Potential risk factors for neural tube defects (according to [3]).
\\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
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Top 10 mango growing countries of the world [accessed from source: FAOSTAT database, 2014].
The mature tree of many can survive for several hundred years and attain a height of 40 meters or more [20]. The mango fruits from Pakistan are well reputed due to its delicious taste, excellent flavor, and high nutritive values [21]. Mango is providing seasonal job opportunities to most common illiterate and less literate villagers of the countryside; thus it is considered a major foreign currency earning fruit crops of Pakistan. The people from the countryside are mostly engaged in various jobs such as growing and managing the orchards, picking, packing, shipment, and processing of mango fruits. The unripe (green) mango fruits are also processed as powder form or in solar-dried slices, which is used in curies as well as in other cookies. Therefore, in the mango growing areas of Tando Qaisar, District Hyderabad, Sindh, Pakistan, it is believed to be one of the best sources of earning for local people [22].
\nMango is a nutritionally rich fruit with a unique flavor, fragrance, and taste. It is an excellent source of vitamin A with flavonoids like beta-carotene, alpha-carotene, and beta-cryptoxanthin. The research reports revealed that the consumption of natural fruits rich in carotenes is known to protect against oral cavity and lung cancers. In addition, mango fruit is also a rich source of vitamins, minerals, fiber, prebiotic dietary, and antioxidant compounds, thus promoting the benefits for human health. Recent research revealed that the consumption of mango fruit protects against colon, breast leukemia, and prostate cancer [23, 24].
\nIt is also believed that almost every part of the mango plant is used for different purposes. The mango is delighted and liked by everyone for its marvelous flavor and delicious taste. Nutritionally as well as medicinally, mango is known to be a rich fruit. It is consumed raw as well as ripe, thus interestingly no any part is wasted. Raw fruits are sliced, dried, and floured (starch), commonly used for cooking. In addition, unripe fruit can be made into chutneys, drinks, and pickles is considered to be an effective antidote for mild forms of sunstroke, whereas ripe fruits besides being consumed as a dessert are processed into jam, squash, slices, pulp, juices, as a flavoring for baked goods, ice cream, milkshakes, jelly, marmalade, yoghurt, nectar, and mango leather. The kernel contains 8–10% fat which is used in the soap industry, while its starch can be used in the confectionary industry [6, 25].
\nAlmost all the products and by-products made from mango are commonly used and preferred by the people in Pakistan and India. Anacardic acid is prepared from the peels (skin); although the wood quality of mango is poor, timber is used for making furniture, flooring, boats, packing cases, and other applications. Tannins mainly used for curing leather are also obtained from the bark of the tree. The twigs as well as young vegetative leaves are used for various religious purposes and for medicinal value [6, 8].
\nSeveral pests, diseases, and disorders have been recorded on various mango varieties, ultimately resulting in severe loses to all parts of the mango around the world. Approximately 260 pest species including major and minor pests have been recorded from seedlings to mature trees at harvest and postharvest stages [26].
\nMango suffers from several infectious diseases caused by many phytopathogens. More than 83 different diseases and disorders including 52 fungal, 3 bacterial, and 3 plant-parasitic nematodes of the mango tree and fruit have been recorded worldwide which cause losses; however, fortunately no single disease is caused by the virus till now in mango [27, 28]. Twenty-seven diseases have been reported in mango trees of Pakistan [28]. Among them the main diseases are anthracnose,
Anthracnose disease (
Powdery mildew disease (
Mango malformation disease (
Bacterial leaf spot (
Crown gall (
Sooty mold (
Fruit rot (
Root rot (
Dieback (
Gummosis (
Mango sudden decline.
Moreover, mango decline, mango sudden decline syndrome (MSDS), mango sudden death syndrome (MSDS), and mango tree mortality (MTM) are the common terms/phrases used for mango sudden decline disease. In the last decade, MSDS remained the most common and destructive diseases throughout Pakistan. Different workers have isolated various fungi and another organism from an infected mango tree. In a recent study, 21 different species of diseases from infected mango trees have been reported. However, it is a complex problem and actually is a result of anthracnose, dieback, root rot, tip dieback, gummosis, and dying of plants, observed very commonly in the orchards of different ages in Sindh province [22].
\nPlant disease control has always been a challenge for the growers and farmers to get optimum production due to pesticide resistance. Resistance to fungicide in current days is a major threat to plant disease management. In many plant pathogens, resistance could develop naturally; thus, several newly developed chemistries of fungicide remain at high risk. However, research toward the increase of resistance and delay in disease development has been undertaken. The existing fungicide chemistry, sometimes, renamed with new trade name does not satisfy the farmer to apply such fungicides [39] for the management of diseases. It is also obvious that even within the same fungal group the nature of resistance can be different. Fungi may develop alternative biochemical pathways around the ones that the fungicides are blocking. The blocked biochemical pathway may also be overwhelmed by the overproduction of precursors. Fungal cells may develop mechanisms to block entry of the fungicide and/or efficiently export the chemical out of cells. The result manifests itself the same way through disease control failure. An example is benzimidazole fungicides which when first introduced were more effective, and even at lower rates, than anything else on the market. The new systemic nature of the compounds and their broad spectrum of activity encouraged the wide use of these fungicides. These fungicides could control many different fungal diseases including powdery mildews, botrytis blights, leaf spots and blights, and root rots on a large variety of crops. There is even nontarget activity on other organisms including earthworms. Benzimidazole fungicides act by blocking the polymerization of tubulin preventing the nuclear division of fungal cells. The mode of action is so specific within the fungi that simple natural mutations allowed for the development of resistant fungi. The resistance is also very stable within the population. Widespread use of benzimidazole fungicides caused widespread development of resistance. Another example is dicarboximide fungicides which when first introduced were highly effective against diseases caused by
Mango diseases as discussed earlier are sometimes hard to manage due to the pathogen cycle and perpetuation in soil and deep root. Several mango diseases are attacking from seedling to maturity; and pre-harvest to postharvest depends on the environmental conditions of the region. Chemical fungicides are believed to be a significant way to control fungal pathogens [40] or sometimes to inhibit and prevent the development and spread of pathogen [41, 42]. However, due to resistance development in pathogen or sometimes in the environment-development of new physiological races, it is hard to manage the plant diseases. The impacts of fungicide management in some importance mango diseases are discussed here.
\nAnthracnose, caused by a fungal pathogen
The use of fungicides for the management of anthracnose disease has been widely done worldwide. Generally, such kinds of fungicides are used when especially anthracnose is out of control due to wet and humid conditions in most commercial mango production situations [50]. To produce commercial market quality fruit, chemicals such as benomyl, copper, and mancozeb have been sprayed weekly on the flowers and at 2- to 3-week intervals on fruit until harvest [51]. Although some mango cultivars are moderately tolerant, none are sufficiently resistant to be produced without fungicides in humid areas [50]. During rainy seasons numerous preventive fungicide applications in the field are necessary to obtain acceptable fruit production [52]. In extreme situations, where fruit develops completely under disease-favorable conditions, up to 25 sprays of fungicides have been reported. It is also mentioned that fungicides are highly effective for anthracnose control reducing the severity in treated fruit by over 90% [52]. Research in India showed that fungicides reduced the severity from 54% infected fruit to 5% [53]. Research has clearly shown that low postharvest decay is associated with effective protection of fruit throughout the growing season [54]. The fungicides carbendazim, prochloraz, and benomyl tested against anthracnose on 40-year-old mango trees revealed that carbendazim showed minimum disease severity when first spraying was done during the emergence of new flushes; second and third spray applications were made at 15-day intervals. Fourth and fifth spray applications were done before monsoon (June) and after the monsoon (first week of October). Reduction in disease severity with the increased average number of fruits per tree on the third year was recorded after application of fungicides [55]. In a field trial, different doses of systemic fungicide, azoxystrobin at 1, 2, and 4 ml L−1 were evaluated against anthracnose disease. All doses of azoxystrobin suppressed the development of both panicle and leaf anthracnose with more production of fruits than control. The results further showed that 2 ml L−1 proved effective against disease than other doses of fungicides [56]. Recently in Pakistan Nasir et al. [57] evaluated seven different organic and one inorganic fungicides for their effectiveness against anthracnose disease. Three bloom sprays were applied: first at 25% flowering and two later applications at 15-day intervals. Best results were achieved with Nativo 75% WDG (tebuconazole+ trifloxystrobin) which controlled anthracnose by 92.03% and powdery mildew by 90.19%. It was followed by Cabriotop 60% WDG (metiram +pyraclostrobin) which reduced the incidence of these diseases by 89.08% and 88.04%, respectively, whereas Topsin-M 72% WP (thiophanate-methyl), Score 25% EC (difenoconazol), and Shincar 50% SC (carbendazim) provided less than 80% control. In general, all the fungicide treatments significantly reduced the incidence of the diseases and produced a higher yield of quality fruits than control in both years.
\nFungicidal resistance/sensitivity among the six different isolates of
However, in recent years growers have experienced problems controlling this disease, and they have suggested that the fungicides used are not providing acceptable levels of control. Products currently registered for pre-harvest use include mancozeb, copper hydroxide, and copper sulfate products—these are routinely used from flowering through to harvest. Prochloraz is used when weather conditions favor disease development, and a strobilurin product has recently been registered. Thus, an experiment was conducted to develop an integrated crop management (ICM) practice for controlling anthracnose (
Mango powdery mildew disease is caused by a fungal pathogen,
Several organic and inorganic fungicides have been evaluated for their effectiveness against powdery mildew disease. The powdery mildew was controlled by applying different fungicides such as benomyl, bitertanol, carbendazim, dinocap, oxythioquinone, thiophanate-methyl, tridemefon, tridemorph, Vigil, wettable sulfur, etc. [81, 82, 83, 84, 85, 86, 87, 88, 89]. However, some chemical fungicides such as benomyl, dinocap, and mancozeb were set up most operational at the time of flower cluster expansions and before the cluster opening [90, 91, 92]. The higher efficacy of carbendazim against powdery mildew was also proven when sprayed three times with the interval of 15 days [93]. Recently, Topas 100% EC (penconazole) and Vangard 25% EC (triadimenol) were found effective against powdery mildew (89.96% and 91.87%, respectively) [57]. In another experiment, three sprays of penconazole at prebloom, full bloom, and after fruit setting against powdery mildew,
Six fungicides such as carbendazim (Bavistin 50 WP) 0.05%, wettable sulfur (Sulfex 80 WP) 0.25%, triadimefon (Bayletan 25 WP) 0.05%, thiophanate-methyl (Roko 70 WP) 0.1%, penconazole (Topas 10% EC) 0.05%, and hexaconazole (Contaf 5EC) 0.05% went through a 3-year experimentation (2006–2008). All the fungicides reduced the disease significantly when applied at prebloom, 10 days after first spray, and at fruit setting stage compared to the untreated control. However, hexaconazole gave the lowest incidence of powdery mildew (21.2%) and was significant over the rest of treatments except triadimefon [100]. Fungicides mostly are of high efficiency in the management of plant diseases [101]. However, the need for reducing pesticide residues in food crops, pressures to maintain a healthy environment, and often the unavailability of commercially acceptable resistant plants intensify the need for alternative methods for disease control. One of the potential methods of reducing the severity of powdery mildew in an environmentally safe manner is the use of inorganic salts like foliar spray by potassium salts [102, 103] as biocompatible fungicides. Monopotassium phosphate and potassium dihydrogen phosphate sprayed alone or in alternation with fungicides have been successful in the control of powdery mildew diseases in apples, grapes, peaches, nectarines, greenhouse cucumbers, roses, melons, and mangoes [103].
\nIt is apparent that several studies have been conducted and workers used different fungicides successfully in order to control powdery mildew disease of mango accompanied by a high yield/tree [104]. However, fungicide resistant races of powdery mildew pathogens have been reported on several crops like as cucumber, grape vines, etc. [105, 106, 107, 108]. The fungicide Punch was the most effective on mango and mustard when tested to managing powdery mildew disease in India [109]. However, once resistant strains appeared, most of them survived for several years, therefore the risk of re-enhancing a resistant population with further applications of ineffective [110].
\nMango malformation disease (MMD) is a serious threat and is significantly increasing because of the great demand for mango in the international market and expansion of mango production worldwide for export [111]. It occurs in almost all mango growing countries of the world and causes severe economic losses every year [112, 113]. Much more studies are carried out on physiological, viral, fungal, acarological, and nutritional causes [114]. Mango malformation is of two distinct types, vegetative malformation (VM) and floral malformation (FM). The floral malformation is more prevalent in bearing mango trees, whereas vegetative malformation mostly appears on seedlings [115]. MMD causes shortened inflorescence, sterility, and aborted hermaphrodite flowers, and the male flowers increase in number and size [116, 117, 118, 119]. MMD was first reported in India in 1891 [120]. It is found elsewhere in Asia (Israel, Malaysia, and Pakistan) [120], Africa (Egypt, South Africa, Sudan, Swaziland, and Uganda) [121], and Americas [Brazil, El Salvador, Mexico, Nicaragua, the USA, and Venezuela [122, 123]. In Pakistan, Khaskheli et al. [38] confirmed pathogenicity of
Several attempts were made to manage the MMD; however, differences in the reported species sometimes make it difficult to control the extent of MMD. Some research lines indicate that broad-spectrum systemic fungicides are beneficial for the control of the disease [124]. Kumar et al. [125] found that mangiferin metabolites of mango induced changes in isolates of
The sooty mold is a fungal disease caused by
It has already been explained that sooty develops on the exudates of sucking insect pests such as aphids, leafhoppers, mealybugs, psyllids (including eucalyptus lerp psyllid), soft scales, and whiteflies. Both the immature and adult stages of these insects feed by sucking sap from plants, producing honeydew. Their common characteristic is that they all suck sap from plants. Therefore, these pests need serious attention and should be controlled through pesticides.
\nIt is also pertinent to mention that sooty mold-causing fungus is a weak parasite; therefore, sometimes uses of fungicides are necessary to apply. The effectiveness of seven organic fungicides, one synthetic fungicide, bagging of fruits, and the untreated control were evaluated to control sooty mold on leaves and fruit of mango “Manila,” in Veracruz, Mexico. Results showed that the bio-fungicides Bio hcaz 3.5, Bio fyb 1.5, Fungicus ph 4 y Fungicus ph 8 provided 95% of leaves in the categories of healthy and light (less than 5% damage). Percentage of healthy fruits was 98% for bagging, 82% for benomyl, 80% for Sunset 3, and 78% for Sulfocop 4 and Bio fyb 1.5. Bio fyb 1.5 showed good control of sooty mold in leaves and fruits. The application of these organic products did not have a negative effect on the yield and fruits quality [136].
\nMango decline or mango sudden decline syndrome or mango sudden death syndrome or mango tree mortality are some common terms/phrases used for this disease. This remained the most common and destructive disease throughout Pakistan in the recent past years. In actual, MSDS is a complex disease of mango, and several pathogenic fungi were isolated from this complex problem [29, 30, 31, 32, 33, 34, 35, 36, 37, 38]. Different investigators have isolated various fungi and another organism from an infected mango tree. Ahmed et al. [137] reported that the onset of dieback become evident by discoloration and darkening of twigs from the tip downward due to
There have been several attempts to manage this severe outbreak of mango; however, the recovery of the affected tree sometimes could not succeed due to the development of fungi in the vascular system of tree. All reported fungi of MSD are soilborne and cause tree decline or wilt after several years of development. Some studies showed that Topsin-M and Daconil are the most effective fungicides, whereas copper oxychloride intermediate and mancozeb were the least effective in inhibiting the mycelial growth of
Mango dieback caused by
Several attempts are made to control the mango dieback throughout the mango growing countries of the world. In Pakistan, mycelial growth of
Spinal dysraphism encompasses congenital problems that result in an abnormal bony formation of the spine and the spinal cord. This congenital pathology is caused by the maldevelopment of the ectodermal, mesodermal, and neuroectodermal tissues. The spina bifida is a congenital anomaly that arises from incomplete development of the neural tube. It is commonly used as a nonspecific term referring to any degree of neural tube closure. The two dominant types of spinal dysraphism are based on the appearance – spina bifida aperta if the lesion is visible and spina bifida occulta if the lesion is not visible [1]. Common manifestations are meningocele, myelomeningocele, lipomeningocele, lipomyelomenigocele, myeloschisis, and rachischisis [1]. Spinal neural tube defects basicaly exist in two forms – open and closed spinal dysraphism. The most simple form with minimal involvement of nervous tissue is closed dysraphism (spina bifida occulta) where the vertebral defect is hidden. More severe open spinal dysraphisms (spina bifida aperta) mostly represented by meningocele or myelomeningocele result in various degrees of neurological deficit according to affected spine level, extent of lesion and amount of structures involved (Figure 1). In this defect there is a communication between nerve tissue and external environment leading to exposure to amniotic fluid and later leads to high risk of infection. Defect can be covered by a thin membrane. The exposed neural tissue degenerates
Types of spinal dysraphism (public domain, source:
The prevalence of neural tube defects has different rates among different ethnicity, geography, gender, and also countries. The prevalence is higher among Whites as compared to Blacks and females as compared to males [7]. Asia has more rate of neural tube defects than western countries due to low socio-economic status of eastern countries directly affecting the economic burden and negligence over the folic acid as a part of multivitamin supplementation [8]. Worldwide data show place to place-variation of the prevalence rate assumed to be due to low standard health care facilities though the exact mechanism is still unknown. The eastern Mediterranean region exhibited high variability with a swat, Pakistan having 124 cases per 10000 births. The prevalence in the African region ranges from 5.2 to 75.4 per 10000 births, the European region ranges from 1.3 to 35.9 per 10000, and American region ranges from 1.4 to 27.9 cases per 10000. Most WHO member states (120/194) did not have any data on the prevalence of neural tube defects. As the prevalence estimates vary widely, efforts need to be stepped up to monitor neural tube disorders, especially in developing countries. The folic acid supplementation and increasing the quality of the population’s diet are important factors in the prevention [9]. A study from Los Angeles showed that the rate of anencephaly and exencephaly is more than spina bifida. But normally, it is supposed that the spina bifida is more common than anencephaly. Same-sex twins had a higher incidence of neural tube defects as well as higher mortality. The study verifies the same etiology between neural tube defects and monozygotic twins. The main role here is played by the common susceptibility to environmental factors [7]. The rate of neural tube defects is more common in twins than singleton and in monozygotic twins than dizygotic twins. The spina bifida most frequently affects lumbosacral spinal level. Only about 0–5% of cases occur in the cervical spine, 5–10% in the thoracic spine, 20–30% in the thoracolumbar junction, 20–30% in the lumbar, 30–50% in the lumbosacral level and 5–15% in the sacral spine [10]. Altogether cervicothoracic spinal dysraphisms are rare, with an incidence of only 1–6,5% [11]. Myelomeningocele occurs in approximately 1 in 1200 to 1400 births. 60% of those children are community ambulators, and 80% are socially continent. The incidence is not higher in any specific ethnic group, but females have a slightly higher incidence in comparison with males [12]. An increased risk of recurrence has been reported of about 3–8% after one affected pregnancy or maternal history of the defect and the risk worsens with an increasing number of affected children [13]. Researchers performed a study in northern China that showed that the recurrence risk in neural tube defects in subsequent pregnancies was 1.7%, which was higher than in the United States. The recurrence rate of neural tube defects was approximately 5-times higher than the overall prevalence in the same region of northern China [14]. The risk of recurrence in myelomeningocele was reported 2–5% in the United States. These data suggest that the genetic basis of closed defects may be same as the basis for myelomeningocele in some families [15]. Another study showed that the recurrence rate has been approximately 2–3% in consecutive pregnancies. Higher incidence rates were reported in females, increased maternal age, and lower socio-economic status. Latin Americans were the most affected population in the United States. Females are affected up to 3- to 7-times more than males [16]. The observed prevalence of the spina bifida varies globally and is largely influenced by differences in surveillance methods, prenatal diagnosis and elective termination policies, and folic acid fortification of staple foods in a given country or region. The spina bifida is more common in countries where there is no legislation providing for the mandatory enrichment of the diet with folic acid in order to reduce its prevalence. African data were scarce, but needed, as many African nations are beginning to adopt folic acid legislation [9, 17, 18]. Ultrasound screening has a major impact on the epidemiology of the spina bifida. The prenatal detection rate of spina bifida is high, and most cases of spina bifida are isolated and have a normal karyotype [19]. Omission of elective terminations clearly underestimates prevalence and may bias risk estimations in etiologic studies. Compared with women who delivered liveborn/stillborn infants with neural tube defects, women who electively terminated neural tube defects-affected pregnancies were disproportionately white, were more highly educated, had higher incomes, and used vitamins containing folic acid more often [20]. The European network of population-based registries for epidemiological surveillance of congenital anomalies (EUROCAT), collects data on pregnancy terminations in addition to live and stillbirths, generating particularly comprehensive prevalence data for neural tube defects and other malformations. During four years (2003 to 2007), this register reports an overall prevalence of serious congenital anomalies of 23.9 per 1,000 live births. As many as 80% of children with severe congenital anomalies were born alive. The mortality of these children in the first week of life was 2.5%. The abortion was performed after prenatal diagnosis in 17.6% of cases. Congenital anomalies mainly concern newborns with specific medical and social care needs. The prevalence of chromosomal abnormalities was 3.6 per 1,000 live births. Their presence led to a 28% incidence of stillbirths or their diagnosis conditioned 48% of all terminations. The most common non-chromosomal subgroups were congenital heart defects, limb anomalies, nervous system disorders and urinary system anomalies. In 2004, perinatal mortality associated with congenital anomaly was 0.93 per 1000 births, and terminations of pregnancy following prenatal diagnosis 4.4 per 1000 births, with considerable country variation. Primary prevention of congenital anomalies in the population based on controlling environmental risk factors is a crucial policy priority, including pre-conceptional care and whole population approaches [21].
The development of nervous system is an embryonal process called neurulation. The primary neurulation is the first phase and includes the closure of the neural tube and thus forming brain and spinal cord. The second phase comprises formation of sacral and coccygeal segment and occurs around 26th day of gestation. Spina bifida is an incomplete closure of dorsal spinal structures and usually happens to appear between 17th to 30th postconceptional day [3]. The etiology of spinal dysraphism is multifactorial [22]. Although no clear etiology is known to result in either the open or closed forms, some regional adverse factors have been reported, primarily involving the mother at conception and early pregnancy. Table 1 lists potential risk factors that are usually considered to be neural tube defects. Grewal et al. report in their study that maternal intake of the alcohol increased the risk for d-transposition of the great arteries, neural tube defects, and multiple cleft lip with or without cleft palate in infants. Smoking in this study was associated with a lower risk of neural tube defects [23]. Positive associations are observed between spina bifida and caffeine consumption and each caffeine source except caffeinated tea, which showed a negative association with the spina bifida. The association between caffeine consumption and anencephaly differed by maternal race and ethnicity. No dose effect of caffeine consumption was found [24]. Plasma levels of folate and vitamin B12 are independent risk factors for the occurrence of neural tube defects. This fact suggests that the enzyme methionine synthase is involved in the etiology of neural tube defects. The surprising finding is that folate and vitamin B12 levels, considered sufficient, continued to be a risk factor for an increased incidence of this defects. This finding is an incentive to re-evaluate daily doses of folate as well as vitamin B12 [25]. The higher quality of the diet of expectant mothers is associated with a reduced incidence of neural tube defects. It is dietary approaches that could further reduce the risk of serious birth defects and complement existing efforts to promote the use of multivitamins during pregnancy [26]. Yazdy et al. refer that high insulin intake is risk factor for genesis of neural tube defects [27]. Results from experimental animals have suggested a role for methionine, an essential amino acid, in normal closure of the neural tube. Shaw et al. observed an approximately 30–40% reduction in neural tube defect-affected pregnancies among women whose average daily dietary intake of methionine was above the lowest quartile of intake. These reductions in neural tube defect risk were observed for both anencephaly and spina bifida, remained after adjustment for maternal race, ethnicity and education; and were observed irrespective of maternal level of folate intake [28]. Shaw al. observed elevated risk of neural tube defects associated with lower levels of total choline, and reduced risks with its higher level [29]. In the systematic review, Ray et al. report a moderate association between low maternal B12 status and the risk of fetal neural tube defects [30]. Studies report a reduction in the risk of neural tube disorders in infants and fetuses when mothers taking zinc in the preconception period. However, it has not been established whether the combination of nutrients or zinc alone is associated with a reduced incidence of neural tube disorders [31]. Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen [32]. Similarly, lower socio-economic status and residence in a socio-economic status-lower neighborhood increased the risk of neural tube defect-affected pregnancy [33]. Although the excess risk for birth defects among children of mothers with diabetes mellitus is well documented, there are few data concerning the risk for specific malformations. No statistically significant differences were found among infants of mothers with gestational diabetes mellitus who did not require insulin during pregnancy. Insulin dependent diabetes mellitus is potential risk factor for malformations of central nervous system [34]. Women who experience stressful life events around the time of conception or early gestation may be at increased risk of delivering infants with certain congenital anomalies. For example, in Mexican population in the United States, the occurrence of stressful life events was associated with the risk of neural tube defects. These findings suggest that stress may increase risk in populations with poor nutritional status and poor economic resources [35, 36]. It is likely that not all malformations of the human fetus associated with valproate exposure during pregnancy have a comparable quantitative dose relationship. The reducing of the valproate dose in early pregnancy will provide more effective protection against the spina bifida and other types of fetal malformations [37]. Lupo et al. found an association between environmental level of benzene and the spina bifida. Mothers living in census tracts with the highest benzene levels were more likely to have offspring with the spina bifida than women living in census tracts with the lowest levels [38]. Waller et al. report moderate positive association of maternal obesity with 7 of 16 categories of birth defects. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes mellitus [39]. Severe obesity has been associated with larger risks of the spina bifida incidence. Underlying mechanisms that have been suggested including aberrant glucose control, oxidative stress, and metabolic syndrome [40]. Higher water nitrate intake was associated with several birth defects in offspring but did not strengthen associations between nitrosatable drugs and birth defects [41]. Cordier et al. report the association between exposure to glycol ethers and neural tube defects, multiple anomalies, and cleft lip [42]. Pesticide exposures were associated with risk of neural tube defects, especially use of pesticides at home and a peri-conceptional residence within 0.25 mile of cultivated fields [43]. Persistent organic pollutants have been associated with a wide range of adverse health effects. Elevated placental concentrations of polycyclic aromatic hydrocarbons, dichlorodiphenyltrichloroethane isomers, and α-hexachloro-cyclohexane are associated with increased risks of neural tube defects [44].
Maternal nutrition | Other maternal factors | Environmental factors |
---|---|---|
Alcohol and caffeine use | Smoking | Ambient air pollution |
Insufficient folate intake | Low socio-economic status | Indoor air pollution |
Low dietary quality | Infections and hyperthermia | Nitrate-related compounds |
Elevated glycemic load | Pregestational diabetes | Organic solvents |
Low methionine and zinc intake | Pregestational obesity | Pesticides |
Low serum choline level | Psychosocial stress | Polycyclic hydrocarbons |
Low vitamin B12 and C level | Valproic acid use | Disinfectant in drinking water |
Potential risk factors for neural tube defects (according to [3]).
Considerable evidence points to a major genetic component in the spina bifida causation, raising the question of which genes are implicated. In animal spina bifida models more than 40 genetic strains were detected to be associated with this disorder. In some human patients were detected various genetic alterations of coding regions of planar cell polarity genes pathway and genes encoding folate metabolism. The study of folate and its association with neural tube defects is an ongoing endeavor that has led to numerous studies of different genes involved in the folate metabolism pathway, including the most commonly studied thermolabile C677T mutation in the methylenetetrahydrofolate reductase gene [3, 45, 46]. Most of observed genetic alterations are sporadic (non-syndromic), only less than 10% of cases are syndromic, connected with genetic disorders such as trisomy 13 or 18. Up to date evidence supports a theory of a multi-factorial origin of neural tube defects as a consequence of both, genetic and non-genetic factors [47]. Recent studies of mouse mutant with transformation related protein 53 showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y chromosome. Involvement of genetic factors in etiology is supported by evidence that the risk for siblings of spina bifida patient is 2–5%, representing 20 to 50-fold higher risk compared to the general population prevalence of 1 per 1000. Relatives of 2nd and 3rd line display lower risk compared to 1st line relatives, though still increased compared to standard population risk. Woman who has child with spina bifida has approximately 3% risk for another pregnancy affected by spina bifida, risk arises to 10% after two affected pregnancies. The agreement of neural tube defects is higher in monozygotic and dizygotic twins of the same sex compared to twins of the opposite sex. Female excess among cranial neural tube defects is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying neural tube defects [3, 48]. Trisomy 18 is the most commonly associated aneuploidy with open neural tube defects. Other genetic disorders include Meckel-Gruber syndrome, Jarcho-Levin dysplasia, HARD (hydrocephalus, agyria and retinal dysplasia), trisomy 13, PHAVER syndrome (pterygia, heart defects, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects), VATER syndrome (vertebral anomalies, anal atresia, trachea-esophageal fistula and renal abnormalities), and X-linked neural tube defects among others. A significant number of fetuses with open defects are chromosomally abnormal. Although prenatal chromosome analysis should be considered in all cases, prenatal ultrasound seems effective in identifying those fetuses with an underlying chromosomal abnormality. It is questionable how many genes in the human genome pose a risk of neural tube defects. Studies often draw conflicting conclusions due to limitations in the design of studies that affect the strength of statistical analysis. Association studies and sequencing of the entire exome or genome are a way to identify genes that affect the incidence of human neural tube defects [16, 49, 50]. If a prenatal diagnosis of myelomeningocele is suspected, karyotype and genetic consultation should be obtained. Multidisciplinary approach is necessary to treat and support this malformation which is a huge burden on the patient, family, and the society. The most of suspected etiological factors does not have strong evidence or occur less frequently. This underlines to theory of multifactorial etiology of neural tube defects.
The development of the normal spinal cord from the second to the sixth week of pregnancy includes gastrulation and primary and secondary neurulation. During the first stage of gastrulation, the endoderm and ectoderm form a bilaminar embryonic disc (Figure 2). Cell division and migration lead to the formation of a mesoderm and a trilaminar disk is formed. The interaction of the notochord with the ectoderm creates a neuroectoderm. The beginning of the neural plate is in the midline and then extends in the proximal and caudal directions. The pathological effects during primary neurulation can lead to the spinal dysraphism. Part of the primary neurulation is the formation of nerve folds - the nerve groove. By joining the nerve folds, the nerve plate changes into a neural tube. Closure of the cranial and caudal openings of the neural tube represents the end of the process of primary neurulation (Figure 3). Disorder of the closure of the caudal neural tube causes the formation of a plaque (exposed nerve tissue). The existence of a neural plaque is a differential feature between myelocele and myelomeningocele [51]. Pluripotent cells forming the caudal end, forms vacuoles and neurons. Their cavitation leads to the formation of a central canal. Apoptosis of said cells leads to the formation of the conus medullaris, filum terminale and ventriculus terminalis. The final closure of the caudal neuropore leads to the transformation from the primary neurulation to the secondary neurulation. During secondary neurulation, the ectoderm and part of the endoderm forms the medullary cord. Two types of cells develop from the medullary epithelium - neuroblasts and spongioblasts. Neuroblasts differentiate into different types of neurons. Ependymal cells, astrocytes and oligodendrocytes differentiate from spongioblasts. The wall of the occluding medullary tube is formed by a layer of cylindrical pluripotent neuroepithelial cells. Towards the cavity, the cells are interconnected by connecting complexes. The luminal surface of the neuroepithelium forms the inner border membrane. From the environment, the neuroepithelium is bounded by a basement membrane, which forms the outer border membrane. As the cells proliferate, the medullary tube wall thickens, making the neuroepithelium multilayered cylindrical. In the area of the future spinal cord, it is possible to histologically distinguish the inner ventricular zone (the primitive ependymal layer), the middle intermediate zone (the future gray matter) and the outer marginal zone (the future white matter). The primitive medullary tube has a thin wall and a wide lumen. Later, the wall is roughened and the lumen has the shape of a slit in cross-section oriented ventrodorsally (the future central canal). On both sides, the cavity is inserted into the wall in the form of a longitudinal notch - sulcus limitans. This incision divides the lateral walls of the neural tube into ventral basal and dorsal alar plate. Neuroblasts of the basal plate become motor neurons, whereas sensory neurons form in the alar plate. In the future spinal cord, unlike the lateral walls, the dorsal and ventral walls do not participate in active cell proliferation. The cells of these parts are mainly involved in the formation of ependyma. The medullary cord separates, gradually condenses and is subject to cavitation. The cavitation combines to form a single tube. The disorder of secondary neurulation is mostly limited to the spinal cord and conditions the formation of closed neural tube defects (neural tissue is not exposed). Factors playing role in etiology of spina bifida, such as genetic, environmental and nutritional factors have mostly effect on neurulation causing its disruption, preventing closure of neuropores and neural folding. Effect of etiological insults is different, disrupting various phases of neural tube formation, but the result in all factors is alike, causing abnormal neurulation [8]. The essential step in pathogenesis of spina bifida is non-union of dorsal spinal structures, in severe forms it is failure of embryonic neural tube closure. Immature neural tube remains uncovered or is covered only by a thin membrane what causes direct exposure of the developing and open neural tube to the amniotic fluid. After relatively normal initial development, neuronal differentiation of bifid neuroepithelium and development of spinal motor and sensitive functions in whole extent including levels below the lesion, with the progression of gestation, destructive effect of exposure of the developing spinal cord to the amniotic fluid manifests as necrosis of neurons and micro-hemorrhagic changes of the spinal cord [3]. Pathological examination of the spinal cords of stillborn human fetuses with myelomeningocele demonstrate varying degrees of neural tissue loss at the site of the defect, but normal-appearing dorsal and ventral horns proximal of the lesion. Recently produced experimental evidence suggests that secondary traumatic injury and degenerative changes, acquired in utero, to the openly exposed neural tissue may be primarily responsible for the massive neurological deficit associated with myelomeningocele. In myelomeningocele as the severe degree of spina bifida the defect consists of dorsally opened vertebral arch, as well as dorsal defect of dura mater that is laterally attached to the dermal layer and defect in layer of pia mater which is fused to the epidermis. The unclosed spinal cord is directly exposed without any covering to the amniotic fluid and later to the surrounding environment. On the surface of spinal cord is only membrane - the abnormal arachnoid sac – which is unable of providing protection against traumatic injury caused by toxic exposition. Another insult to the nervous tissue can occur during passage through the birth canal in case of vaginal delivery leading to further hemorrhage and abrasion. The devastating role of secondary insult to the exposed nervous tissue underlines the presence of dorsal and ventral parts of the spinal cord with developed nerve roots and ganglia, what is evidence of preexisting appropriate early embryogenic development. This finding emphasizes the role of early in utero surgery in protection from secondary injury caused by prolonged exposition of the unprotected neural tissue to the amniotic fluid and in preservation of neurological functions [52, 53]. Regular sonographic observations of human fetuses with myelomeningocele show progressive deterioration of leg movements during pregnancy [54]. Experimental data on fetuses with the spina bifida aperta strongly indicate that a discrepancy exists between the occurrence of prenatal leg movements and the spinal location of the meningomyelocele on the one hand, and between the occurrence of pre- and postnatal leg movements [55]. In hemimyelocele, half of the dysgraphic spinal cord is not covered by the dura mater and is exposed to the intrauterine environment. The correlating lower limb shows a motor or sensitive deficit, while the function of the other lower limb is normal or only slightly altered [56]. Staged series of animal fetuses with myelomeningocele have demonstrated gain of neurological function even after the lesion has formed, followed by loss of this function. This finding correlates with a progressive loss of spinal cord tissue integrity. Stiefel et al. studied the development of neuronal connections and neurological function of mice during fetal and neonatal stages in a genetic model of exposed lumbosacral spina bifida. Their findings support the hypothesis that neurological deficits in human myelomeningocele arise after secondary destruction of nerve tissue and loss of function during pregnancy [57]. Meuli et al. report findings that secondary neural tissue destruction during pregnancy is primarily responsible for the functional loss and that timely in utero repair of the open spina bifida might rescue neurologic function [58]. Drewek et al. dealt with the toxic effects of human amniotic fluid on organotypic cultures of rat spinal cord. Using a lactate dehydrogenase outflow test to evaluate toxicity, amniotic fluid was found to become toxic at approximately 34 weeks of gestation. This toxic effect of amniotic fluid occurs relatively suddenly. Surgical closure of a myelomeningocele defect prior to the onset of amniotic fluid toxicity has the potential to prevent injury to sensitive myelodysplastic spinal cord tissue [59].
The process of the gastrulation (author’s archive).
The process of primary neurulation (public domain, source:
The number of mouse mutants and strains with neural tube defects at present exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains. Some mutations in isolation do not cause neural tube disorders, but are caused by di-genic, tri-genic, and oligo-genic combinations. This fact corresponds to the nature of the genetic etiology of human neural tube defects. Experimental mouse mutants that have only exencephaly are 4-fold more frequent than those that have spina bifida aperta with or without exencephaly. Many diverse cellular functions and biochemical pathways are involved; the mutants with neural tube defect draw new attention to chromatin modification, the protease-activated receptor cascade, and the ciliopathies. Few mutants directly involve folate metabolism. The research of many mutants is the basis for a complete understanding of the processes of elevation and fusion of nerve folds along mechanically distinct cranial-caudal segments of the neural tube [60]. Neural tube closure is affected by many cellular biological functions, with cytoskeletal, cell cycle, and molecular regulation of cell viability present in mutant mice. Neural tube closure is also affected by transcriptional regulators and proteins that affect chromatin structure. Folic acid supplementation is one of the most effective methods of primary prevention of some neural tube disorders in humans, although the mechanism of action of folate is unclear. In cases where folic acid has no preventive effect, it is possible to reduce the risk of mouse mutants by administering inositol. This finding may determine the strategy for preventing neural tube defects in the future [61]. Exencephaly, the developmental precursor of anencephaly, is most commonly encountered after gene mutation in mice, but spina bifida aperta is also observed in more than 40 mutant strains. Rare putative mutations in the planar cell polarity genes Vangl2 (Vang-like protein 2), Scrib (Scribble planar cell polarity protein), Dact1 (Disheveled binding antagonist of β-catenin 1), and Celsr1 (Cadherin EGF LAG seven-pass G-type receptor 1) cumulatively contribute to over 20% of cases with craniorachischisis, a rare defect; no contributing variants were found for Prickle1 (Prickle planar cell polarity protein 1) or Ptk7 (Protein tyrosine kinase 7). Planar cell polarity rare putative mutations have a weaker role in myelomeningocele, being found in approximately 6% of cases and cumulated across Celsr1, Fuz (Fuzzy planar cell polarity protein), Fzd6 (Frizzled class receptor 6), Prickle1, Vangl1 (Vang-like protein 1), and Vangl2. These results demonstrate that planar cell polarity - gene alterations contribute to the etiology of human neural tube defects [60, 62]. Opposite to unaffected individuals, patients with neural tube defects display though rare, but present missense gene mutations were confirmed by sequenation of the coding regions of human orthologues of these genes. Substantial part of neural tube defects is associated with variants in genes of the planar cell polarity and a non-canonical Wnt signaling pathways [62]. This is particularly significant, since planar cell polarity-gene mutations are potent causes of mouse neural tube defects, generating several phenotypes particularly the severe defect craniorachischisis. Initiation of neural tube closure is disrupted in homozygous mice due to the presence of mutations in planar cell polarity genes. This fact provides a strong association between neural tube defects and planar cell polarity signaling. Missense gene sequence variants detected in humans with neural tube defects are heterozygous and have a wider range of phenotypes than in mouse mutants. It is the interactions between mutations in several heterozygous genes that may be responsible for neural tube defects in humans [63]. Genes of folate one-carbon metabolism are another group of genes linked to neural tube defects. Methylene tetrahydrofolate reductase is an enzyme essential for conversion of homocysteine to methionine generating 5-methyltetrahydrofolate. Variant of this gene 677C > T results in the conversion of valine to alanine at codon 222. This variant causes reduced activity of this enzyme. The homozygous 677TT genotype, in either mother or fetus, particularly in connection with folate deficiency could be a risk factor for neural tube defects. The examination of non-Latin European studies revealed that the association of homozygous dominant genotype with neural tube defect has only been proven for Irish populations, both by case–control studies, and by family-based tests, such as the allele transmission disequilibrium test [64]. Pickell et al. refer that biological evidence linking maternal methylene-tetrahydrofolate reductase and folate deficiencies to adverse pregnancy outcomes in mice mutants. It underscores the importance of folate in reducing the incidence of early embryonic defects and in the prevention of the development of placental abnormalities that may increase susceptibility to other defects [65]. The glycine cleavage system is a multi-enzyme component of mitochondrial folate metabolism, and glycine cleavage system-encoding genes therefore represent candidates for involvement in neural tube defects. Mutations in genes of the glycine cleavage system, which reduce the activity of two mitochondrial enzymes of folate-mediated one-carbon metabolism (glycine-decarboxylase and amino-methyltransferase), are also found among patients with neural tube defects and in this case loss of function of the mouse orthologues produces neural tube defects [66]. Glycine decarboxylase in the glycine cleavage system acts to transfer one carbon unit to the folate metabolism of one carbon. Mutations in glycine decarboxylase cause a rare recessive disease - non-ketotic hyperglycemia. However, these mutations have also been identified in patients with neural tube disorders. Nevertheless, the relationship between non-ketotic hyperglycemia and neural tube disorders remains unclear. Formate supplementation normalizes the folate profile, restores embryonic growth and prevents neural tube defects, suggesting that glycine decarboxylase-deficiency causes neural tube defects through limiting supply of one-carbon units from mitochondrial folate metabolism [67]. Mitochondrial enzyme activity supplies 70% of the cell’s one-carbon units for metabolism, as formate molecules, and it seems possible that genetic variants in this pathway may prove to be important risk factors for neural tube defects [3].
A variety of environmental factors have been linked with neural tube defects (Table 1). Folic acid seems to play crucial role in the pathophysiology of neural tube disorders. It is inevitable in the synthesis of deoxyribonucleic acid and ribonucleic acid precursors. Dihydrofolate reductases convert folic acid into tetrahydrofolate. Essential step is methylation of the folic acid that is responsible for its functionality. Supplementation of folic acid is linked with decreased incidence of neural tube defects by 71% [68]. Animal studies have not provided enough information to establish metabolic and genomic mechanism underlying human folic acid responsiveness in neural tube defects [69]. 5-methyl-tetrahydrofolate is the active co-factor of enzymes involving one-carbon transfer reactions forming purine and pyrimidine. Folate receptors take up MTHF into the cell, glutamates and carrier protein can be added to form polyglutamate folates that cannot cross cell membranes. Folic acid is directly associated with cell proliferation as for in neurulation. Neural folds express the folate receptors. The absence of folic acid halts neural tissue proliferation and migration during neurulation leading to neural tube disorders. In the last decades there has been significant worldwide decrease in overall incidence of neural tube defects due to the periconceptional supplementation of folic acid. Folate food fortification became priority in many countries. However, despite indisputable benefits of folic acid supplementation neural tube defects continue to be a substantial part of perinatal morbidity and mortality worldwide. Recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored [70]. Despite the great effect of the folate food fortification programs, there are still cases of neural tube defects also after periconceptional supplementation. This might be due to defects in folate metabolism, receptors or transport proteins that put these women into higher susceptibility. Genetic alterations leading to impaired structure or function of receptor proteins, particularly α- and β-folate-receptors, which have function in neural cells, can lead to failure in neurulation [8, 71]. The C677T polymorphism in the methylenetetrahydrofolate reductase gene has been reported to play a critical role in the pathogenesis of neural tube defects. This association has been widely demonstrated, but the results are inconclusive. Meta-analysis performed to rule out the relation between C677T polymorphism in the methylenetetrahydrofolate reductase gene and neural tube defects demonstrated that this mutation decreases the activity of enzymes required for folate metabolism, thus reducing the serum folate concentration. Yang et al. found no association between any of the fathers’ genotypes and neural tube defects, whereas a significant correlation between C677T polymorphism in the methylene-tetrahydrofolate reductase gene and neural tube defect-risk was found in patients with neural tube defect and in their mother [8, 72]. Folate antagonists such as phenytoin, valproic acid, and carbamazepine have a direct effect on neural tube defects due to inhibiting the activity of folate [73]. Apoptosis and proliferation play important roles in embryonic development and are required for neural tube closure. The antifolate drug methotrexate induces folate dysmetabolism by inhibition of dihydrofolate reductase and causes abnormal apoptosis and proliferation. Methotrexate causes a folate and folate-associated dysmetabolism, and further induced abnormal apoptosis and proliferation, which may play a critical role in the occurrence of neural tube defects caused by folate deficiency [74]. Mutation in homeobox genes and fibroblast growth factor dysfunction has some roles in the pathogenesis of neural tube defects [8]. The important role of vitamin B12 in development of nervous system is known. It is necessary in folate metabolism in converting homocysteine from this metabolic pathway into methionine. Along with methionine synthase it reduces the toxicity of homocysteine. Under circumstances of vitamin B12 deficiency homocysteine serum levels increase. The high homocysteine level can cause posttranslational modification of folate receptors that can after modification represent an autoantigen. Production of antibodies against these autoantigens leads to decrease of folate activity [8, 70]. Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. This anticonvulsant increases risk of neural tube defects by 10-fold when taken during the first trimester of pregnancy [67]. Potent histone deacetylase inhibitory activity of valproic acid may disturb the balance of protein acetylation and deacetylation, leading to neurulation failure [75]. Valproic acid activates transcription from diverse exogenous and endogenous promoters and have teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription [76]. Production of neural tube defects due to fumonisin (group of mycotoxins derived from Fusarium and their Liseola section) exposure in rodent embryos has identified sphingosine phosphate metabolism as a key target of the toxin, potentially compromising folate utilization [3]. Neural tube defects are among the most common of the malformations associated with diabetic embryopathy. Pax3 (paired box 3) is an important developmental control gene, the expression of which is impaired in the embryos of diabetic mice, and therefore neural tube apoptosis occurs [77].
Two phases of neural tube formation occur in higher vertebrates: closure and canalization. Primary neurulation is initiated at the boundary between future hindbrain and cervical spine on day 22 after fertilization (Figure 3). At the rostral extremity of the forebrain begins closure and backwards continues zipping to meet forward closure from the hindbrain. On the 24th postconceptional day rostral neuropore closure is completed, spinal closure lasts longer till the 26th day, progressively forming lower parts of the neuroaxis. Meningomyelocele is an open defect of neural tube as a result of closure failure of the neural folds in the dorsal midline. It can be consequence of failure of any part of neurulation process. Craniorachischisis is the most severe neural tube defect with almost completely dorsally opened brain and spine. This defect is a result of closure failure on 22nd day. Analysis of mice with mutations of Vangl2 gene has revealed a defect of late gastrulation. The process of convergent extension involves the intercalation of cells in the midline to lengthen and narrow the body axis [3]. Planar cell polarity signaling is necessary for initiation of neural tube closure in higher vertebrates. In mice with planar cell polarity gene mutations, a broad embryonic midline prevents the onset of neurulation through wide spacing of the neural folds. Cellular autonomic error of convergent spread requiring planar cell polarity signaling via Rho-associated protein kinase plays a role in development of neural tube defects [78]. Anencephaly is a defect of neural tube closure where initial closure is successful but cranial neurulation fails. Open spina bifida defects are results of failure in subsequent spinal neurulation. These lesions can be of various levels and sizes depending on the stage at which the ‘zipping’ process fails [3]. The molecular mechanism based on the antagonism of Bmp2 (Bone morphogenetic protein 2) signaling is the basis for the regulation of the formation of dorsolateral hinge points during mouse neural tube closure. Spinal closure in the curly tail (Grainy head like transcription factor 3) mutant fails later, due to enhanced curvature of the body axis, producing a spina bifida confined to the lumbar and sacral region [79]. Zic2-mutant (Zic family member 2) mice fail early in spinal neurulation, owing to lack of dorsolateral neural plate bending, and display a large spina bifida from thoracic level downwards [78].
Secondary neurulation is responsible for forming of the neural tube in the low sacro-coccygeal regions, following the closure of the caudal neuropore. The end of the embryo comprises the tail bud whose mesenchymal cell core progressively reorganizes into longitudinal cell condensations. The most dorsal of these condensations undergoes canalization, converting the solid neural precursor into epithelial secondary neural tube [77, 80]. Closed spinal dysraphisms are covered with skin and they are not in contact with surrounding environment as they are consequence of failure of secondary neurulation. Occult spina bifida is outcome of inappropriate separation and differentiation of neural and mesenchymal tissues. Research helped to identify a bipotential neuro-mesodermal precursor cell lineage within the tail bud. Differentiation and separation of these precursor cells are essential for proper development and existence of this cells explains incomplete separation of these layers in case of its malfunction. The histological and ultrastructural properties of secondary neurulation in C57BL/6 mouse embryos were examined as a first step to analyze the cause of the presence of this process in mammalian embryos. Secondary neurulation in mouse embryos consists of two phases - platelet formation and cavitation. These two events occur simultaneously. The medullary rosette consists of elongated tail bud cells, radially arranged around a central lumen formed by cavitation. The secondary portion of the neural tube forms in 10-day embryos by progressive enlargement of the central lumen and addition of tail bud cells to the rosette. The medullary plate also consists of elongated tail bud cells. These cells expand ventrally from the basal aspect of the dorsal superficial ectoderm into the slit-like cavity formed by cavitation. The formation of the secondary neural tube occurs in 11- to 12-day-old embryos in the process of forming additional lateral and ventral tail cells into the medullary plate. Free cells and cell debris that do not show signs of necrosis often occur in the forming lumen of the secondary neural tube. Small intercellular junctions form at the juxta-luminal ends of the tail bud cells during the formation of the medullary rosette or plate, and cavitation occurs. Cavitation per se during secondary neurulation is a relatively passive phenomenon, which results principally from neighboring cells becoming polarized apicobasal and incorporated into a primitive neuroepithelium. The latter constitutes the walls of the forming secondary neural tube [3, 81]. The clinical observation that the distal spinal cord is often tethered to surrounding tissues, in spina bifida occulta, can therefore be recognized as a disorder of secondary neurulation. The frequent and striking association of closed spinal dysraphism with intradural lipoma is not well explained. The progressive generation of axial tissues (spinal cord, skeleton and musculature) of the body has long been proposed to depend on the activity of multipotent stem cells. The data strongly support their existence, there is little definitive information about their multipotency or extent of contribution to the axis [3, 82]. Spinal lipomas are the most common form of occult spinal dysraphism. Lipomas represent a wide spectrum of diseases in regard to pathological anatomy, symptomatology, and treatment options. These lesions are united by a similar embryology and pathophysiology. The treatment of these lesions is controversial. Some physicians advocating surgical treatment for all patients regardless of clinical symptoms and others proposing that surgery in cases of the clinical manifestation [83].
The spina bifida is associated with another brain malformations and development of the hydrocephalus. Brain defects involve the spectrum of anomalies related to the Chiari II malformation in about 90% of cases [83]. Chiari II malformation is associated with herniation of normal-sized cerebellum caudally through the foramen magnum [84]. Insufficient distribution of the embryonic ventricular system can be considered to be the cause of Chiari II malformation in children with myelomeningocele. Defective occlusion and an open neural tube secrete fluid accumulation, which affects the normal development of the brain. These mechanisms result in small posterior fossa and disorganization of the brain [85]. Volume reduction of the cerebellum is more associated with thoracic level spinal lesions than lumbar or sacral lesions. Few volumetric MRI studies of the entire cerebellum have been published. Even less quantitative information is available in patients with hindbrain malformations, including the Chiari II malformation which is ubiquitous in patients with meningomyelocele. Children with thoracic level lesions have smaller cerebellar volumes relative to those with lumbo-sacral lesions, who had smaller volumes compared to children without the pathological development. The reduction in cerebellar volume in children with meningomyelocele represents a reconfiguration involving anterior lobe enlargement and posterior lobe reduction [86]. Most of patients with open spinal defect display abnormal MRI finding. Distortion of the midbrain where colliculi fuse into a single beak pointing posteriorly and invaginate into cerebellum are present in about 65% of cases [3]. About 70% of patients have elongated medulla with kinking at the spino-medullary junction [83]. The basal ganglia and subcortical structures usually have normal appearance on MRI. Meningomyelocele differentially disrupts brain regions whereby some structures are volumetrically normal whereas others are reduced or enlarged. In hippocampus, volumetric reduction coupled with increased mean diffusivity may imply reduce cellular density and aberrant organization. The increased volume and markedly reduced mean diffusivity of putamen indicate increased density. The hippocampus, but not the amygdala, is reduced in volume, and the putamen is enlarged [3, 87]. Almost half of the children with meningomyelocele have hypogenesis of the corpus callosum involving either the splenium and posterior body or the rostrum [83]. The results of the Treble-Barna et al. study contribute to emerging evidence of memory impairment in adults with meningomyelocele and provide quantitative evidence of impaired hippocampal macrostructure as a neural correlate of memory impairment in this population. These anomalies suggest that the disruption of neural migration associated with meningomyelocele is prolonged into the second trimester, since the corpus callosum develops from 8 to 20 weeks prenatally [88]. Anomalies of the corpus callosum are an important indicator of additional brain anomalies. Quantitative studies show marked volume and integrity differences, especially posteriorly in cases with hypogenesis or severe hypoplasia [89]. The hypoplastic corpus callosum is not macro- or microstructurally intact in cases of the spina bifida, even when it appears radiologically intact. Both volume and integrity of posterior regions are related to reductions in intelligence quotient and to interhemispheric processing. Reduced integrity of the corpus callosum has been shown also in the genu, but not in commissura anterior [90]. Anomalies of the corpus callosum are associated with reduced interhemispheric communication and general difficulties integrating information in language, reading, and social domains [3]. Abnormalities of the corpus callosum are known to occur in the majority of patients with Chiari II malformation, and also callosal defects can be associated with spinal closed dysraphism. Chiari II malformation is associated with eye movement difficulties as well as problems with the precision and timing of motor movements and rhythmicity. When the neuroaxis emerges as a whole, the structures of embryological ectodermal origin and cranial and spinal structures are not independent regions from each other and thus, asymptomatic closed spinal dysraphisms have been demonstrated to accompany dysgenesis of the corpus callosum [91]. Secondary consequences of the spina bifida include hydrocephalus which results primarily from obstruction of cerebrospinal fluid flow at the IV. ventricle level, with other factors including aqueductal stenosis, venous hemodynamics and ependymal denudation. Cortical reorganization occurs around the area of ventricular dilatation [3]. Frontal regions are enlarged and there is a reduction in the volume of posterior cortical regions [92]. The reduction of cortex thickness and also white matter is associated with the mechanical effects of hydrocephalus. Overall reduction in white matter and increased neocortical thickness in the frontal lobes suggest that the spina bifida reflects a long-term disruption of brain development that extends far beyond the neural tube defect [93]. Hydrocephalus associated with the spina bifida is caused by an obstruction of the cerebrospinal fluid flow from IV. ventricular or malformation of the cerebral aqueduct. Ventriculomegaly causes systematic destruction of white matter periventricular axons. Motor, sensory, visual as well as memory systems can be disrupted by stiffening of periventricular structures, including the corpus callosum and the fimbria-fornix pathway. Secondary changes occur in neuronal cell bodies and synapses, with neurons not undergoing apoptosis. The clinical syndrome of hydrocephalic brain dysfunction is caused by subcortical detachment. Some of the brain dysfunctions are reversible due to the restoration of blood flow through the brain and the normalization of the extracellular environment [94]. Diffusion tensor tractography revealed diffusion tensor characteristics of myelination impairment and pathological development as well as abnormalities in intrinsic axonal characteristics and extra-axonal space in the association pathways of children with the development of the spina bifida. The differences in the diffusion metrics are suggestive of the pathological white matter development and persistent degeneration with increased age [95]. Hydrocephalus exerts primarily a linear effect on cognitive and motor outcomes. Deviations from normative standards for volumes of frontal versus posterior regions are associated with reductions in intelligence quotient and fine motor dexterity [3]. With the exception of fine motor skills and small differences in memory and spatial domains, children with spina bifida and arrested or shunt-dependent hydrocephalus have similar neuropsychological profiles [96]. Patients with the spina bifida have extensive motor deficits in the trunk, upper limbs, eyes, and speech articulators that correspond to disorders characteristic for cerebellar lesions. The structure and function of the brain correlates with a number of motor dysfunctions. Motor learning is maintained in the spina bifida. Pathological are motor functions that require predictive signals and accurate calibration of motion time signs. This creates a deficit in the coordination of smooth movement and the cerebellar triad - ataxia, dysmetria, and dysarthria. Said motor function in individuals with the spina bifida is impaired phenotypically very similarly to cerebellar lesions. The age-based cerebellar motor plasticity is limited in individuals with this neurodevelopmental disorder [97]. Attention deficit reflecting problems with posterior attention systems involving orienting and arousal mediated by the midbrain, with tectal anomalies directly correlated with the severity of difficulties with stimulus control. Procedural learning and attention functions involving sustained attention and persistence are relatively preserved, possibly reflecting less impairment in frontal-striatal regions and basal ganglia [3, 98]. Impairments in attentional disengagement in the spina bifida are not attributable to the general effects of hydrocephalus but are instead associated with specific midbrain anomalies that are part of the Chiari II malformation [99]. Development of individuals with severe forms of spina bifida throughout the lifetime is strongly affected by neurocognitive and movement disorders. Neurocognitive difficulties cause problems in keeping attention, learning, language comprehension and pragmatics as well as in assimilation of information. Procedural learning, word reading, vocabulary and social activation are usually not affected. Infants with spina bifida do not learn motor contingencies as easily or at the same rate as infants with typical development and are more likely to decrease motor responses when sensory feedback is absent. Intellectual disability is relatively infrequent, affecting perhaps 20–25% of people with the spina bifida and often after complications associated with the hydrocephalus. Status of cognitive functions in spina bifida patients is very variable as well as intelligence quotient scores. Impairment of intelligence and cognitive skills is mostly associated with presence of possible complications, such as hydrocephalus. Treatment of hydrocephalus is burdened with eventual complications as shunt obstruction, malfunction or infections. Repeated shunt complications can have impact on intellectual performance. Environmental and socio-economic factors also influence achieved abilities. Motor and cognitive outcomes are directly related to level and extent of spinal lesion, what reflects the association of more severe brain pathology with higher level and bigger extent of defect [3, 100]. Executive function impairments potentially have a detrimental effect on the individual’s emotional health and coping. Goal management training is a cognitive rehabilitation method for improving executive function. Compensatory intervention to manage executive dysfunction, effective and lasting benefits can be achieved in regard to aspects of perceived emotional health and coping [101].
The spina bifida involves congenital problems that result in abnormal bone formation in the spine and spinal cord. Closed spinal dysraphism is the mildest form of the neural tube defects which involves a hidden vertebral defect and minimal neural involvement. Open spinal dysraphism refers to a defect in which neural tissues communicate with the external environment such as meningocele and myelomeningocele. The incidence of neural tube defects has different rates among different ethnicity, geography, gender, and also countries. Various nutritional, maternal and environmental factors play a role in the etiology and pathogenesis of the spina bifida. However, the impact of these factors is ambiguous and further research is needed in this area.
The authors declare no conflict of interest.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. 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. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. 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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The techniques of artificial insemination with estrous synchronization programs and ovulation with current research results will be described.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"Fernando Sánchez Dávila, Alejandro Sergio del Bosque González\nand Hugo Bernal Barragán",authors:[{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila"},{id:"206127",title:"Dr.",name:"Alejandro Sergio",middleName:null,surname:"Del Bosque-Gonzalez",slug:"alejandro-sergio-del-bosque-gonzalez",fullName:"Alejandro Sergio Del Bosque-Gonzalez"},{id:"206128",title:"Dr.",name:"Hugo",middleName:null,surname:"Bernal-Barragán",slug:"hugo-bernal-barragan",fullName:"Hugo Bernal-Barragán"}]},{id:"58095",title:"The Innovative Techniques in Animal Husbandry",slug:"the-innovative-techniques-in-animal-husbandry",totalDownloads:3826,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Technology is developing rapidly. In this development, the transfer of computer systems and software to the application has made an important contribution. Technologic instruments made farmers can work more comfortable and increased animal production efficiency and profitability. Therefore, technologic developments are the main research area for animal productivity and sustainability. Many technologic equipment and tools made animal husbandry easier and comfortable. Especially management decisions and applications are effected highly ratio with this rapid development. In animal husbandry management decisions that need to be done daily are configured according to the correctness of the decisions to be made. At this point, smart systems give many opportunities to farmers. Milking, feeding, environmental control, reproductive performance constitute everyday jobs most affected by correct management decisions. Human errors in this works and decisions made big effect on last product quality and profitability are not able to be risked. This chapter deal with valuable information on the latest challenges and key innovations affecting the animal husbandry. Also, innovative approaches and applications for animal husbandry are tried to be summarized with detail latest research results.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Serap Göncü and Cahit Güngör",authors:[{id:"215579",title:"Prof.",name:"Serap",middleName:null,surname:"Goncu",slug:"serap-goncu",fullName:"Serap Goncu"},{id:"218971",title:"Dr.",name:"Cahit",middleName:null,surname:"Güngör",slug:"cahit-gungor",fullName:"Cahit Güngör"}]},{id:"58486",title:"Quality of Chicken Meat",slug:"quality-of-chicken-meat",totalDownloads:3354,totalCrossrefCites:19,totalDimensionsCites:29,abstract:"Chicken meat is considered as an easily available source of high-quality protein and other nutrients that are necessary for proper body functioning. In order to meet the consumers’ growing demands for high-quality protein, the poultry industry focused on selection of fast-growing broilers, which reach a body mass of about 2.5 kg within 6-week-intensive fattening. Relatively low sales prices of chicken meat, in comparison to other types of meat, speak in favor of the increased chicken meat consumption. In addition, chicken meat is known by its nutritional quality, as it contains significant amount of high-quality and easily digestible protein and a low portion of saturated fat. Therefore, chicken meat is recommended for consumption by all age groups. The technological parameters of chicken meat quality are related to various factors (keeping conditions, feeding treatment, feed composition, transport, stress before slaughter, etc.). Composition of chicken meat can be influenced through modification of chicken feed composition (addition of different types of oils, vitamins, microelements and amino acids), to produce meat enriched with functional ingredients (n-3 PUFA, carnosine, selenium and vitamin E). By this way, chicken meat becomes a foodstuff with added value, which, in addition to high-quality nutritional composition, also contains ingredients that are beneficial to human health.",book:{id:"6384",slug:"animal-husbandry-and-nutrition",title:"Animal Husbandry and Nutrition",fullTitle:"Animal Husbandry and Nutrition"},signatures:"Gordana Kralik, Zlata Kralik, Manuela Grčević and Danica Hanžek",authors:[{id:"207236",title:"Dr.",name:"Gordana",middleName:null,surname:"Kralik",slug:"gordana-kralik",fullName:"Gordana Kralik"},{id:"227281",title:"Prof.",name:"Zlata",middleName:null,surname:"Kralik",slug:"zlata-kralik",fullName:"Zlata Kralik"},{id:"227283",title:"Dr.",name:"Manuela",middleName:null,surname:"Grčević",slug:"manuela-grcevic",fullName:"Manuela Grčević"},{id:"227284",title:"BSc.",name:"Danica",middleName:null,surname:"Hanžek",slug:"danica-hanzek",fullName:"Danica Hanžek"}]},{id:"56453",title:"Goat System Productions: Advantages and Disadvantages to the Animal, Environment and Farmer",slug:"goat-system-productions-advantages-and-disadvantages-to-the-animal-environment-and-farmer",totalDownloads:4388,totalCrossrefCites:5,totalDimensionsCites:20,abstract:"Goats have always been considered very useful animals. Goats success is related to its excellent adaptability to the difficult mountain conditions, extreme weather and low value feed acceptance, versatile habits and high production considering their size. These are some reasons because goats are among the first animals to be domesticated. In terms of evolution, goats could be separated by their dispersion area in three large groups: the European, the Asian, and the African. Global goat populations, mainly in Africa and in Asia, have increased for centuries but very strongly in the past decades, well above the world population growth. They are also used for forest grazing, an integrated and alternative production system, very useful to control weed growth reducing fire risk. Despite some exceptions, no large‐scale effort to professionalize this industry has been made so far. There are consumers for goat dairy products and there is enough global production, but misses a professional network between both. Regarding goat meat, the world leadership also stays in Africa and Asia, namely in China, and there is a new phenomenon, the spreading of goat meat tradition through Europe due to migrants from Africa and other places with strong goat meat consumption.",book:{id:"5987",slug:"goat-science",title:"Goat Science",fullTitle:"Goat Science"},signatures:"António Monteiro, José Manuel Costa and Maria João Lima",authors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"},{id:"203680",title:"Prof.",name:"Maria João",middleName:null,surname:"Lima",slug:"maria-joao-lima",fullName:"Maria João Lima"},{id:"203683",title:"MSc.",name:"José Manuel",middleName:null,surname:"Costa",slug:"jose-manuel-costa",fullName:"José Manuel Costa"}]},{id:"70760",title:"Induction and Synchronization of Estrus",slug:"induction-and-synchronization-of-estrus",totalDownloads:1758,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Estrus cycle is a rhythmic change that occur in the reproductive system of females starting from one estrus phase to another. The normal duration of estrus cycle is 21 days in cow, sow, and mare, 17 days in ewe, and 20 days in doe. The species which exhibit a single estrus cycle are known as monstrous and species which come into estrus twice or more are termed polyestrous animals. Among them some species have estrus cycles in a particular season and defined as seasonal polyestrous. It includes goats, sheep, and horses. On the other hand, cattle undergo estrus throughout the year. The estrus inducers can grossly be divided into two parts, that is, non-hormonal and hormonal. Non-hormonal treatments include plant-derived heat inducers, mineral supplementation, uterine and ovarian massage, and use of Lugol’s iodine. The hormones that are used in estrus induction are estrogen, progesterone, GnRH, prostaglandin, insulin, and anti-prolactin-based treatment. Synchronization can shorten the breeding period to less than 5 days, instead of females being bred over a 21-day period, depending on the treatment regimen. The combination of GnRH with the prostaglandin F2α (PGF2α)- and progesterone-based synchronization program has shown a novel direction in the estrus synchronization of cattle with the follicular development manipulation.",book:{id:"8545",slug:"animal-reproduction-in-veterinary-medicine",title:"Animal Reproduction in Veterinary Medicine",fullTitle:"Animal Reproduction in Veterinary Medicine"},signatures:"Prasanna Pal and Mohammad Rayees Dar",authors:[{id:"299126",title:"Dr.",name:"Mohammad Rayees",middleName:null,surname:"Dar",slug:"mohammad-rayees-dar",fullName:"Mohammad Rayees Dar"},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal"}]}],onlineFirstChaptersFilter:{topicId:"25",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83115",title:"Fungi and Oomycetes–Allies in Eliminating Environmental Pathogens",slug:"fungi-and-oomycetes-allies-in-eliminating-environmental-pathogens",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.106498",abstract:"Fungi and oomycetes are the subjects of numerous current research studies. These are natural agents that can control parasitic populations, and arthropod populations with a role in the transmission of various diseases but can also eliminate various pollutants that are found in the external environment. Therefore, their conservation and exploitation are a global necessity, due to the benefits they confer on the quality of life of animals, but also of humans. Science must be aimed at finding a balance between the different constituents of the ecosystem and establishing coexistence relationships that are beneficial to all. Thus, research should be directed at investigating the potential actions of fungi and oomycetes against the various agents with which they coexist naturally in the external environment. This chapter provides information regarding the mechanism of action of these natural constituents and updates information on the species of fungi and oomycetes that have been studied so far. Thus, readers can have a base in this field and can further exploit what they have discovered to continue to improve the welfare of animals, addressing an ecological and healthy vision.",book:{id:"11579",title:"Animal Welfare - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11579.jpg"},signatures:"Iasmina Luca"},{id:"82991",title:"Diseases of the Canine Prostate Gland",slug:"diseases-of-the-canine-prostate-gland",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.105835",abstract:"In dogs, the most frequent diseases of the prostate gland are benign prostate gland hyperplasia (BPH), acute and chronic prostatitis, squamous metaplasia, and prostate tumors. New diagnostic tools comprise diagnostic markers in the blood and urine, as well as advanced imaging methods. The therapy can be initialized with the 5α-reductase-inhibitor finasteride or an anti-androgenic compound, and prolonged with a long-acting gonadotropin-releasing-hormone (GnRH)-agonist such as deslorelin. In case of prostatitis, effective antibiotics must be applied for weeks. Antibiotics must be able to penetrate into the prostate tissue; fluoroquinolones, clindamycin, and erythromycin are good choices and are in addition effective against mycoplasms. The chronical prostatitis cannot be differentiated from a neoplasia by sonography; a biopsy, histological, and bacteriological examination are required. Tumors of the prostate gland are seldom and mostly occur in castrated but in intact dogs. For the final diagnosis, a biopsy must be taken. Partial and total resection of the prostate gland by use of laser technique is possible but coincedes with many side effects and the prognosis is still futile. Immunotherapy combined with NSAIDs, targeted noninvasive thermotherapy, BRAF gene inhibitors, or prostate artery chemoembolization are promising methods.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Sabine Schäfer-Somi"},{id:"82956",title:"Potential Substitutes of Antibiotics for Swine and Poultry Production",slug:"potential-substitutes-of-antibiotics-for-swine-and-poultry-production",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.106081",abstract:"Early of the last century, it was detected that antibiotics added to the animal feeds at low doses and for a long time can improve technical performances such as average daily gain and gain-to-feed ratio. Since then, the antibiotics have been used worldwide as feed additives for many decades. At the end of the twentieth century, the consequences of the uses of antibiotics in animal feeds as growth promoters were informed. Since then, many research studies have been done to find other solutions to replace partly or fully to antibiotic as growth promoters (AGPs). Many achievements in finding alternatives to AGPs in which probiotics and direct-fed microorganism, prebiotics, organic acids and their salts, feed enzymes, bacteriophages, herbs, spices, and other plant extractives (phytogenics), mineral and essential oils are included.",book:{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg"},signatures:"Ho Trung Thong, Le Nu Anh Thu and Ho Viet Duc"},{id:"82905",title:"A Review of Application Strategies and Efficacy of Probiotics in Pet Food",slug:"a-review-of-application-strategies-and-efficacy-of-probiotics-in-pet-food",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.105829",abstract:"In companion animal nutrition, probiotics (direct-fed microbials) are marketed as functional ingredients that add value to pet foods due to the impact they have on gastrointestinal and immune health of dogs and cats. The nature of the beneficial effect each probiotic strain exerts depends on its metabolic properties and perhaps most importantly, the arrival of a sufficient number of viable cells to the large bowel of the host. Pet food manufacturing processes are designed to improve food safety and prolong shelf-life, which is counterproductive to the survival of direct-fed microbials. Therefore, a prerequisite for the effective formulation of pet foods with probiotics is an understanding of the conditions each beneficial bacterial strain needs to survive. The aims of this chapter are: (1) To summarize the inherent characteristics of probiotic strains used in commercial pet foods, and (2) To review recently published literature on the applications of probiotics to pet foods and their associated challenges to viability.",book:{id:"11578",title:"Antibiotics and Probiotics in Animal Food - Impact and Regulation",coverURL:"https://cdn.intechopen.com/books/images_new/11578.jpg"},signatures:"Heather Acuff and Charles G. Aldrich"},{id:"82773",title:"Canine Transmissible Venereal Tumor: An Infectious Neoplasia in Dogs",slug:"canine-transmissible-venereal-tumor-an-infectious-neoplasia-in-dogs",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.106150",abstract:"Canine transmissible venereal tumor is the oldest cancer in dogs and is transplanted via viable cancer cells. This cancer has a specific host, easy transmission, noticeable gross lesions, a predictable growth pattern, an immunologic relative host response, unique molecular characteristics, and is responsive to chemotherapeutic treatment. These points make researchers and practitioners interested in this cancer. Genital cases are noticeable and therefore easier to diagnose and treat than extragenital cases. By contrasting the anatomical features of the two types of cases, we highlight the uniqueness of canine transmissible venereal tumors and discuss the diagnosis, treatment, and prevention of this ancient cancer.",book:{id:"11580",title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg"},signatures:"Chanokchon Setthawongsin, Somporn Techangamsuwan and Anudep Rungsipipat"},{id:"82797",title:"Anatomical Guide to the Paranasal Sinuses of Domestic Animals",slug:"anatomical-guide-to-the-paranasal-sinuses-of-domestic-animals",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.106157",abstract:"Paranasal sinuses are paired cavities within the skull, which develop by evagination into the spongy bone between the external and internal plates of the cranial and facial bones. Thus, each sinus is lined by respiratory epithelium and has direct or indirect communication to the nasal cavity. The purpose of this chapter is to present an anatomical reference guide of the paranasal sinuses in domestic animals, including large and small ruminants (cattle, buffalo, sheep, and goats), camels, canines (dog) and equines (horse and donkey), appropriate for use by anatomists, radiologists, clinicians, and veterinary students. Topographic descriptions and the relationships between the various air cavities and paranasal sinuses have been visualized using computed tomography and cadaver sections images. The anatomical features (including head bones, muscles, and soft tissues) have been compared using both dissected heads and skulls and computed tomography images. This chapter will therefore be useful as a normal reference guide for clinical applications.",book:{id:"10665",title:"Updates on Veterinary Anatomy and Physiology",coverURL:"https://cdn.intechopen.com/books/images_new/10665.jpg"},signatures:"Mohamed A.M. Alsafy, Samir A.A. El-Gendy and Catrin Sian Rutland"}],onlineFirstChaptersTotal:26},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,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:333,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:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:125,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,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:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,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:"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 17th, 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:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. 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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},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,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. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"117248",title:"Dr.",name:"Andrew",middleName:null,surname:"Macnab",slug:"andrew-macnab",fullName:"Andrew Macnab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. 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A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",institutionString:null,institution:{name:"Universidade Paulista",institutionURL:null,country:{name:"Brazil"}}},{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBfcQAG/Profile_Picture_1631354558068",institutionString:"Universidad Michoacana de San Nicolás de Hidalgo",institution:{name:"Universidad Michoacana de San Nicolás de Hidalgo",institutionURL:null,country:{name:"Mexico"}}},{id:"161556",title:"Dr.",name:"Maria Dos Anjos",middleName:null,surname:"Pires",slug:"maria-dos-anjos-pires",fullName:"Maria Dos Anjos Pires",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS8q2QAC/Profile_Picture_1633432838418",institutionString:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}},{id:"209839",title:"Dr.",name:"Marina",middleName:null,surname:"Spinu",slug:"marina-spinu",fullName:"Marina Spinu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLXpQAO/Profile_Picture_1630044895475",institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",institutionURL:null,country:{name:"Romania"}}},{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",institutionString:'Scientific Veterinary Institute "Novi Sad"',institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}]},onlineFirstChapters:{paginationCount:18,paginationItems:[{id:"83115",title:"Fungi and Oomycetes–Allies in Eliminating Environmental Pathogens",doi:"10.5772/intechopen.106498",signatures:"Iasmina Luca",slug:"fungi-and-oomycetes-allies-in-eliminating-environmental-pathogens",totalDownloads:0,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Animal Welfare - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11579.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"82991",title:"Diseases of the Canine Prostate Gland",doi:"10.5772/intechopen.105835",signatures:"Sabine Schäfer-Somi",slug:"diseases-of-the-canine-prostate-gland",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"82773",title:"Canine Transmissible Venereal Tumor: An Infectious Neoplasia in Dogs",doi:"10.5772/intechopen.106150",signatures:"Chanokchon Setthawongsin, Somporn Techangamsuwan and Anudep Rungsipipat",slug:"canine-transmissible-venereal-tumor-an-infectious-neoplasia-in-dogs",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"82797",title:"Anatomical Guide to the Paranasal Sinuses of Domestic Animals",doi:"10.5772/intechopen.106157",signatures:"Mohamed A.M. 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