
The procedure is done by laying open intersphincteric space through internal anal with preservation of external sphincter. The external tracts in the ischioanal fossa should be curetted and the intersphincteric space is left open for secondary healing. In the initial prospective cohort which included 61 patients, the success rate was 84.6% with no significant changes with continence. The study included patients with high transsphincteric (anterior and posterior) and high intersphincteric type of fistula [8].
TROPIS procedure is an excellent approach for posterior high transsphincteric type and high intersphincteric type of anal fistula, especially if transsphincteric fistula is located at the puborectalis level. However, combination with drainage (preoperative seton placement and postoperative drain placement in remaining tract from external fistula opening), curettement or excision of external tracts is necessary to reduce recurrences.
Autologous platelet rich plasma (APRP) is nowadays used in various fields of medicine such as orthopedics, plastic surgery, dental medicine, but also in the treatment of anal fistula in the last decade. APRP is platelet concentration derived from centrifuged full blood after removal of red blood cells. Such prepared plasma is a rich source of various growth factors implicated in regeneration and tissue healing [63, 64].
The procedure consists of curettement of fistula tract and closure of internal fistula opening with an additional injection of previously prepared platelet rich autologous blood sample [65]. The majority of publications combined mucosal advancement flap with APRP injection [65, 66, 67]. Several publications reported an average healing rate from 60 to 90% [40, 66, 67, 68]. The drawbacks of mentioned publications were that they had a relatively small number of patients enrolled and still no meta-analyses exist on the subject. No problem with any type of postoperative fecal incontinence was reported. This is still considered to be a somewhat experimental procedure and is not widely used. The platelet separation procedure requires special equipment that is often only available in larger institutions. Also cost per patient exceeds that of the other techniques, which is why this technique needs more solid evidence for a patient benefit before it can be considered to become one of the mainstream sphincters preserving treatments.
We can say that fistulas associated with Crohn’s disease present a special entity in the treatment of anal fistulas. This kind of fistula presents a huge challenge for surgeons despite numerous surgical possibilities and technical advancements in recent years. Symptoms associated with Crohn’s anal fistula include purulent drainage, severe pain, possible continence disturbance which all can lead to a significant reduction in quality of life. These kinds of fistulas are often recurrent and hard to treat. The incidence of anal fistulas in patients with Crohn’s disease is 5 to 40% and is more common in patients who have a higher severity of colorectal inflammation [69, 70, 71].
Even though numerous surgical techniques have been described for the treatment of this kind of anal fistulas, the choice of which technique is best often depends on the anatomy, presence of local inflammation, type of fistula, and surgeon’s experience (Figure 11) [72, 73, 74].
Perianal form of Crohn’s disease in female patient: multiple treatment methods combined (fistulotomy with marsupialization, seton placement, VAAFT).
Many management proposals have been published, but all had higher reports of postoperative complications such as continence disturbance, infection and high recurrence rate compared to the same type of fistulas not associated with Crohn’s disease. Currently, numerous novel surgical sphincters preserving techniques are being studied to less invasively induce fistula healing while maintaining fecal continence. When we discuss surgical treatment of complex anal fistulas in Crohn’s disease, the goal should be to ameliorate symptoms associated with this kind of fistulas and to improve patients’ quality of life. Although, various endoscopic and surgical techniques exist, there is no gold-standard treatment strategy for patients with perianal fistulas [44, 47, 75, 76].
Treatment of Crohn’s disease-associated anal fistula should always be multidisciplinary including surgeons, radiologists and gastroenterologists with the use of antibiotics, immunosuppressors and anti-inflammatory agents [77, 78, 79, 80, 81].
General principles in the treatment of this condition are underlined here, but the treatment of an anal form of Crohn’s disease is a complex topic, requiring a chapter on its own.
The problem of anal continence presents a big obstacle when trying to treat anal fistula. It is of paramount importance to avoid any continence disturbances which in itself presents a hurdle to implementing more successful but invasive procedures regarding the anal sphincter mechanism. The solution might lie in a relatively new paradigm that puts intersphincteric space as a likely culprit to fistula recurrence or nonhealing, and subsequent shift in surgical approach. These new approaches still require multicentric verifications to be implemented as a mainstream treatment option.
Overall, novel approaches in anal fistula treatment, while not entirely successful in all of the patients, offer a significant increase in patients’ quality of life, and allow for repeated surgical procedures if the initial operation fails at no expense on the anal sphincter.
While various researchers made different molecular research on anal fistula that increased our understanding of fundamental pathologic mechanisms, still no findings translate into clinical practice in the sense that they made any difference on already existing surgical approaches.
The most widespread classification of fistulas are somewhat inadequate and do not transfer well to clinical situations. Parks classification may describe the relation of the anal fistula to anal sphincter muscles but does not distinguish between simple and complex fistulas. St. James University Hospital classification also doesn’t seem relatable to the clinical situations in the era of sphincter preserving techniques. A possible solution to this may be Garg classification that still needs confirmatory commentaries from other colorectal surgeons and proctologists.
Anal fistulas in Crohn’s disease present a different challenge. With current surgical solutions, we cannot hope to cure the condition but rather to ameliorate symptoms. Medical therapy in combination with surgical solutions can significantly reduce the severity of the disease and even hope to eradicate it completely.
The anal fistula condition remains a daunting task for the surgeon and a strenuous malady for the patient. Even though recent years brought advancements in the form of sphincter preserving techniques, which greatly improved treatment options, still no golden standard for anal fistula treatment exists. This problem still seems unlikely to resolve given the heterogeneity of pathology unless a radically different approach or breakthrough isn’t achieved.
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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. 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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:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 12th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!0,editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",slug:"tomas-jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",biography:"Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his Ph.D. degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his D.Sc. degree. His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. He is also a reviewer and a member of editorial boards of a number of international journals.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",slug:"katarzyna-garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",biography:"Katarzyna Maria Garbacz, MD, is an Associate Professor at the Medical University of Gdańsk, Poland and she is head of the Department of Oral Microbiology of the Medical University of Gdańsk. She has published more than 50 scientific publications in peer-reviewed journals. She has been a project leader funded by the National Science Centre of Poland. Prof. Garbacz is a microbiologist working on applied and fundamental questions in microbial epidemiology and pathogenesis. Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. 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