Characteristics of the radioisotopes used in synovectomy.
\r\n\tAlthough the microorganism was later described by several other researchers with multiple synonyms, Escherich was recognized as the first, establishing the definitive name of the microbe as Escherichia coli in 1954.
\r\n\tIn 1933, Alfred Adam showed that certain serotypes of "dyspepsia Koli" (as he called the diarrheagenic E. coli strains) were implicated in epidemics of pediatric diarrhoea. In 1944, Kauffman proposed a classification scheme that is still in use today for the purpose of differentiating commensal types from pathogens and subclassifying them.
\r\n\tEscherichia coli, in its natural habitat, lives in the intestines of most healthy mammals. It is the main facultative anaerobic organism of the digestive system. In healthy individuals, that is, if the bacterium does not acquire genetic elements that encode virulent factors, the bacterium acts as a commensal forming part of the intestinal microbiota and thus helping the absorption of nutrients.
\r\n\tIn humans, E. coli colonizes the gastrointestinal tract of a neonate by adhering to the mucus of the large intestine within a few hours of birth. Since then, it remains in a relationship of mutual benefit. However, these commensal strains can cause infections in immunosuppressed patients.
\r\n\r\n\tPathogenic strains of E. coli, on the other hand, as soon as they colonize a healthy host, can cause infections of varying severity in the intestine, urinary tract, meningitis, and sepsis, among other infections.
\r\n\tDiarrhea caused by pathogenic strains of E. coli is an important cause of death in children under 5 years of age, especially in sub-Saharan Africa and South Asia, where it is one of the four most important causes of moderate and severe diarrhea, potentially lethal An increase in mortality is associated with enteropathogenic strains.
\r\n\tUrinary tract infections are more common in women because of the short length of the urethra (25 to 50 mm) compared to men (about 15 cm). Among the elderly, urinary infections tend to be of the same proportion between men and women.
\r\n\tBecause the bacteria invariably enter the urinary tract through the urethra (an ascending infection), poor hygiene habits can predispose to infection; however, other factors become important, such as pregnancy, benign or malignant hypertrophy of the prostate, and in In many cases, the initiating event of the infection is unknown. Although ascending infections are the cause of lower urinary tract infections and cystitis, this is not necessarily the cause of upper infections such as pyelonephritis, which may have a hematogenous origin.
A proteoglycan-rich matrix, the perineuronal net (PNN) is a dense structure within the extracellular matrix (ECM), whose synapses form through gaps around many neuronal bodies and dendrites at a late stage in brain development. PNNs are formed at the end of a critical period of neurodevelopment, following the transformation of the central nervous system (CNS) from an environment conducive to neuronal growth and motility to one that is more restrictive, in response to several sensory inputs from both neurons and glia driving increased neuroplasticity [1]. The main components of the PNN matrix include several chondroitin sulfate proteoglycans (CSPGs), such as hyaluronan, link proteins, and tenascin-R and -C.
During mammalian development, hyaluronan binds to members of the lectican family originally produced in neurons, including versican V0 and V1 and neurocan [2], whereas aggrecan seems to be expressed by astroglial cells in the juvenile matrix [3]. Other lecticans include versican 2, brevican, phosphacan, tenascin-R and the link proteins HAPLN2/Bral1 and HAPLN4/Bral2 are only observed in more mature matrix environments approximately 2 weeks after birth [4, 5, 6], in contrast to the composition of the juvenile matrix. Following this period, shifts in brevican expression occur at the end of myelination, leading to white-matter precursor changes from an oligodendroglial to an astrocytic lineage [7], and resulting in a compact extracellular matrix forming the PPN [8].
PNNs have been observed 2–5 weeks after birth around parvalbumin (PV+)-expressing GABAergic interneurons in pyramidal cortex, and around large motor neurons of the brainstem and spinal cord. This period coincides with the end of experience-dependent refinement of the synaptic network [8], but marked by a still critical period of matrix turnover and proteoglycan degradation by ADAMTS metalloendopeptidases and matrix metalloproteinases (MMPs) [8, 9]. PNN formations can also be observed in several distinct areas of the CNS, such as other regions of the cerebral cortex, the hippocampus (HPC), thalamus, and cerebellum [8].
PNNs in the adult CNS secrete hyaluronan through the action of membrane-bound HA synthase, an enzyme linked to the action of link proteins, lecticans, tenascin-R and chondroitin sulphate proteoglycans (CSPGs), creating supramolecular aggregates on the surface of neurons [1]. Other relevant glycoproteins besides CSPGs include Reelin, mainly secreted by Cajal–Retzius cells and involved in the control of neuronal migration and the establishment of cell aggregation and dendrite formation during the embryonic and early postnatal stages of development [10]. In adulthood, Reelin signalling is involved in the modulation of synaptic function and binds to very-low-density lipoprotein receptors and apolipoprotein E receptor 2 [11]. Increased clustering of Reelin receptors leads to a build-up of DAB1 proteins on the neuron membrane, greater activation of Src/SFK family kinases, and tyrosine phosphorylation of N-methyl-D-aspartate receptors (NMDARs), resulting in a net increase of receptor activity (Figure 1) [12]. Reelin insufficiency may lead to alterations in NMDAR clustering and LTP, such as in dysfunctional GABA-ergic transmission in the cerebral cortex and hippocampus observed among the morphofunctional signalling changes in schizophrenia (SZ) [12].
Effect of Reelin concentrations in the ECM on NMDA signalling. Reelin activates adaptor protein disabled 1 (DAB1) by binding with its very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (APOER2). DAB1 is phosphorylated by Src family kinases (SFK) at different sites on the protein - this phosphorylation occurs mainly through the action of a co-receptor, tyrosine kinase receptor (RTK or Trk), implicated in a variety of cellular processes including growth, differentiation, and regulation of energy metabolism in the neuron. DAB1 phosphorylation leads to inhibition of the serine/threonine kinase Gsk3β via protein kinase B (Akt), where a decrease in AKT phosphorylation levels with subsequent high levels of GSK-3β phosphorylation, has been observed in lymphocytes and brains of individuals with schizophrenia (SZ). Clustering of Reelin receptors via SKF activation also leads to greater tyrosine phosphorylation of N-methyl-D-aspartate receptors (NMDARs), resulting in a net increase of receptor activity following the induction of long-term potentiation via Ca2+ regulation. This signalling cascade appears to be an essential process for neurobiological regulation during neurodevelopment (modified from [
In fact, alterations of GABAergic signalling within a prenatal stress period have been identified as important factors in the development of SZ [13], autism spectrum disorder (ASD) [14], and epilepsy [15], often leading to an altered density of GABAergic cells and aberrant oscillatory activity. However, one functional model of brain development has proposed that prenatal stress involves DNA methylation, possibly inducing methylation of the gene responsible for Reelin promoter, with the consequent down-expression of Reelin resulting in abnormalities within the neuronal architecture of the prefrontal cortex, a reduction in dendritic complexity and a decreased number of GABAergic neurons, leading to altered developmental neuronal connectivity [13].
Animal studies have demonstrated that DNA methylation in the BDNF gene controls its expression during forebrain development in mice [16]. Furthermore, binding of BDNF and nerve growth factor (NGF) neurotrophins to their respective receptors (TrkB/A) triggers the PI-3kinase/AKT pathway, with activation of the mammalian target of rapamycin (mTOR) [17] and Akt-dependent inhibition of the serine/threonine kinase Gsk3β, resulting in decreased transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) [18]. Since Reelin/lipoprotein receptors do not contain a cytoplasmic kinase domain, the core Reelin signalling pathway seems to be associated with tyrosine kinase receptor (RTK or Trk) activity [19], the most likely coreceptor candidate [20]. As such, Reelin signalling from the ECM in collaboration with TrkB/A receptor activation, leads to increased phosphorylation of serine-9 GSK3β, with the inhibition of GSK3β in glial cells and leukocytes resulting in more CREB being translocated from the cytoplasm to the nucleus, and an increase in the transcription of anti-inflammatory cytokines (IL-10) (Figure 2) [21].
Hypothetical signalling cascades for GSK3β modulation of the expression of pro-inflammatory and anti-inflammatory cytokines in glial cells. Receptor crosstalk between receptors TrkB/A and Reelin in the ECM (see
PNN development and the maturation of PV+ inhibitory cells, as well as processes such as myelination, mark the end of the critical period of human neurodevelopment [22]. Disruption or delay to the formation of the PNN results in the resumption or extension of the time window for neuroplasticity in the brain [23], wherein the nervous system is more sensitive to epigenetic, physical, biochemical, environmental, and nutritional factors. The effects of nutrition on individuals during gestational and early development have been extensively researched, leading many researchers to conclude that nutritional factors such as vitamins, folate and iodine can cause long-lasting impacts in neurodevelopment [24, 25]. As the foetus’ and newborn’s acquisition of vitamins like B12 and D, depends to a great extent on maternal diet, such research has increasingly focussed on the impact of the mothers’ vitamin deficiency on their offspring’s brain development during the foetal and exclusive breastfeeding stages.
S-adenosyl methionine (SAM) is a universal methyl donor for some of the main methylation reactions. Vitamin B12 is an important cofactor in the one-carbon cycle and is involved in the formation of SAM. Vitamin B12 supplements have been shown to improve pregnancy outcomes and reduce the risk of neurodevelopmental disorders in the developing child [26]. In rats, dose-dependent vitamin B12 supplementation was able to maintain the levels of docosahexaenoic acid (DHA) and BDNF in the hippocampus and cortex in pups at birth, and BDNF in the hippocampus at 3 months of age [17]. In addition, the combination of omega-3 fatty acid and vitamin B12 administration maintained spatial memory performance in neonates [17]. Experimental evidence suggests that DHA, together with greater levels of physical exercise, increases activated forms of CREB and synapsin I, reducing oxidative stress in the hippocampus [18].
Vitamin D deficiency may also reduce the integrity of PNNs and synaptic plasticity in neuropsychiatric disorders through the modulation of MMPs. Vitamin D deficiency has been associated with vulnerability to SZ [27], as well as ASD [28] and attention deficit and hyperactivity disorder (ADHD) [29], the two most common neurodevelopmental disorders. As mentioned earlier, ADAMTS and MMPs are two families of endogenous zinc-dependent proteases, secreted as inactive proenzymes that cleave ECM components. Alterations in the genes that encode MMP-16 and MMP-9 have been observed in patients with SZ [30]. High levels of MMP-9 can support the proteolytic cleavage of ECM with permissive synaptic plasticity but also lead to abnormal aggrecan degradation, abnormal development and neural excitability [30]. Chronic stress and neurological trauma can enhance MMP-9 levels in the brain [31, 32], and consequently raise the risk of SZ. A plausible proposal has been made that vitamin D deficiency leads to PNN degradation in patients with SZ [27]. In fact, vitamin D deficiency is associated with increased MMP-9 production [33] and calcium activity on the neuronal membrane, leading to increased nitric oxide (NO) formation and higher MMP-9 levels, and further appears to modulate its endogenous inhibitor TIMP1 (tissue inhibitor of MMP) [34]. Aggrecan-rich PNNs undergo restructuring leading to the occurrence of more synaptic anomalies and greater network dysfunction in GABAergic, glutamatergic, and dopaminergic neurotransmission, as evidenced by some forms of SZ (Figure 3) [34]. Cognitive deficits, such as spatial learning deficits, have been observed in adult mice with vitamin D deficiencies, with reduced density of PNNs and neural networks within the hippocampus [35].
Vitamin D deficiency and PNN formation during neurodevelopment. The figure above shows a neuron enveloped by a PNN. Vitamin D deficiency may induce a deficit in ECM organisation over the course of neurodevelopment, leading to the PNN loss and network-wide dysfunction in GABAergic, glutamatergic, and dopaminergic neurotransmission. Vitamin D deficiency is also linked to altered transcription of calcium channels (L-VGCC) potentially increasing the level of calcium input into the neuron, and to altered neuronal nitric oxide synthase (nNOS) activity, resulting in an increase of nitric oxide (NO) secretion into the extracellular space and elevated levels of MMP-9. This enhanced MMP-9 expression induces increased aggrecan synthesis, resulting in disruptions to the network of several neurotransmission systems important for normal cognitive function (spatial learning deficits), and SZ, autism and ADHD. Abbreviations: L-VGCC: L-type voltage-gated calcium channel; ECM: Extracellular matrix; MMP-9: Matrix metalloproteinase-9; nNOS: Neuronal nitric oxide synthase; NO: Nitric oxide; PNN: Perineuronal net; SZ: Schizophrenia; ADHD: Attention deficit and hyperactivity disorder (modified from [
Vitamin B12 is a member of the cobalamin family and can usually be obtained in sufficient quantities from meat, eggs, and dairy products. It is critical for the production of red blood cells, and the growth and maintenance of the nervous system.
Major causes of vitamin B12 deficiency include autoimmune pernicious anaemia, gastrectomy, ileal resection, pancreatic insufficiency, and malabsorption syndromes [36]. The human body is incapable of endogenous B12 production so it must be obtained from external sources in the individual’s diet [37, 38]. Currently, a nutritional B12 deficiency is common in vegans, a fast-growing eating trend in many Western countries [39]. Vitamin B12 deficiency is also common in developing countries, with more widespread occurrence over more widespread sections of society beginning in early life and persisting throughout adulthood [40].
Pregnant women require a greater amount of vitamin B12 (2.5 g/day) compared to the general adult population (2.4 g/day), to adequately meet the nutritional needs of the foetus via absorption through the placenta [41]. The lack of sufficient vitamin B12 ingestion by the mother during pregnancy results in its deficiency in breast milk and the foetal bloodstream [42, 43]. Indeed, several studies have linked maternal deficiency in vitamin B12 concentration to developmental complications, including spontaneous abortion [44], low birth weight [45, 46], intrauterine growth restriction [45], and neural tube defects [47]. Lack of sufficient vitamin B12 in the mother’s diet is reflected in similarly low concentrations of B12 in the bloodstream of breastfed babies during the period of exclusive breastfeeding, when the baby is dependent on breast milk for vitamin absorption, despite the relatively short window of this development period [48].
As in adults, vitamin B12 is mainly stored in the newborn’s liver and is used on demand. However, as newborns have limited hepatic reserves, even if they are born at a healthy weight and size, symptoms resulting from vitamin B12 deficiency may appear from as early as 2 months of age [49]. Such symptoms imply a clinical pattern including abnormal pigmentation, hypotonia, liver and spleen enlargement, anorexia and growth failure associated with poor brain growth, which were first described by Jadhav and colleagues in 1962 [50].
Cellular deficiency of vitamin B12 results in slower proliferation and a faster differentiation of neuroblastoma cells [51], which point to its pivotal role in cell division and differentiation. In addition, deficiency of vitamin B12 in rodents is associated with selective brain damage, vascular and cognitive impairment [52], long-lasting functional disabilities in exploratory behaviour, learning and memory functions, and a mild decrease in hippocampal neurogenesis [53]. Moreover, vitamin B12 seems to play an important role in myelination as its deficiency leads to demyelination and may cause severe retardation of myelination during prenatal development [54].
Different mechanisms have been proposed to account for the effects of vitamin B12 deficiency on general neural function, most especially in relation to neurodevelopment. The most well-understood mechanisms are related to the metabolic reactions in which vitamin B12 is the exclusive cofactor for mammalian cells [55], and the importance of the coenzyme forms of vitamin B12, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) to the methionine and methyl groups that are used for DNA synthesis, epigenetic and cellular division.
When vitamin B12 is in MeCbl form it is a cofactor for methionine synthetase, which promotes the methylation of homocysteine (HCY) to methionine required in cases of a reduced methionine status of dietary ingestion. The synthesised form of methionine is subsequently condensed into SAM, which is finally demethylated into S-adenosylhomocysteine (SAH) and is a methyl donor for the conversion of phosphatidylethanolamine to phosphatidylcholine [56]. The altered SAM:SAH ratio may be the result of B12 deficiency as SAH and HCY levels increase while SAM levels decrease. This decreased SAM:SAH ratio may impair the methylation that is necessary for the synthesis of proteins, lipids, and neurotransmitters [57, 58] and leads to inhibition of DNA synthesis and cell division, since folate is not being recycled [59]. These results show that without methionine, the myelin and neurotransmitters considered essential for neurodevelopment cannot be produced. Methionine is synthesised from homocysteine, increased levels of which are observed in many neurodegenerative diseases, and which are functionally linked to brain injury and cognitive impairment [60].
When vitamin B12 is found in adenosylcobalamin (AdoCbl) form, it is required as the cofactor of the enzyme L-methylmalonyl-CoA mutase (EC 5.4.99.2) in the mitochondria and promotes the conversion of methylmalonyl CoA to succinyl CoA. This pathway is important for the mitochondria to reuse propionyl CoA and the energy obtained through the Krebs cycle. In other instances, this pathway may be recruited in response to increased levels of SAM in which the elimination of HCY is necessary [61]. The inappropriate conversion of methylmalonyl CoA to succinyl CoA leads to excessive production of the precursor propionyl CoA, resulting in odd-chain fatty acid synthesis and subsequent incorporation of these abnormal fatty acids into the nerve sheaths, which leads to altered myelin formation, reduced quantities of ethanolamine, phospholipids, and sphingomyelin (Figure 4) [56]. In addition, the inefficient conversion of phosphatidylethanolamine to phosphatidylcholine may impair propionyl CoA production by the mitochondria and the myelination, or lead to demyelination [62]. Myelination, together with synaptic refinement and the physiological maturation of inhibitory neural networks, are key processes of brain development that seem to coincide with the appearance of PNNs. In fact, alterations in these processes are well described in disorders such as SZ and ASD [63, 64].
Cellular processing of vitamin B in normal and deficiency conditions. Transcobalamin (TC) binds to vitamin B12 with high affinity and transports it by TC receptor-mediated endocytosis. The TC undergoes degradation into the lysosome, liberating the vitamin B12, that can be in two forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). When the vitamin B is in MeCbl form, it participates in HCY cascade as a cofactor, promoting the methylation of HCY to methionine that is subsequently condensed into SAM, which is finally demethylated into S-adenosylhomocysteine (SAH) and it a methyl donor for the conversion of phosphatidylethanolamine (PE) to phosphatidylcholine. The propionate (propionic acid) reacts with coenzyme A yielding propionyl CoA that is converted first to D-methylmalonyl-CoA and then to L-methylmalonyl-CoA and finally to Succinyl-CoA with the participation of AdoCbl form of vitamin B12 in this step. The deficiency of vitamin B12 leads to an inappropriate conversion of methylmalonyl CoA to succinyl CoA resulting in excessive production of the propionyl CoA, and consequently an increase of odd-chain fatty acid synthesis, and the inefficient conversion of PE to PC may impair propionyl CoA production by the mitochondria, resulting in an altered myelin formation.
Vitamin D is known as the “neglected neurosteroid”, a term proposed by McGrath and colleagues in 2001 [65], and exerts a great variety of effects during brain development.
In 2005, a study conducted the first description of the distribution of 1,25-dihydroxyvitamin D3 receptors (VDR) and 1α-hydroxylase (1α-OHase), the enzyme responsible for the formation of the active vitamin D, in the human brain. They are found both in neurons and glial cells and show a region- and layer-specific pattern of expression in the brain. VDR receptors are absent in the macrocellular cells within the nucleus basalis of Meynert (NBM) and Purkinje cells in the cerebellum, while both VDRs and 1α-OHase have been identified in the substantia nigra and the hypothalamus [66]. VDRs can also be found in the developing brain during the critical period of cell proliferation, in the temporal lobe, cingulate, thalamus, cerebellum, amygdala and hippocampus [67].
Similarly to vitamin B12 deficiency, vitamin D deficiency during pregnancy appears to have serious consequences for foetal health. In the literature, abortions within the first trimester of gestation have been reported in association with the mothers’ lack of sufficient vitamin D concentration [68, 69, 70]. Moreover, as foetus are dependent on access to the mother’s supply of vitamin D, in conjunction with the large distribution of vitamin D receptors in the brain, there is a high probability that the vitamin D status of pregnant mothers may affect child neurocognitive development [67]. Among other sequelae, researchers have found cognitive and neural deficits in foetus and young infants due to maternal vitamin D deficiency during pregnancy, such as suboptimal neurocognitive development [71] and delays in the development of gross and fine motor function, problem-solving and communication [72]. However, a recent study analysed high-dosage vitamin D supplementation in the third trimester of pregnancy and its effects on child brain development and failed to report any improvements in the neurobiological mechanisms underlying developmental behaviour, such as motor milestones and cognitive and language development [73]. Few studies of the direct effects of vitamin D on brain development have been conducted to date in humans and many of them are inconclusive, probably because of differences in the timing of vitamin D exposure, the types of assessment used, and the age at which the assessment occurred.
Studies in rats have identified similar critical periods to vitamin B12 during neurodevelopment in which maternal vitamin D deficiency can result in neurodevelopmental alterations, such as abnormal cell proliferation and decreased expression of neuronal structure genes in the brain of mice offspring [74]. VDRs are temporally regulated in the rat brain during development, with the first VDR expression occurring in the mesencephalon on day 12 [75]. VDR expression continues across different areas throughout the course of development [75, 76] and is directly correlated to the onset of natural cell elimination [77]. Because of its key role in regulating developmental processes throughout the brain, altered levels of vitamin D or VDR dysfunction can result in long-lasting behavioural disruption in animal models [67]. Consistent with its role in PNN formation, altered vitamin D levels and VDR signalling during development have been associated with neuropsychiatric disorders such as SZ [78] and autism [79, 80].
The mechanisms by which vitamin D influences brain development are diverse. There is evidence that vitamin D modulates neurotrophic factors such as NGF and glial cell line-derived neurotrophic factor (GDNF), suggesting that it may have a neuroprotective function [81, 82]. Other neuroprotective functions of vitamin D include the reduction of the neurotoxicity of glutamate and reactive oxygen species (ROS), the upregulation of antioxidant molecules [83, 84], and the suppression of macrophage activity, leading to decreased neuroinflammation activity [85]. When used as an immune suppressant, vitamin D has been reported to suppress the concentration of proinflammatory cytokines in the brain [86, 87], to reduce blood–brain barrier disruption and macrophage/microglia activation in induced autoimmune encephalomyelitis [88], and to attenuate proinflammatory processes and up-regulate anti-inflammatory processes such as the M2 microglia phenotype, in a mouse model of Parkinson’s disease [89].
Vitamin D is known to reduce calcium levels in the brain, preventing cell death via excitotoxicity, and to downregulate or modulate L-type voltage-gated calcium channels (L-VGCCs) [90] (Figure 5). L-VGCCs are expressed in great quantity in the developing brain and have a critical role in synaptic plasticity and in regulating basal and burst firing activity in dopaminergic neurons within the ventral tegmental area [91]. Interestingly, disruption of L-VGCC function in hippocampal PV+ interneurons during development leads to significant morphological changes, such as reduced cell number and a decrease in dendritic arbour complexity [92, 93].
Effects of vitamin D in presynaptic transmission Vitamin D plays an important role in several neurodevelopmental processes, such as neurotransmission and calcium signalling, preventing cell damage, especially mitochondrial dysfunction. As mentioned above, vitamin D acts by regulating L-VGCC in order that, for example, prevent the accumulation of intracellular calcium and the concomitant activation of pathways that can lead to cell death. With vitamin D deficiency, L-VGCC becomes functionality altered, leading to increased intracellular calcium, mitochondrial dysfunction, and the consequent generation of free radicals such as reactive oxygen species (ROS) and inhibitory/excitatory synaptic imbalance, illustrated by the increase in glutamate release and GABA neurotransmitter decrease, resulting in excitotoxicity and neuroinflammation (modified from [
The association between vitamin D and L-VGCC function in the dopaminergic system and PV+ interneurons strengthen the hypothesis that vitamin D (dys) regulation plays a role in the onset of SZ [94]. Both epidemiological research and rodent models have shown a correlation between vitamin D deficiency and SZ. Alterations in the dopaminergic system have been frequently reported in response to vitamin D deficiency, consistent with increased VDR expression in brain areas primarily innervated by dopaminergic projections [95].
Associations have also been made between vitamin D receptors, calcium channels, PV+ interneurons and PNNs. L-VGCCs regulate PV+ expression and interneuron development [92] which are significantly disrupted in SZ. Curiously, the appearance of PNNs coincides with the synaptic refinement, myelination and maturation of inhibitory networks, and there is therefore strong evidence that PNNs have a pivotal role in the pathogenesis of SZ [63].
Following this same reasoning, vitamin D deficiency is considered a potential candidate for the development of several key alterations in ASD pathophysiology, most of them present mid to early development. John Cannell has been the main proponent of this hypothesis [96] and since its inception a number of studies have contributed to this line of research. The pathophysiology of ASD is multifactorial with solid evidence for both a genetic background and an environmental component. Some epidemiological findings have raised the additional hypothesis of specific genes which are environmentally responsive to the ASD, as epidemiological observations have pointed to changes in genotype expression. Cannell and others have cited neurosteroid pathway genes as good examples of environmentally responsive genes, since alterations in neurosteroid concentration may affect the genetic expression of the neural proteins regulated by steroids.
As already mentioned before, PNNs appear during postnatal development and surround cortical inhibitory GABA neurons expressing PV+, which control the output of mainly cortical and hippocampal neurons and are necessary for fast rhythmic neuronal synchrony during information processing in cognitive tasks [97, 98]. PNNs enveloping PV+-inhibitory interneurons are known to be vital for cognition [99]. These cortical PV+-inhibitory interneurons express specific NMDA receptor (NMDAR) subunits such as NR2A, and are targets of the NMDA receptor antagonist MK-801. MK-801 is the main component for studying an important hypothesis for our understanding of the aetiology of SZ, the cortical hypofunction of NMDA receptors (i.e. the glutamatergic hypothesis) [100]. This hypothesis is compatible with the concurrent descriptions provided by the neurodevelopmental hypothesis, with respect to the disruptions to the central nervous system over the course of development [101].
An animal model using MK-801 treatment revealed a critical postnatal period, specifically from 7 to 14 days after birth (P 7–14), resulting in SZ-like behaviour during adulthood, with a significant reduction in PV+-expressing cells in the PFC but not in the hippocampus, for mice treated with MK-801 from P 7–14 compared to matched controls [102]. In addition, mice in the treated group showed changes in performance on cognitive, social and behavioural tasks, while electrophysiological recordings from brain slices within the PFC showed significantly reduced frequency of up-states in MK-801-treated mice, but increased gamma activity in MK-801-treated mice compared to saline-treated mice [102]. Recent memory reactivation has been shown to occur in the presence of slow oscillatory up-states, contributing to memory consolidation [103]. This electrophysiological profile is altered in humans with SZ, with increased delta oscillations and irregular gamma rhythm [104, 105]. Moreover, PNN removal from visual cortex during a critical postnatal period alters the balance between excitatory and inhibitory PV+ spiking activity, inducing greater potentiation of gamma activity and restoring the neural network to an immature or juvenile ECM state, suggesting that the maturation of GABAergic fast spiking and PV+-inhibitory neurons suppresses the spontaneous activity of excitatory neurons [106].
Together with these electrophysiological findings, the metabolic requirements of PNN function have also been explored in fast-spiking cells, as well as their intrinsic vulnerability. In fact, PNNs appear to promote interneuron maturation and network stability and may also protect neurons against iron sequestration and oxidative stress [107, 108]. Oxidative stress has been observed in the PFC of SZ patients in conjunction with decreased levels of glutathione (GSH), an endogenous antioxidant and redox regulator [109]. This outcome can in turn be aggravated by the overexpression of truncated DISC1 that is associated with SZ in humans, causing mitochondrial dysfunction with decreased mitochondrial NADH dehydrogenase activity, diminished cellular ATP contents, and overactivity of mitochondrial Ca2+ mechanisms [110].
As mentioned previously with regards to the role of GSH, there are two metabolically active forms of vitamin B12, AdoCbl, and MeCbl: essential as a cofactor for the reaction necessary folate-dependent methylation of HCY by methionine synthase (MS) in the cytoplasm. As MS levels determine the ratio of methyl donor SAM to the endogenous methylation inhibitor SAH, the MeCbl reaction can influence SAM-dependent methylation reactions mainly through methylation of DNA and histones [111], an effect previously described with in relation to BDNF and epigenetic control. Zhang et al. 2016 analysed the postmortem human frontal cortex of autistic and schizophrenic individuals and 80-year-old individuals and found that the MeCbl form of vitamin B12 decreases with age, as well as to age of onset of ASD and SZ, as compared to age-matched controls. Additionally, they also observed an abnormally lower total cobalamin Cbl and MeCbl concentration in ASD and SZ subjects, leading the authors to propose a “Redox/Methylation Hypothesis of Autism” in light of the impaired GSH-dependent synthesis observed in the brains of autistic individuals [111]. In the same study, the authors further found that certain brain regions, as cerebellum and temporal cortex, in ASD, showed synthesis of reduced and oxidised glutathione (GSH/GSSG) (stable redox status), while other regions maintained SAM/SAH production (stable methylation status) [111], suggesting regional differences for metabolic disorders.
Concomitantly, several neurobiological changes found in ASD subjects or ASD animal models are consistent with an account of vitamin D deficiency. The main neurobiological processes mediated by vitamin D in neurodevelopment include neural cell proliferation [74], GABA, glutamate and serotonin neurotransmission [92], calcium signalling, mitochondrial regulation, oxidative stress and neuroinflammation (for review see [112]). Most of these processes are altered in ASD, resulting in the reduction of brain volume and changes in the number of glial and neuron cells, excitatory/inhibitory imbalance, disrupted calcium signalling, increased oxidative stress, the overactivation of microglia, and immune system dysregulation [113].
One of the best-studied hypotheses about the pathophysiology of ASD is the occurrence of changes in brain connectivity during development, which posits a reduced number of connections between distal brain regions and an increase in connections between proximal brain regions [114]. However, this hypothesis shows some inconsistencies in the light of several findings, such as reports of hyperconnectivity over long axonal fibres in autism or even mixed patterns of hypo- and hyper-connectivity [115, 116, 117, 118].
Another hypothesis regarding the pathophysiology of ASD is one of excitatory-inhibitory imbalance, caused both by the probable hyperactivity of excitatory cells and a reduction in the number, activity or even delay of inhibitory interneurons in the maturation process [119, 120, 121].
PV+-expressing interneurons are the main regulators of inhibitory/excitatory balance and orchestrate the coordinative function of brain microcircuitry via their fast-spiking inhibitory inputs onto pyramidal neurons [97, 122]. As such, the healthy maturation of PV+-interneurons is crucial for the establishment of optimal neural and behavioural development. Disruption to PV+ expression in PFC caused by early-life adversity leads to altered social interactions [123] and anxiety-related behaviour in rodents [124, 125]. Both forms of altered behaviour can be found in patients diagnosed with ASD [126, 127, 128].
As mentioned previously, the maturation of PV+ interneurons are mostly regulated by PNNs [129, 130]. Despite the protective actions of the PNN-PV+, the interneurons are very susceptible to oxidative stress [131, 132], and as such vitamin D deficiency represents a threat to the integrity of PNN function and consequently to the development of the GABAergic system.
Lastly, it is important to highlight the dysregulation of the immune system that is observed in ASD. ASD patients suffer from chronic systemic inflammation with a disbalance in cytokine expression, leading to increased production of proinflammatory cytokines. Vitamin D has been shown to contain immunomodulatory properties and may be an alternative treatment for slowing or minimising behavioural alterations in ASD (for review see [133]). Chronic systemic inflammation in early life may disrupt PV+ interneuron maturation and consequently lead to changes in PNNs. Taken together, these findings reveal the important role of vitamin D in maintaining the integrity of PNNs and the efficiency of synaptic transmission as a whole.
The ECM is one component of the tetrapartite synapse, together with the network of glial cells. The PNN is a dense ECM structure that enwraps inhibitory fast-spiking parvalbumin (PV+) interneurons, serving both as a protective barrier and to regulate synaptic plasticity. The destruction of those PNNs during the critical postnatal period of brain development alters the balance between excitatory and inhibitory PV+ spiking activity, inducing a greater potentiation of gamma-band activity, and reverting the firing pattern of the neural network to a so-called immature or juvenile ECM state. Studies have shown that a vitamin D deficiency in early development may lead to a reduction in the PNN integrity and synaptic plasticity through modulation of MMPs, contributing to increased risk of the onset of neuropsychiatric disorders, as SZ, ASD, and ADHD. Also, in preclinical studies, dose-dependent vitamin B12 supplements were sufficient to maintain the levels of DHA and BDNF in the hippocampus and cortex in neonates, and BDNF levels in the hippocampus at 3 months of age, considered a sensitive window or critical period during neurodevelopment. In addition, the ingestion and metabolism of vitamin B12 methylcobalamin (MeCbl) variants can influence S- adenosyl methionine and SAM-dependent methylation reactions, mainly through the methylation of DNA and histones, and the MeCbl deficiency can result in impairment of GSH-dependent synthesis, inducing oxidative stress in the PFC of schizophrenic patients, or with autism diagnosis. Thus, adequate levels of vitamin B12 and D appear to contribute to maintaining the integrity of PNNs, consequently lead to PV+ interneuron maturation.
The authors wish to thank IntechOpen for their support and payment of the Open Access Publishing Fee.
The authors declare no conflict of interest.
The treatment of joints using radioactive material began in the 1950s, more specifically in 1952, with chromic phosphate P32 [10]. It was initially aimed at joint involvement caused by rheumatoid arthritis and, to a lesser degree, pigmented villonodular synovitis, ankylosing spondylitis, collagenosis and psoriatic arthritis in the years that followed [24]. With the advent of longer follow-up studies, it has also benefitted rheumatic diseases and haemophilic arthropathy, which exhibit a similar sequence of events including repetitive intra-articular haemorrhages causing synovitis, joint pain, limited mobility and posterior muscular atrophy. Recurrent synovitis results in cartilage destruction, progressive loss of movement, joint deformities, bone damage and ultimately total ankylosis. The treatment procedure was originally denominated synovectomy (from the Greek ‘ectomía’ meaning ‘to cut out’) and later synoviorthesis (from the Greek word ‘orthesis’ meaning ‘restoration’) via radionuclides [8].
\nDifferent radioactive materials have been used to eradicate synovitis, some emitting only beta radiation and others beta and gamma radiation. Synovectomy in haemophilia using radioactive material began in 1971 [1]. Since then, a variety of materials have been used, including P32, colloidal 198Au, 186Re, 90Y, 165Dy, 166Ho, and 169Er. \nTable 1\n shows the characteristics of the materials used [1, 12, 16, 17, 18, 21, 28].
\nRadioisotopes | \nHalf-life (days) | \nMax. beta energy (MeV) | \nGamma energy (KeV) | \nPenetration (mm) | \nParticle size (μm) | \nLeakage (%) | \n|
---|---|---|---|---|---|---|---|
Max. | \nAv. | \n||||||
Colloidal 198Au | \n2.7 | \n0.96 | \n110 | \n3.6 | \n1.2 | \n0.02–0.04 | \n20–35 | \n
P32 (chromic phosphate) | \n14.0 | \n1.7 | \n– | \n7.9 | \n2.6 | \n0.05–0.1 | \n2–4 | \n
186Re (sulphide colloid) | \n3.75 | \n1.07 | \n140 | \n3.6 | \n1.2 | \n0.05–0.1 | \n2 | \n
Colloidal 90Y | \n2.7 | \n2.2 | \n– | \n10.8 | \n3.8 | \n1.5–3.5 | \n3 | \n
166Ho (FHMA) | \n1.2 | \n1.85 | \n81 | \n8.7 | \n2.2 | \n1.82–12 | \n1 | \n
165Dy (FHMA) | \n0.095 | \n1.3 | \n95 | \n5.6 | \n1.4 | \n0.8–12 | \n1 | \n
169Er (citrate) | \n9.4 | \n0.34 | \n– | \n1.0 | \n0.3 | \n0.1–10 | \n1 | \n
153Sm (HA) | \n1.95 | \n0.80 | \n100 | \n3.1 | \n0.8 | \n1–10 | \n0.1 | \n
Characteristics of the radioisotopes used in synovectomy.
FHMA = ferric hydroxide macroaggregates.
Irradiation occurs via the intra-articular retention of the radioactive material. However, it should be noted that the radioactive material is bound to larger particles, known as carriers, which undergo phagocytosis by the macrophages in the inflammatory process, favouring greater retention in the joint space. These macrophages migrate through the interstice of synovial cell layers, resulting in more homogeneous action by the ionising radiation. This behaviour was highlighted in autoradiographic studies [7], which more clearly indicate the location of samarium-153 particulate at different synovial tissue depths than other materials used, such as 186Re. This is also reported by Schneider et al. [23] (shown in \nFigure 1\n), in addition to direct irradiation by the intra-articular radionuclide. As such, average penetration is ascertained by the range of the β particle and maximum penetration by macrophage permeation into synovial cell layers.
\n(A) β-Emitting colloidal particles (yellow stars) phagocytised by inflamed hypertrophic synovial lining with proliferating synoviocytes (pink). The cartilage layer remains unaffected. (B) Subsequent cell damage and sclerosis of synovial membrane.
Another noteworthy aspect is that radionuclide leakage from the joint is inversely proportional to particle size. This is clearly evident in the last two columns of \nTable 1\n. The presence of gamma radiation allows synovectomy to be monitored over several days via scintigraphy.
\nHaemophilia is a congenital bleeding disorder linked to the X chromosome of the human genome, with the two most common types being haemophilia A, a lack of blood clotting factor VIII, and haemophilia B, caused by missing of defective factor IX. Joint bleeding associated with muscle bleeding represents 90% of bleeding episodes in haemophilia patients, while haemarthrosis alone accounts for 70–80% of these episodes. In 80% of cases, haemarthrosis occurs in the knees, elbows and ankles [22], producing inflammatory changes in the synovial membrane. Recurrence of this inflammation over time triggers a chain of events that lead to joint ankylosis, including the direct damage of blood on the articular cartilage [15].
\nIn cases of arthropathy mediated by reactive synovitis, synovectomy with radioactive material is an alternative to intra-articular injection of glucocorticoids and other chemical agents (osmic acid, collagenase, rifocin and thiotepa) or surgery. Furthermore, radiosynovectomy, introduced by Ahlberg in the 1970s, has been proposed as a first-line treatment option for haemophilic arthropathy [22, 23].
\n153-samarium was obtained in an IEA-R1 research reactor (IPEN-CNEN, São Paulo, Brazil) by neutron irradiation of 152Sm2O3 (99.4%) in the nitrate form, 152Sm(n,p)153Sm, for 30–36 h. The labelling process was performed with 40 mg of hydroxyapatite, using appropriately sized particles (20 μm), according to Barboza et al. [2]. Percentage bound activity or labelling efficiency was determined by centrifugation, measuring the activity of the precipitate (153Sm-HA) and supernatant (153Sm-free) using a dose calibrator, and was always >90%. Radiochemical purity was higher than 98%, measured using Whatman 3MM paper chromatography (from GE, Milwaukee, WI, USA) in 0.9% saline, remaining stable for 24 h. Particle size was determined by laser scattering and filtration in a filter system of known sizes (1–15 μm), with a mean of 10 μm (range: 3–12 μm). Microbiological tests for sterility and pyrogen were always negative in all samples.
\nParticipants were haemophilic patients with chronic synovitis, monitored at the Department of Haematology – Hospital de Apoio in the Federal District (DF), and the Orthopaedics and Nuclear Medicine Service of the Hospital de Base (DF), between 2002 and 2011.
\nPatients were assessed by clinical history and a physical examination, paying special attention to the compromised joint. Particular emphasis should be given to haematology tests in order to characterise the type and severity of haemophilia, as well as the absence of coagulation inhibition factors. Imaging (radiology) tests make it possible to determine the degree of arthropathy, with the Pettersson score being widely used. Three-phase whole-body scans are used to identify any other joints involved and more accurately characterise the synovial inflammatory process. Other procedures used for this purpose include ultrasound or magnetic resonance imaging (particularly for the knees).
\nInclusion criteria were the following: chronic synovitis when occurs repetitive effusions (minimum: once a month), pain on joint palpation and absence of other joint disease, like the rheumatologic or orthopaedic nature. Exclusion criteria were ruptured Baker’s cyst, major effusions, signs of acute synovitis or presence of an articular or periarticular infectious process.
\nSynovectomy of the radioactive material was made by an orthopaedist with previous use of the deficient clotting factor, applying topical anaesthesia in accordance with the asepsis and antisepsis performances used for invasive intra-articular orthopaedic procedures. The use of ultrasound to guide the punctures was not necessary, as these were assured by the aspiration of synovial fluid before administration of the radionuclide (\nFigure 2\n). Fixed doses of 5 mCi (185 MBq) or 20 mCi (740 MBq) of 153Sm-hydroxyapatite were used, with only one injection administered per patient. The maximum volume of radioactive material was 0.5 mL; material adhered to the puncture site was washed away with saline, at fractions of 0.5 mL, without exceeding the final volume of 1.5–2.0 mL.
\nInjection of the knee.
The reflux and homogeneity (or lack thereof) of the intra-articular material and its escape from the joint were monitored by a scintigraphic study in a gamma camera, with a wide field of vision detector and low-energy collimator. Imaging was made using a 128-pixel matrix and the spectrometer window was centred at 100 keV, using precocious, 1 and 2 h, and later times, 3–7 days, after 153Sm-HA injection. A summary of this protocol is shown in \nTable 2\n.
\n1 | \nUse a coagulation factor before the procedure; | \n
2 | \nLocal asepsis; | \n
3 | \nUse local anaesthetic; | \n
4 | \nJoint puncture using a 21G needle; | \n
5 | \nAspirate synovial fluid; | \n
6 | \nInject 5 mCi of 153Sm-HA into the intermediate joints and 20 mCi into the knees; | \n
7 | \nWash the puncture site with a total of 2.0 mL of saline without using corticosteroids; | \n
8 | \nCompression bandaging using crepe bandage; | \n
9 | \nMonitor the material used in the puncture; | \n
10 | \nFunctionally permissible joint mobility; | \n
11 | \nImmediate (1–2 hours after synovectomy) and later (3–7 days) scintigraphy image | \n
Protocol for synovectomy with 153Sm-hydroxyapatite.
Reactive synovitis may occur in the days following application of the radiopharmaceutical agent, which was treated using conservative measure such as joint rest, local application of ice and a non-steroid anti-inflammatory agent. The cases observed in our study were mild and occurred in 4–8% of joints.
\nRadionecrosis may occur if the material leaks from the administration route. This complication did not occur in the cases we treated because the material was only administered after correct injection and the puncture site was washed with saline to prevent leakage.
\nImmobilisation of the affected limb will ultimately result in thrombosis; however, this was prevented by the protocol used.
\nThere is no concern about possible carcinogenic effects of this procedure. Systemic irradiation can result from fluid leakage or the gamma component of 153Sm. Studies on chromosomal abnormalities in circulating lymphocytes related to samarium [19] have shown no definitive changes, but rather transient and reversible ones. It is important to note that this irradiation is smaller than in diagnosis by conventional bone scintigraphy or whole-body scanning with 67Ga. Considering the local effect at joint level, several studies with long follow-up times have shown no occurrence of tumours [14, 26, 27], indicating that this possibility has not yet been characterised.
\nThe first study was conducted to evaluate the efficiency of treatment with 153-samarium hydroxyapatite (153-Sm-HA) in haemophilic arthropathy. Thirty-one patients (30 males) between 8 and 34 years old (medium age = 20.6 years) were treated with a fixed intra-articular dose of 5 mCi (185 MBq) and divided into two groups: paediatric (13 patients aged up to 18 years, with a medium age of 12.7 years and arthropathy evolution of 7.8 years); and adults (18 patients over 18 years old, with an average age of 24 years and arthropathy evolution of 18.7 years). Clinical assessment before and 1 year after synoviorthesis used the following criteria: subjective (pain according to the visual analogue scale, joint inspection), objective (joint movement through flexion level, pain to palpation and leakage through joint circumference), reduced use of the coagulation factor, number of haemarthroses, and the occurrence of adverse effects. The results were classified as: 1, good (symptom remission of 70–100%); 2, moderate (symptom remission between 40 and 69%); and 3, poor (0–39% symptom remission). Seventy-eight joints were tested: 15 knees, 36 elbows, 24 ankles, 1 shoulder and 2 hips. Early (1–2 h) and late phase scintigraphic imaging (24–72 h) was made after synovectomy. No significant inter-group difference in synovectomy results was observed. The results obtained were good for 75% of elbows, 87.5% of ankles and 40% of knees; reduction in effusions and use of the coagulation factor were, respectively, 78% and 80% for elbows, 82% and 85% for ankles, and 30% and 35% for knees. Four cases of reactive synovitis were observed in the 78 joints tested. Scintigraphy showed homogeneous distribution of the material with no leakage. The introduction of 153Sm-HA in the treatment of the haemophilic arthropathy is effective for intermediate joints (elbows and ankles), but less so for knees. Moreover, this treatment offers excellent safety and is affordable [3].
\nThe penetration of beta energy from 153samarium (153Sm) (0.8 MeV) is not only suitable for synoviorthesis of intermediate joints, but can improve the radionecrosis effect using higher radioactivity levels. The next study assessed the efficacy of 5 mCi (185 MBq) and 20 mCi (740 MBq) of 153-Sm hydroxyapatite (153Sm-HA) in the knees of haemophilic patients. Thirty-one patients (36 knees, 30 males) were divided into two groups without corticosteroid co-injection: 1 – 14 patients (17 knees) treated with an intra-articular dose of 5 mCi of 153Sm-HA, medium age 23 years; 2 – 17 patients (19 knees), administering 20 mCi of 153Sm-HA, medium age 21.3 years. Evaluation before and 1 year after synoviorthesis used the following points: reduction in the number of effusions and use of the coagulation factor, and increment in joint mobility. The occurrence of side effects was also considered. Early and late-phase scintillations studies were made after synovectomy and no articular immobilisation was recommended. Reduction in effusions and use of the coagulation factor, respectively, were: group 1 – 31.3% and 25%; group 2 – 81.5% and 79%, with p < 0.001. No significant increment in knee mobility was observed in either group. Four cases of mild reactive synovitis were observed in each group. Scintigraphy showed homogenous distribution of the radioactive material with no leakage; the material was considered safe by its retention in the joint. A significant increment was observed in the synoviorthesis of haemophilic knees with 20 mCi of 153Sm-HA; the lower penetration of its beta radiation was offset by the improved radiobiological effect when higher radioactivity is used [4].
\nAnother study compared the use of 20 mCi (740 MBq) of 153Sm and 5 mCi (185 MBq) of 90Y, both labelling hydroxyapatite (HA), for knee synoviorthesis in haemophilic patients, 1 year after the procedure. Thirty-three men (36 knees) were studied, divided into two groups: a – injection of 740 MBq of 153Sm-HA: 20 knees of 18 patients, with an average age of 21.4 ± 13.3 years (range: 7–56 years) and medium Pettersson score of 5.3; b – injection of 185 MBq of 90Y-HA: 16 knees of 15 patients, with an average age of 26.3 ± 10.3 (range: 7–51 years) and medium Pettersson score of 6.3. Episodes of haemarthrosis, use of clotting factors and pain intensity were evaluated before and after treatment, as well as improved joint mobility. The occurrence of side effects in the treatment was also considered. The chi-squared, Wilcoxon and Mann–Whitney tests were applied, with a significance level of p ≤ 0.05. The occurrence of effusions decreased by 65.7% with the use of 153Sm-HA and 82.6% for 90Y-HA, without statistical significance between the groups (p = 0.632); pain reduction was 42.5% in group a and 30.7% in group b, again without statistical significance (p = 0.637). Increment in joint mobility was not significative for either group. Two cases of mild reactive synovitis were observed in group a and one in group b, which had resolution without medical intervention. Although the beta energy from 90Y is the more appropriate for knee synoviorthesis, the higher radioactivity levels of 153Sm is an alternative in locations that only produce this material [5].
\nThis study aimed to evaluate synovectomy with 153Sm-hydroxyapatite (153Sm-HA) in synovitis of the elbows and ankles of haemophilic patients. Synovectomy was performed using 185 MBq of 153Sm-HA in 166 joints (63 ankles and 84 elbows) of 82 haemophilic patients (average age 24.4 years) with follow-up of 12 and 42 months. Arthropathy was characterised by recurrent joint bleeding. Episodes of haemarthrosis, use of clotting factors and pain intensity were evaluated before and after treatment. Scintigraphic analyses and adverse effects were also considered. Statistics used p ≤ 0.05. The results indicated: (a) reduction in haemarthrosis was 78% and 68%, in elbows and 82% and 72% in ankles; (b) use of clotting factors was 80% and 70% for elbows, and 85% and 75% for ankles; (c) pain intensity was 37% and 34% in elbows, and 61% and 57% in ankles, after 12 and 42 months, respectively. Among the 166 joints studied, three cases of mild reactive synovitis were observed in ankles and four in elbows, with no leakage in any of the cases. In conclusion, the use of 153Sm-HA in elbows and ankles was effective, very safe, minimally invasive and the results showed consistency at follow-up [6].
\nAnother interesting aspect to consider is treatment repetition. We recommend this be done after 1 year, but a minimum interval of 6 months is permitted.
\nThe radioactive material (153Sm) was aggregated with hydroxyapatite particles to ensure longer intra-articular retention without arterial-venous or peri-articular lymphatic leakage. When the two are separated, the advantage of the compound is that the carrier (hydroxyapatite) enters the body’s metabolism because it is part of the bone matrix.
\nNo escape (lymphatic or vascular) was detected with 153-samarium because when it separates from the carrier (hydroxyapatite), it forms insoluble compounds with the synovial fluid that precipitate in the articulation; this permanence was confirmed by other previous studies [20] and by our controls (see \nFigure 3\n).
\nKnee scintigraphy showing good joint distribution and no leakage.
Scintigraphic images obtained after early and late-phase injection showed appropriate intra-articular distribution, as well as the absence of leakage to regional lymph nodes or other organs, or urinary elimination. The ability to obtain good-quality scintigraphic images is an advantage of 153Sm since gamma emission occurs in the energy amplitude of 100 keV. Another possible advantage is the mild reactive synovitis observed in all the studies, resolved without invasive medical intervention, possibly due to low beta energy penetration.
\nThese studies are among the few that evaluate only the therapeutic effect of intra-articular radioactive material, since it is often administered in conjunction with corticosteroids. This creates bias in result analysis because corticosteroids are also used for the same purpose in the treatment of haemophilic arthropathy [11]. This combination has been called into question [13] and is one of the reasons why we chose not to use it when beginning treatment [3], in addition to the lack of information in the literature characterising the nature of its effect as competitive, additive or synergistic.
\nThe reduction in haemarthrosis for ankles (82%), elbows (78%) and knees (65.7%) was similar to values recorded in other studies of haemophilic patients with different types of radioactive material. A German revision pointed nine studies between 1982 and 1991 with good and excellent results for radiosynovectomy in 60–80% of the haemophilic arthropathy [9]. The findings presented in our studies also corroborate those summarised by Siegel et al. [25] regarding the benefits of radiosynoviorthesis, with an approximate 75% decrease in effusions, few adverse effects and better quality of life in 75% of the cases. This can be extended to shoulders and hips, which exhibited similar results to intermediate joints. Finally, it can be concluded that 153samarium labelled with hydroxyapatite is a useful tool in the treatment of chronic synovitis in haemophilic patients.
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Evans",authors:[{id:"96409",title:"Prof.",name:"Carla",middleName:null,surname:"Evans",slug:"carla-evans",fullName:"Carla Evans"},{id:"96472",title:"Prof.",name:"Budi",middleName:null,surname:"Kusnoto",slug:"budi-kusnoto",fullName:"Budi Kusnoto"},{id:"172854",title:"Dr.",name:"Emilia Taneva",middleName:null,surname:"Taneva",slug:"emilia-taneva-taneva",fullName:"Emilia Taneva Taneva"}]},{id:"18426",doi:"10.5772/18746",title:"Factors Affecting the Success of Dental Implants",slug:"factors-affecting-the-success-of-dental-implants",totalDownloads:17504,totalCrossrefCites:9,totalDimensionsCites:36,abstract:null,book:{id:"179",slug:"implant-dentistry-a-rapidly-evolving-practice",title:"Implant Dentistry",fullTitle:"Implant Dentistry - A Rapidly Evolving Practice"},signatures:"Carlos Nelson Elias",authors:[{id:"32438",title:"Prof.",name:"Carlos",middleName:null,surname:"Elias",slug:"carlos-elias",fullName:"Carlos Elias"}]},{id:"32161",doi:"10.5772/38059",title:"Caries Through Time: An Anthropological Overview",slug:"caries-archaeological-and-historical-record",totalDownloads:6550,totalCrossrefCites:4,totalDimensionsCites:33,abstract:null,book:{id:"1742",slug:"contemporary-approach-to-dental-caries",title:"Contemporary Approach to Dental Caries",fullTitle:"Contemporary Approach to Dental Caries"},signatures:"Luis Pezo Lanfranco and Sabine Eggers",authors:[{id:"115399",title:"Dr.",name:"Luis",middleName:null,surname:"Pezo-Lanfranco",slug:"luis-pezo-lanfranco",fullName:"Luis Pezo-Lanfranco"}]}],mostDownloadedChaptersLast30Days:[{id:"61046",title:"Optical Diagnostics to Improve Periodontal Diagnosis and Treatment",slug:"optical-diagnostics-to-improve-periodontal-diagnosis-and-treatment",totalDownloads:7339,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The performance of clinicians undertaking periodontal assessment or periodontal therapy can be improved by using optical methods as adjuncts to visual inspection and periodontal probing. Subtle changes that occur over time in periodontal tissues that are below the detection limit of visual examination or periodontal probing can be found and tracked accurately over time using 3D imaging, fluorescence spectroscopy, and optical coherence tomography. During debridement of teeth and dental implants, the effective removal of subgingival microbial biofilms and dental calculus deposits can be enhanced using magnifying loupes and operating microscopes and by novel methods based on the interactions of light with bacterial deposits, such as differential reflectometry and light-induced fluorescence. While such techniques can also be used using initial case assessment, their primary purpose is for checking debridement procedures, since the point when bacterial deposits are no longer present represents an endpoint for treatment. The concept of real-time feedback has been developed, using fluorescence readings to control the removal of deposits. Overall, optical methods can support traditional periodontal diagnosis and improve treatment planning and clinical periodontal care.",book:{id:"7244",slug:"periodontology-and-dental-implantology",title:"Periodontology and Dental Implantology",fullTitle:"Periodontology and Dental Implantology"},signatures:"Fardad Shakibaie and Laurence Walsh",authors:[{id:"179467",title:"Prof.",name:"Laurence",middleName:null,surname:"Walsh",slug:"laurence-walsh",fullName:"Laurence Walsh"},{id:"235443",title:"Dr.",name:"Fardad",middleName:null,surname:"Shakibaie",slug:"fardad-shakibaie",fullName:"Fardad Shakibaie"}]},{id:"24363",title:"Biomechanics of Tooth-Movement: Current Look at Orthodontic Fundamental",slug:"biomechanics-of-tooth-movement-current-look-at-orthodontic-fundamental",totalDownloads:26816,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"277",slug:"principles-in-contemporary-orthodontics",title:"Principles in Contemporary Orthodontics",fullTitle:"Principles in Contemporary Orthodontics"},signatures:"Joanna Antoszewska and Nazan Küçükkeles",authors:[{id:"50158",title:"Prof.",name:"Joanna",middleName:null,surname:"Antoszewska",slug:"joanna-antoszewska",fullName:"Joanna Antoszewska"}]},{id:"71271",title:"Flap Techniques in Dentoalveolar Surgery",slug:"flap-techniques-in-dentoalveolar-surgery",totalDownloads:2628,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Most dentoalveolar procedures involve the reflection of mucosal flaps. This step is crucial for exposure or removal of impacted teeth, implant bed preparation, exposure of the alveolar bone for augmentation, periodontal surgeries, and repair of mucosal soft tissue defects, such as oroantral fistula. Because of the rich vascularity of the oral mucosa, great freedom is allowed for flap design, but it tends to result in carelessness and lack of thoughtful planning, which may lead to uneventful outcomes or/and complications. In this chapter, we review oral anatomy, classification, indications, and complications of common oral flap techniques; common flap designs are illustrated, and their fundamental principles are highlighted. The review has covered various flap designs based on their indications. Yet the common flap’s principles are fundamental for all types of flaps regardless of their application, namely, it should provide wide exposure, clear vision, good access, and assure rich vascularity and good final aesthetic outcome.",book:{id:"9387",slug:"oral-diseases",title:"Oral Diseases",fullTitle:"Oral Diseases"},signatures:"Randa Abdulmoein AlFotawi",authors:[{id:"308701",title:"Dr.",name:"Randa",middleName:"Abdulmoein",surname:"Alfotawi",slug:"randa-alfotawi",fullName:"Randa Alfotawi"}]},{id:"65088",title:"Evaluation and Management of Mandibular Fracture",slug:"evaluation-and-management-of-mandibular-fracture",totalDownloads:2903,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The mandibular bone is an important component of the facial bone, which has a unique role in digestive system, speech, and facial esthetics. For these important functions of mandibular bone, it is vital that surgeons should not only treat function but also consider the esthetics together. Mandibular fractures are among the most common traumatic injuries of the maxillofacial region. Even though treatment modalities are well established and being practiced for a long time, untreated and postoperative complications still decrease the patient’s quality of life. This chapter aims to describe the cause, clinical presentations, diagnoses, and current treatment methods on the basis of resent literature.",book:{id:"7572",slug:"trauma-in-dentistry",title:"Trauma in Dentistry",fullTitle:"Trauma in Dentistry"},signatures:"Guhan Dergin, Yusuf Emes and Buket Aybar",authors:[{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin"},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes"},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar"}]},{id:"56461",title:"Permanent Maxillary and Mandibular Incisors",slug:"permanent-maxillary-and-mandibular-incisors",totalDownloads:2715,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The permanent incisors are the front teeth that erupt between 6 and 8 years of age. They are eight in number, four upper and four lower, two centrals and two laterals. They have sharp biting surfaces designed for shearing and cutting of food materials into small chewable pieces. They are the teeth most visible to the others during eating, smiling and talking, and thus, they have high aesthetic value for the individuals. The unique characteristics, arch position, function, development and chronological age of each tooth will be highlighted. In addition, the different aspects with their geometric outlines, outlines and surface anatomy of these teeth will be described. A brief explanation about the pulp cavity, tooth socket and normal occlusion for each tooth will be included.",book:{id:"5814",slug:"dental-anatomy",title:"Dental Anatomy",fullTitle:"Dental Anatomy"},signatures:"Mohammed E. Grawish, Lamyaa M. Grawish and Hala M. Grawish",authors:[{id:"82989",title:"Prof.",name:"Mohammed",middleName:"E",surname:"Grawish",slug:"mohammed-grawish",fullName:"Mohammed Grawish"}]}],onlineFirstChaptersFilter:{topicId:"174",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"80964",title:"Upper Airway Expansion in Disabled Children",slug:"upper-airway-expansion-in-disabled-children",totalDownloads:44,totalDimensionsCites:0,doi:"10.5772/intechopen.102830",abstract:"Breathing is essential for life in all of its stages. Cellular, mitochondrial respiration requires an adequate supply of oxygen, provided by the air we breathe, after airway conduction, treatment by the lungs, and transport to tissues. At different stages of life, pediatric dentists and orthodontists can intervene in the upper airway, expanding it, which helps with ventilation. The greater airway space, if used, contributes in different ways to the child’s development and the recovery of respiratory problems and should always be present as a weapon that physicians and the population should know. The value of the techniques becomes even more important when applied to children and young people with disabilities who can significantly improve their development and performance. Rapid Maxillary Expansion and Extraoral Traction Appliances are two important pediatric resources to treat these children. Clinical practice of the authors, is discussed, emphasizing the importance of early intervention and the need for multi and interdisciplinary collaboration in the follow-up of disabled people.",book:{id:"10827",title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg"},signatures:"David Andrade, Joana Andrade, Maria-João Palha, Cristina Areias, Paula Macedo, Ana Norton, Miguel Palha, Lurdes Morais, Dóris Rocha Ruiz and Sônia Groisman"},{id:"80963",title:"Pain Perception in Patients Treated with Ligating/Self-Ligating Brackets versus Patients Treated with Aligners",slug:"pain-perception-in-patients-treated-with-ligating-self-ligating-brackets-versus-patients-treated-wit",totalDownloads:33,totalDimensionsCites:0,doi:"10.5772/intechopen.102796",abstract:"This study compared the perception of pain experienced by patients undergoing orthodontic treatment with conventional, self-ligating brackets and aligners, and investigated the impact that pain had on their daily lives. 346 consecutive patients were included in the study: 115 patients treated with conventional brackets, 112 Patients treated with self-ligating brackets, and 119 patients treated with aligners. The quantitative aspect of pain was assessed using the Visual Analogue Scale, while the qualitative aspect of pain was evaluated using the Moroccan Short Form of McGILL Pain questionnaire. In all three groups experienced pain after activation tended to decrease in the following week. This pain was greater in patients with conventional braces and less in patients with aligners. Using the M-SF-MPQ to describe the qualitative aspect of the pain revealed that the “cramping مزير,” “aching تيألم ” aspect was most accentuated in the 3 groups. Medication intake was correlated with the intensity of pain experienced in all 3 systems. As for the impact of pain on daily activities, patients in groups of conventional and self-ligating braces showed more pain than those in the aligners group. Overall, aligners were less painful than conventional and self-ligating appliances. Patients did not suffer from an alteration in their quality of life due to orthodontic treatment.",book:{id:"10780",title:"Current Trends in Orthodontics",coverURL:"https://cdn.intechopen.com/books/images_new/10780.jpg"},signatures:"Farid Bourzgui, Rania Fastani, Salwa Khairat, Samir Diouny, Mohamed El Had, Zineb Serhier and Mohamed Bennani Othmani"},{id:"80839",title:"Herbs and Oral Health",slug:"herbs-and-oral-health",totalDownloads:69,totalDimensionsCites:0,doi:"10.5772/intechopen.103715",abstract:"Herbal medicine has long been used to prevent and control disease, and it can minimize the potential side effects of chemical products. However, side effects from herbs do exist. Most of the challenges with herbal medicine revolves around inadequate information about the effect of herbs in the oral cavity, the mechanism of action, and potential side effects. There are several herbs described in this chapter have anti-inflammatory, anti-bacterial, anti-viral, anti-fungal in oral micro-organisms. It includes aloe vera, ginger, clove, cinnamon, garlic, neem, miswak, turmeric, tulsi, green tea, chamomile, fenugreek, anise plant, peppermint, bloodroot, caraway, eucalyptus, phyllanthus emblica, black seed, myrrh, rosemary, sage, and thyme; some may act as an alternative management option to current treatments for oral conditions such as caries prevention, gingivitis, periodontitis, oral burn, ulcers and inflammation, after extraction, dry mouth, pain reduction, anesthesia, intracanal medications, ill-fitting dentures, peri-implant mucositis and peri-implantitis. It can be used in several forms such as mouthwashes, toothpastes, topical agents or local drug delivery devices. However, more research is needed to understand their mechanisms and potential side effects.",book:{id:"10827",title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg"},signatures:"Zuhair S. Natto"},{id:"80441",title:"Periodontitis and Heart Disease: Current Perspectives on the Associative Relationships and Preventive Impact",slug:"periodontitis-and-heart-disease-current-perspectives-on-the-associative-relationships-and-preventive",totalDownloads:66,totalDimensionsCites:0,doi:"10.5772/intechopen.102669",abstract:"Due to the important advancement and the accumulation of new evidence on the periodontitis-cardiovascular disease (CVD) relationship as well as the major medical, economic and social burden caused by both diseases this chapter aims to review existing epidemiological and pathogenetic links related to this topic. Also, this chapter aims to highlight the impact of the periodontitis-CVD relationships on clinical practice and on the preventive approaches targeting to decrease the impact of periodontitis on CVD. Periodontitis is an infectious disease eliciting local and general inflammation, which leads to periodontal destruction and systemic involvement. Several pathways could explain the link between periodontitis and CVD such as bacteraemia, chronic persistent systemic inflammation and oxidative stress. The first step in the treatment of periodontitis addresses the elimination of microbial components, which lead to a decrease in local and systemic inflammation. Periodontal therapy seems to positively impact CVD. Specialists should inform patients with CVD on the negative impact of periodontitis on their systemic status and refer patients to the periodontist for an extensive examination as routine management of CVD. Some possible risks of periodontal therapy should be considered in patients undergoing antithrombotic medication.",book:{id:"10827",title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg"},signatures:"Alexandra Roman, Andrada Soancă, Bogdan Caloian, Alexandru Bucur, Gabriela Valentina Caracostea, Andreia Paraschiva Preda, Dora Maria Popescu, Iulia Cristina Micu, Petra Șurlin, Andreea Ciurea, Diana Oneț, Mircea Viorel Ciurea, Dragoș Alexandru Țermure and Marius Negucioiu"},{id:"79498",title:"Oral Aspects and Dental Management of Special Needs Patient",slug:"oral-aspects-and-dental-management-of-special-needs-patient",totalDownloads:113,totalDimensionsCites:0,doi:"10.5772/intechopen.101067",abstract:"Individuals with special needs are the most underserved regarding healthcare needs in almost all populations. Special needs patients with intellectual disability have muscle coordination disorder, impaired oral motor function, drooling, weak muscles that cause chewing and swallowing problems. Also, soft diet consumption makes this population more prone to dental disease. They have more caries, missing teeth, orthodontic and periodontal problems. Besides more difficulties obtaining professional dental care than other segments of the population. Though many countries developed community-based systems to improve oral health for people with special needs, providing good oral health mainly depends on the effort of the families. Therefore the education of the caregiver about oral hygiene provision is also critical for the special needs patient to enjoy a lifetime of oral health the same as other members of the society.",book:{id:"10827",title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg"},signatures:"Pinar Kiymet Karataban"},{id:"79699",title:"Metabolomics Distinction of Cigarette Smokers from Non-Smokers Using Non-Stationary Benchtop Nuclear Magnetic Resonance (NMR) Analysis of Human Saliva",slug:"metabolomics-distinction-of-cigarette-smokers-from-non-smokers-using-non-stationary-benchtop-nuclear",totalDownloads:56,totalDimensionsCites:0,doi:"10.5772/intechopen.101414",abstract:"Implementations of high-field nuclear magnetic resonance (NMR) facilities into metabolomics studies are unfortunately restricted by their large dimensions, high costings, and specialist technical staff requirements. Therefore, here the application and practical advantages offered by low-field (60 MHz), compact NMR spectrometers for probing the metabolic profiles of human saliva was explored, as was their value in salivary metabolomics studies. Saliva samples were collected from cigarette smoking (n = 11) and non-smoking (n = 31) human participants. 1H NMR spectra were acquired on both low-field (60 MHz) and medium-field (400 MHz) spectrometers. Metabolomics analyses were employed to evaluate the consistencies of salivary metabolite levels determined, and their abilities to distinguish between smokers and non-smokers. Low-field 1H NMR analysis detected up to 15, albeit permitted the reliable quantification of 5, potentially key diagnostic biomolecules simultaneously (LLOQ values 250–400 μmol/L), although these were limited to those with the most prominent resonances. Such low-field profiles were also found to be suitable for salivary metabolomics investigations, which confirmed the successful discrimination between smoking and non-smoking participant sample donors. Differences observed between these groups were largely ascribable to upregulated salivary levels of methanol, and its metabolite formate, in the smoking group, but higher smoking-mediated concentrations of acetate, propionate and glycine may arise from a diminished salivary flow-rate in these participants. In conclusion, determination of salivary biomolecules using low-field, benchtop 1H NMR analysis techniques were found to be valuable for bioanalytical and metabolomics investigations. Future perspectives for the applications of this non-stationary NMR technique, for example for the on-site ‘point-of-care’ testing of saliva samples for diagnostic oral disease screening purposes at dental surgeries and community pharmacies, are considered.",book:{id:"10827",title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg"},signatures:"Benita C. Percival, Angela Wann, Sophie Taylor, Mark Edgar, Miles Gibson and Martin Grootveld"}],onlineFirstChaptersTotal:36},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"3",title:"Dentistry",doi:"10.5772/intechopen.71199",issn:"2631-6218",scope:"\r\n\tThis book series will offer a comprehensive overview of recent research trends as well as clinical applications within different specialties of dentistry. Topics will include overviews of the health of the oral cavity, from prevention and care to different treatments for the rehabilitation of problems that may affect the organs and/or tissues present. 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",coverUrl:"https://cdn.intechopen.com/series/covers/3.jpg",latestPublicationDate:"August 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"1",title:"Oral Health",coverUrl:"https://cdn.intechopen.com/series_topics/covers/1.jpg",isOpenForSubmission:!0,annualVolume:11397,editor:{id:"173955",title:"Prof.",name:"Sandra",middleName:null,surname:"Marinho",slug:"sandra-marinho",fullName:"Sandra Marinho",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGYMQA4/Profile_Picture_2022-06-01T13:22:41.png",biography:"Dr. Sandra A. Marinho is an Associate Professor and Brazilian researcher at the State University of Paraíba (Universidade Estadual da Paraíba- UEPB), Campus VIII, located in Araruna, state of Paraíba since 2011. She holds a degree in Dentistry from the Federal University of Alfenas (UNIFAL), while her specialization and professional improvement in Stomatology took place at Hospital Heliopolis (São Paulo, SP). Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). Dr. Marinho's experience in Dentistry mainly covers the following subjects: oral diagnosis, oral radiology; oral medicine; lesions and oral infections; oral pathology, laser therapy and epidemiological studies.",institutionString:null,institution:{name:"State University of Paraíba",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"2",title:"Prosthodontics and Implant Dentistry",coverUrl:"https://cdn.intechopen.com/series_topics/covers/2.jpg",isOpenForSubmission:!0,annualVolume:11398,editor:{id:"179568",title:"Associate Prof.",name:"Wen Lin",middleName:null,surname:"Chai",slug:"wen-lin-chai",fullName:"Wen Lin Chai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHGAQA4/Profile_Picture_2022-05-23T14:31:12.png",biography:"Professor Dr. Chai Wen Lin is currently a lecturer at the Department of Restorative Dentistry, Faculty of Dentistry of the University of Malaya. She obtained a Master of Dental Science in 2006 and a Ph.D. in 2011. Her Ph.D. research work on the soft tissue-implant interface at the University of Sheffield has yielded several important publications in the key implant journals. She was awarded an Excellent Exchange Award by the University of Sheffield which gave her the opportunity to work at the famous Faculty of Dentistry of the University of Gothenburg, Sweden, under the tutelage of Prof. Peter Thomsen. In 2016, she was appointed as a visiting scholar at UCLA, USA, with attachment in Hospital Dentistry, and involvement in research work related to zirconia implant. In 2016, her contribution to dentistry was recognized by the Royal College of Surgeon of Edinburgh with her being awarded a Fellowship in Dental Surgery. She has authored numerous papers published both in local and international journals. She was the Editor of the Malaysian Dental Journal for several years. 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Currently, he is a professor of Orthodontics. He holds a Certificate of Advanced Study type A in Technology of Biomaterials used in Dentistry (1995); Certificate of Advanced Study type B in Dento-Facial Orthopaedics (1997) from the Faculty of Dental Surgery, University Denis Diderot-Paris VII, France; Diploma of Advanced Study (DESA) in Biocompatibility of Biomaterials from the Faculty of Medicine and Pharmacy of Casablanca (2002); Certificate of Clinical Occlusodontics from the Faculty of Dentistry of Casablanca (2004); University Diploma of Biostatistics and Perceptual Health Measurement from the Faculty of Medicine and Pharmacy of Casablanca (2011); and a University Diploma of Pedagogy of Odontological Sciences from the Faculty of Dentistry of Casablanca (2013). He is the author of several scientific articles, book chapters, and books.",institutionString:"University of Hassan II Casablanca",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"7",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Hassan II Casablanca",institutionURL:null,country:{name:"Morocco"}}},equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7060",title:"Gingival Disease",subtitle:"A Professional Approach for Treatment and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/7060.jpg",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",publishedDate:"October 23rd 2019",editedByType:"Edited by",bookSignature:"Alaa Eddin Omar Al Ostwani",hash:"b81d39988cba3a3cf746c1616912cf41",volumeInSeries:4,fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention",editors:[{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Prosthodontics and Implant Dentistry",value:2,count:3},{group:"subseries",caption:"Oral Health",value:1,count:6}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:3},{group:"publicationYear",caption:"2020",value:2020,count:2},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",fullName:"Reda R. Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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