\r\n\tFrom a public health perspective, reduced health literacy can lead to widespread consequences. “Low health literacy is also costly for the country because when people don't understand health information and instructions, they are more likely to have worse health outcomes and unnecessarily use emergency room services,”. Experts agree that health literacy is vital to reducing healthcare costs and improving public health. The path to improving health literacy isn’t always straightforward, however.
\r\n
\r\n\t \r\n\t“Unfortunately, up to 9 out of 10 adults can have limited health literacy, and this can be fluid,” Blue says. “It can be more challenging to be health literate when we are sick or in pain, so even someone who normally has a high level of health literacy may struggle at times to understand and process health information.”
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1. Introduction
In Parkinson’s disease (PD) dopamine producing neurons in the substantia nigra, pars compacta of the midbrain and with their axons projecting to the neostriatum degenerate. PD is classified as being familiar when it is known to be the result of genetic abnormalities, and this represents about 5 to 10 percent of all cases. The other cases are idiopathic, represent 90 – 95 percent of all cases of PD and the causes are unknown. The expression of the specific symptoms of idiopathic PD vary among individuals, and may be accompanied with other brain disorders, including Alzheimer’s type dementia, depression and amyotrophic lateral sclerosis (ALS). The common relationship among all of the degenerative disorders is that all are caused by failure of specific functions that are under the control of identifiable neuronal sets, with relatively low population number of larger neurons that usually occur in clusters and with far reaching axons. These neurons are well represented by the nigrostriatal dopamine neurons, and the degeneration of the neuronal set represents the major pathology of PD. They are also represented by the basal nucleus of Meynert acetylcholine neurons with major projections to the cerebral cortex that degenerate in Alzheimer’s disease (AD), and by the upper and lower motor neurons with projections to the brainstem, spinal cord or motor-end plate, that degenerate in ALS. These neuronal sets have specific prenatal and fetal periods for their neurogenesis, migration and axonal extension during which they acquire their specific phenotype that can be influenced by internally and externally derived biochemical forces, including toxins and excesses and deficiency of regulatory factors that will shape the physiological and functional destiny of these neuronal sets. If the influence is of a positive or enhancing nature, the neuronal set will turn out to be functionally superior or with exceptional resilience and longevity and will impart an enhanced character to the individual. However, if the influence is deleterious it will cause harm to the neuronal set and likewise will influence the character of the individual. For the latter, deficiencies may occur at sub-threshold level, may continue in a subliminal and a graded way and may compromise resilience and functional longevity, finally serving as the ‘weak link’ and pairing with deteriorating changes that occur during aging to cause diseases, such as Parkinson’s disease. Whereas the gene has inherent command over the variation of biological forms and some biological outcomes, it is the interacting entities derived from the environment that really sway functional outcomes. Toxins, that may be endogenous or exogenous, represent a set of these environmental factors and quite likely are responsible for the cause of idiopathic PD and other degenerative disorders. So, this chapter will discuss the idea, supported by experimental findings, that the substantia nigra dopamine neurons that deteriorate to the point of causing idiopathic PD were impaired early in life at a sub-threshold level. This occurs during the vulnerable stage of neurogenesis, neuronal development and neuronal migration. The exposures of the substantia nigra dopamine neurons to toxic or harmful influences early in life cause sub-threshold harm, and further exposures to stress during aging cause additive insults that precipitate the symptoms of PD. The early insults, the naturally low population of nigrostriatal neurons, the continuous functional demands placed on the few nigrostriatal DA neurons and the far-reaching nature of the axonal projections render the nigrostriatal DA neurons vulnerable. The high content of cytoskeleton and their kinases seen as pathological markers for various degenerative disorders (McGee and Steele, 2011) indicate that axonal damage to far-reaching neurons is a preeminent occurrence in PD.
2. Major symptoms and the proposed causes for Parkinson’s disease
The major clinical symptoms of Parkinson’s disease (PD), an age-related disorder, are resting tremors, hypokinesia, rigidity and postural instability (Tetriakoff, 1919: Foix and Nicolesco, 1925) caused by the degeneration of the nigrostriatal (NS) dopaminergic pathway and the depletion of dopamine (DA) (Greenfield and Bosanquet, 1953; Hornykiewicz, 1966). The pathological features include extensive (about 70% or more) loss of dopaminergic neurons in the pars compacta of the substantia nigra, the presence of inter-cytoplasmic inclusions known as Lewy’s bodies and gliosis. It was reported also that norepinephrine (NE) (Erhinger and Hornykiewicz, 1960) and serotonin (5-HT) Bernheimer et al., 1961) levels are decreased and that acetylcholine neurotransmission (Yahr, 1968) is increased. A small population of PD cases is caused by genetic abnormalities, involving alpha–synuclein (Polymeropoulos et al, 1997; Papadimitrior et al, 1999 and Kruger et al,1998, Dauer et al, 2002), ubiquitin (Leroy et al, 1998) and apolipoprotein E (APOE), (Kruger et al, 1999). Changes in chromosome 2p13 (Gasser et al, 1998), cyp2D6 (Kruger et al, 1999; Christensen et al, 1998; Kosel et al, 1996; Bon et al, 1999, Sabbagh et al, 1999) as well as mitochondria tRNA (A4336G) (Epensperger et al, 1997) have also been reported. The mutation of the parkin gene is closely associated with juvenile PD (Kitada et al, 1998), which has about eight variants (Lansbury and Brice, 2002). It should be noted however, that multiple other PD cases have been screened and they did not harbor mutations (Giasson et al, 2000), but gene mutations may serve as vulnerable markers, superimposed by environmental factors and age-related wear-and–tear. The root-cause of idiopathic PD is unknown, but various factors are implicated, including the oxidation of dopamine, free radical-mediated oxidative injury, mitochondrial abnormalities, excitotoxins, over exposure to manganese (Chu et al, 1995; Hochberg et al, 1996) and carbon monoxide, the intake of beta-methylaminoalanine (Spencer, 1987), benzyl-tetra-hydroisoquinolines and tetra-hydroprotoberines (Caparros-Lefebvre and Steele, 2005), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Davis et al, 1979), methanol (Guggenheim et al, 1971). As well as the potent methylating agent, methylazoxymethanol (Ince and Codd, 2005) and excess methylation via high utilization of the endogenous S-adenosyl-L- methionine in the brain (Charlton and Way, 1978; Charlton et al, 1992; Charlton and Mack, 1994).
2.1. Aberrations in non-basal ganglia systems.
In PD the basal ganglia is the primary affected structure, but lesions have been identified in the locus ceruleus (Selby, 1968; Alvord et al, 1974), the hypothalamus (Jagar and Bethlem, 1969; Ohama and Ikuta, 1976; Langston and Forno, 1978), the dorsal motor nucleus of vagus (Eadie, 1963; Vanderhaegen et al 1970), the sympathetic ganglia (Jagar and Bethlem, 1960; Vanderhaeghen et al., 1970; Rajput and Rozdilsky, 1970 and Forno and Norvill, 1976) and in the adrenal medulla (Jager, 1969) as well. Furthermore, Lewy’s bodies, the standard marker for PD, have been seen in the cerebral cortex, anterior thalamus, hypothalamus, amygdala, basal forebrain, dorsal motor nucleus of vagus, adrenal medulla and locus ceruleus. The clearly un-circumscribed localization of lesions in the patients or victims of PD means that the changes or the incidents that cause the dopaminergic cell loss in the nigrostriatal system may not specifically target the basal ganglia, but instead the nigrostriatal dopaminergic neurons may be more vulnerable or sensitive. In other words, the factors that are involved in the cause of, at least, some cases of PD may also cause harm to other cell populations, but the basal ganglia neurons are more vulnerable and will die when other neuronal sets remain alive and function normally. This means that a state of vulnerability or sensitization may exists for PD and that the occurrence of damage to other neuronal pool may help to explain the variation in the expression of the PD syndrome.
3. The fetal basis hypothesis for Parkinson’s disease.
PD is age-related but a large percentage of the older population does not suffer from the disorder, although aging is accompanied with pronounced and progressing reduction in motor and other functions. The age-dependent increase in the frequency of essential tremor (Elble 1995; Koller and Huber, 1989), the occurrence of kyphotic posture, diminished arm swing, shorter strides (Murray et al, 1969; Elble et al, 1992; Elble et al, 1991, bradykinesia (Waite et al, 1996) and slowed reaction time (Weiss 1965; Welford, 1977) are signs found to be associated with aging, but the abnormalities are distinguishable from the changes that occur in PD. This suggests that, during normal aging and as a rule, the nigrostriatal DA neurons do not deteriorate to the point of causing PD. Therefore, it is very possible that for PD symptoms to be expressed in the aged, some primary changes that render the nigrostriatal DA neurons vulnerable occur during the earlier life of the PD patients and serve as the underpinning for the deleterious age-related changes that normally occur. So, the functional age-related changes pair with the early predispositions to precipitate the symptoms of PD. Furthermore, there is the high probability that the causes of the vulnerability that occur early in life are based on chance and occur during a critical period when nigrostriatal dopamine neurons are structurally responsive to endogenous and exogenous toxic type of interventions.
3.1. Chance encounter of the nigrostriatal neurons with harmful factors.
It is proposed that chance encounter of factors with the NS DA neurons at critical times during their development eventually shape the long-term outcome of the neuronal pool. If the encounter decreases the longevity of the neurons idiopathic PD will occur. This will underlie the sporadic feature of idiopathic PD, and the nature of the early encounter will determine the pathological characteristics. So, the cluster of PD cases caused by the outbreak of the epidemic encephalitis lethargic in 1919 that killed about one million people worldwide and left millions more ‘frozen’ with the symptoms of PD and which decline rapidly after 1925 (Ravenholt et al, 1982) represent a special but a typical set of parkinsonism. The Guam Parkinson’s dementia complex (PDC)-amyotrophic lateral sclerosis (ALS) syndrome proposed to be caused by the toxins contained in flour prepared from the cycad plant (Spencer et al, 1987) suggests a syndrome that is caused by long–term exposures that target the nigrostriatal neurons, motor neurons and basal nucleus of Meynert acetlycholinergic neurons. In these cases the diversity in the character of the syndrome is a reflection of the neuronal sets that were harmed. So, the individuals that develop idiopathic Parkinson\'s disease, and likely other neurodegenerative disorders, were marked early in life for the disorder. The early process may be synonymous to natural selection that occurs by chance, and helps to define the variation of phenotypes among a population. In the case of PD, the variation may be defined by the magnitude of the reduction in the number of nigrostriatal dopaminergic neurons, and/or deficiencies in the metabolic capability or resilience of the neurons. Therefore, the nigrostriatal DA neurons of the PD patients may have experienced early exposure to environmental, nutritional and/or metabolic toxic interventions. This early exposures may result in DA neurons that lack the reserve capacity to survive during the natural life of the individual, but they function at a level of output that is above the threshold at which the symptoms of PD occur (pre-threshold). During the progression of time or during aging, however, subtle but accumulative changes occur that further damage the nigrostriatal DA neurons and the additive effects precipitate PD-like symptoms. Thus, the fetal basis hypothesis proposes that by chance early interventions render the nigrostriatal neurons sensitive, susceptible or vulnerable, characteristics that enable changes involving the wear-and-tear of living or the exposure to toxins or traumatic events later in life to take a toll on the vulnerable NS neurons and cause PD.
3.2. High workload may explain the vulnerability of the nigrostriatal neurons.
The normal population of nigrostriatal pigmented neurons is relatively low, showing a mean value of 163,238 ± 42,372 in normal human (Ma et al, 1997). The relatively low population number of the nigrostriatal neurons and the high workload placed on these specialized cells play a role in their metabolic durability. This relationship may help to explain the rapid decline in the ability to effectively execute rapid and skillful movement-related skills as a function of aging. This is evident in the short time that a competitive athlete can maintain his or her exceptional ability. A 100-meter runner, for example, is normally competitive for only one or two olympic game and skillful ballet dancers are young people. Even the ability to play the game of golf requires skills that deteriorate to non-competitiveness by the time the athlete reaches early middle age. So, even under normal living condition the nigrostriatal neurons are under moment-by-moment demands by the motor and other functions that they control, and their capability naturally deteriorates in time. The demands placed on these neurons by muscles, for example, are continuously occurring, even during sleep, since skeletal muscle activities are maintained for limb and eye movements. Demands on the nigrostriatal neurons are continuous during regular activities and increased during stress-related physical activities, so, these neurons never rest, unlike neurons that control functions such as hearing, vision and cognition that are at rest at least during sleep. Therefore, while other neuronal sets with less stressful functions and without experiencing an early assault will age at a regular rate, the functional stress imposed on already susceptible dopamine neurons, during the process of living, will cause them to deteriorate at a fast rate to below the threshold that maintains normal functions. This means, therefore, that the prenatal exposure hypothesis will explain cases of juvenile PD that occur at about the age of forty years, in patients that are functionally normal high into the thirties. So, early markers for juvenile PD that are known to be caused by genetic abnormalities, likely exist long before the occurrence of the PD symptoms. The early markers may exist as subtle but serious sub-threshold genetic nigrostriatal abnormality that is below the threshold at which PD symptoms are expressed. So, as compared to idiopathic PD, that has its onset about in the sixth decade, juvenile PD, because of it more serious early impairments, requires a shorter duration of time before the added stress induces threshold level nigrostriatal damage. The overall analogy, therefore, means that at least two stages or two sets of factors or groups of factors are involved in PD:
The first stage: the predisposing/sensitization/susceptible/vulnerable stage.
The second stage: the inducing/precipitating/superimposing stage.
Again, the first stage is defined by subtle or sub-threshold level of adverse changes that start early in life and form the weak link for the second stage, defined by stressful events occurring later in life and coupled with the first stage to cause the expression of the disease symptoms. It should be noted that normal functional and age-related existence may cause enough stress to produce the ‘added-on’ second stage damage to the nigrostriatal neurons in individuals with early stage predisposition.
4. The predisposing, sensitization, susceptible or vulnerable stage of the hypothesis
Normally, immature neurons or neuroblast are subject to chemical and mechanical influences that cause them to migrate to various locations in the nervous system, to extend axonal and dendritic processes toward other cells and then to make and break synaptic connections with these cells before a final pattern of branching and connections are established (Levitan and Kaczmarek, 2002). Moreover, factors released by other cells influence the type of neurotransmitter the neuron will synthesize and the specific type and mixture of receptor, ion channels and other proteins that determine the characteristics of the fully differentiated neurons (Levitan and Kaczmarek, 2002). Along with or besides the normal pattern of development that occur, the differentiating and young neurons may be subjected to toxic and interfering influences that shape them for life. There could be failure in the normal process of apoptosis, that acts via cytochrome c, caspase 9, caspase 3 and other cellular constituents, to cause cellular pruning and to allow the remaining neurons to survive and to be properly organized.
In general, brain neurons are known to be susceptible or vulnerable to insults during prenatal and the early postnatal stage of the life of the individual. This is the basic reasons for the practice of protecting the pregnant mother, new born and young children from chemical and other potentially harmful exposures. For the midbrain dopaminergic system, the most susceptible time is likely to be the period of neurogenesis, proliferation and migration of the cells to produce the nigrostriatal dopaminergic phenotype. These midbrain dopamine neurons are generated early during development, first in the midbrain-hindbrain junction (Voorn et al, 1988), and they migrated radially to their final position in the ventral midbrain to form the substantia nigra, the ventral tegmental area and the retrorubal nuclei (Perrone-Capano and di Porzio 1996). Tyrosine hydroxylase (TH) immunoreactivity is used to identify those dopamine tegmental neurons, and the first appearance of the TH marker is regarded as the birth of the tegmental cells, which occurs on embryonic day 9 for the mouse. The periods close to the birth of these neurons are likely to be a very critical window through which the environment causes long-term changes to the cells and to the motor performance of the organism. In fact, it is these types of manipulations that may be relevant in causing diseases and in enhancing special features related to the functions of the basal ganglia, and they will have effects similar to natural selection and imprinting.
The signal for the differentiation of the NS DA neurons is through a protein called the sonic hedgehog (SHH). The amino-terminal product is the inductive moiety. SHH is produced by the floor plate cells and induces the dopaminergic phenotype (Hayes, et al., 1995). The signal for the SHH protein can be antagonized by increasing the activity of cyclic AMP-dependent protein kinase A. High activity of cAMP blocked the induction of dopamine neurons (Hayes et al, 1995), therefore it could be reasoned that other molecules, e.g. environmental toxins, that modulate cyclic AMP-dependent protein kinase A will interfere with cellular differentiation and migration of these emerging DA neurons. Biomolecules may also affect the metabolic and structural components of the emerging DA neurons, resulting in different degrees of effects that may be enhancing or detrimental to the functions and longevity of the new born DA neurons. If the modulation enhances the metabolism and functions of the nigrostriatal neurons it is expected that the adult may possess motor features that are superior in functions, and will endure to advance ages. On the other hand if the modulations impair metabolism and functions of the nigrostriatal neurons, it is expected that the adult will possess motor features that fail early in life to produce PD symptoms. So, the severity of the prenatal impairment will dictate the age of onset of PD symptoms. Susceptible type of impairments that are most severe, and do not result in death of the fetus, will be closest to the threshold at which PD symptoms are seen, so patients with early onset or juvenile PD may be endowed with sub-threshold but severely impaired NS system that developed early in life.
In summary, the period for the reorganization of the cellular membranes, organization of the chromatid for cell division, the synthesis of structural proteins, production of sub-systems for neurotransmitter synthesis and storage and the synthesis of molecules for intracellular transport and cell movement make the emerging dopaminergic cells well exposed to interfering factors and incidents. During this transforming cellular period the lack of essential metabolites, exposure to inappropriate metabolites and to exogenous and/or endogenous toxins can interfere with the molecular processes to cause permanent changes to the differentiating and migrating cells, that will reduce the resilience of the cell population. The affected neuronal set will become sensitive, susceptible, predisposed or vulnerable to the “wear-and-tear” of living or to toxic type of interventions that are encountered later in life. So, harmful basal ganglia neuronal changes that occur early in life could set the stage and shape the destiny of the individuals to the development of PD.
The dopamine neurons that are degenerated in PD have as their distinguishing feature long axons that project from the substantia nigra in the midbrain to the neostriatum in the forebrain region. One of the key sub-structures of the axon is cytoskeleton. Since they are involved in major cytoarchitectural changes during the development of the nigrostriatal dopamine neurons, the cytoskeleton and other associated molecules, including the kinases, are prime targets for modifications that will determine the outcome of the nigrostriatal dopaminergic neurons.
4.1. The involvement of cytoskeleton and alpha-synuclein as axonal constituents
The cytoskeleton proteins are important structures in the developmental and maintenance of the basal ganglia dopaminergic neurons. They support cellular shape, axonal and dendritic extensions, trafficking and transportation of macromolecules. More importantly, they allow the neurons to extend their reaches and influences far distances from the soma in the midbrain to the striatum in the forebrain region. So, the cytoskeleton serves to distinguish the new nigrostriatal dopaminergic neurons from the parent parochial cells and is the key components that enable the neurons to be functional; noting that the cell bodies may be correctly in place in the substantia nigra, but they will be non-functional without their far-reaching axons. So, by virtue of their relative cyto-architectural and functional significance, cytoskeleton synthesis and assembling ought to be one of the most vulnerable features affected by agents that interfere with the differentiation and proliferation of the far-reaching nigrostriatal dopaminergic neurons. Accordingly the molecules of the cytoskeleton protein classes, (i) microtubules, (ii) neurofilaments and (iii) microfilaments are seen as prime targets. Their vulnerability may help to explain why key markers of neurodegenerative disorders are mostly insoluble remnants of cytoskeleton protein. Lewy bodies, the major pathological marker for PD are composed principally of neurofilament proteins, alpha synuclein, actin-like protein, microtubules associated protein 2 (MAT 2), microtubules associated protein 5 (MAT 5), syaptophysin, tubulin (Giasson et al, 2000). Lewy bodies are also reactive for cytoskeletal protein kinases, calcium/calmodulin-dependent protein kinase (Iwatsubo et al, 1991), cyclin-dependent kinase 5 (Nakamura et al, 1997) and stress activated protein kinases (Giasson et al, 2000).
The microtubules include the subunits, (i) alpha-tubulin and beta-tubulin and (ii) polymerization regulator proteins that include microtubule associated protein 2 and 5 (MAP2 and MAP5). Microtubules span the length of axon and dendrites, serving as the track for macromolecular transport. They are the major component of mitotic spindle, an organelle that participates in cell division and are of importance in the differentiation of cells to form the nigrostriatal dopaminergic neuronal phenotype. Microtubules also play an important role in cell movement. The subunit, tubulin, synthesized in the cell body is actively transported down the axon, so they are relatively easy target for interfering molecules, such as colchicines. Moreover, the turnover of microtubules requires the polymerization and depolymerization of the molecule. This is a cyclic process that is more stable in mature dendrites and axons but is active in dividing cells, which again is a potential target for molecules, such as colchicines and vinblastine. So, the process that involves polymerization and depolymerization of microtubules is a weak link in the life of a far-reaching neuron during which modifications of a permanent nature can be made.
The neurofilaments are the most abundant fibrillar components of axon (Schwartz, 1991). They include the light (L), medium (M) and heavy (H) molecular weight neurofilament subunit proteins. Neurofilaments are oriented along the length of the axons, are most abundant in axons and are critical for axonal extension, a feature that enables the DA cell bodies in the substantia nigra to extend their axons to the striatum. So, neurofilament proteins form the ‘backbones of the nigrostriatal DA neurons and interference with the protein will likely cause significant and permanent change.
Microfilaments are made up of globular subunits of (i) beta-actin and (ii) gamma-actin. Actin plays a major role in the function of growth cones and in dendritic spines. High concentrations occur in dendritic spines and they are located just underneath the plasmalemma, together with a large number of actin binding proteins, including spectrin-fodrin, ankyrin, talin and actinin. They play key role in motility of growth cone during development, the generation of specialized micro domains on the cell surface and in the formation of presynaptic and postsynaptic morphological specializations. They undergo cycles of polymerization and depolymerization (Kandel, Schwartz and Jessel, 2000).
Alpha-synuclein is also a likely prime target for prenatal toxins. It is a heat stable protein associated with synaptic vesicles and axonal terminals (Withers et al, 1997). It plays important roles in neurotransmission, synaptic organization and neuronal plasticity (George et al, 1995). Alpha-Synuclein is the major building block for the fibrillary component of Lewy’s bodies (Pollannen et al, 1993), the major antigenic component of Lewy’s bodies (Baba et al. 1997; Spillantini et al, 1997) and may be critical for the expression of PD symptoms (van Duinen et al, 1999). It is also a component of the thread-like structures seen in the perikarya of some neurons in the brainstem nuclei of the PD victims (Arima at al, 1998). It has been shown also that the association of alpha-synuclein with membrane promotes alpha synuclein aggregation (Lee et al. 2002) and that alpha-synuclein binds with dopamine transporters (Lee et al. 2001).
The interaction of the cytoskeleton proteins and other proteins of interest has been observed. For example, tubulin seeds the fibrillar form of alpha synuclein (Alim et al, 2002) and parkin has been shown to be a novel tubulin binding protein (Ren et al, 2003). It was also observed that 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of MPTP, reduced the synthesis of tubulin in PC12 cell model (Capelletti et al, 1999, Capelletti et al, 2000) and that MPP+ inhibited tubulin polymerization (Capelletti et al, 2001), by specifically binding to tubulin in the microtubule lattice (Capelletti et al, 2005). Antibodies that recognize phosphorylated neurofilamant-M and neurofilaments-H also label Lewy’s bodies, therefore the phosphorylation state of neurofilaments may be important in the formation of Lewy’s bodies (Julien and Mushynski, 1998; Sternberger et al. 1983; Lee et al. 1987).
4.2. There may be a window of vulnerability for nigrostriatal dopamine neuronal sensitization
PD occurs in a relatively small number of the population, which may be so because a relatively short window of time exists during which the nigrostriatal DA neurons of the individual can be easily harmed. Such a window of vulnerability, we believe, is the period of differentiation, neurogenesis and migration of cells to form the nigrostriatal DA neurons, and this period occurs during gestational day 9-11 in mice. As mentioned above, the synthesis and laying down of cytoskeleton and neurotransmitter synthesis, storage, uptake and release capacities are likely the prime time during which the transforming cells are most vulnerable to toxic type of interference and inappropriate levels of metabolites and factors. So, idiopathic PD and some other degenerative disorders may have their origin in the fetus and the vulnerability may occur during pregnancy. This should not be seen as shifting the blame of having PD on pregnancy, but the fact is, pregnancy also produces the life and existence of the individual in the first place. So, the probability of having PD would be proportionate to the duration of the neurogenesis/neuronal development time, the number of pregnancy, the frequency by the individual encounter the toxic factor and the potency of the toxic encounter.
4.3. The susceptible stage may set the age of onset of PD and the severity of PD symptoms
If the rate of change is constant during the precipitating stage, it means that the more severe the sensitization, susceptible or vulnerable stage of affliction is, the earlier will the threshold reached for expressing the symptoms of PD. Thus, the age at which PD occurs may be directly related to the severity of the impairments that occur during the sensitization or the first stage affliction. So, juvenile PD may be marked by basal ganglia that were severely affected or were made less resilience by the changes that occur during the sensitization, susceptible or vulnerable stage of affliction. The individuas whose basal ganglia are less severely affected during the sensitization, susceptible or vulnerable stage may experience a delay in the expression of PD symptoms, since more harm will need to be made during the precipitating stage to reach the threshold at which PD symptoms will be seen. So individuals with the least affected nigrostriatal system during the susceptible stage are those that may live without the experiencing the symptoms of PD. In other words, the severity of the changes that occur during the sensitization, susceptible or vulnerable stage may very well predetermine the age at which PD symptoms will occur and the severity of the symptoms.
4.4. The number of NS DA neurons may also determine the susceptibility to PD
The proposed early exposures of the basal ganglia may reduce the number of NS neurons in a random pattern, among the population, so that the average individual possesses a normal population of, say 120,000 (120K) NS DA neurons and with various fractions of the population having values above and below the 120K. Thus, a bell-shaped frequency distribution pattern will exist, with some individuals represented at the far left of the curve, say with 30K or 25%. The individuals among the population who will most likely develop PD would be those endowed with a low (pre-threshold) population of 30K NS DA neuronal subset and PD will occur following a reduction of merely 6K neurons, to 20% of the mean. This low population number of neurons, similar to the marginally resilience neurons mentioned above, would constitute the 1st stage or the sensitization, susceptible or vulnerable stage, and contributes to the cause of PD. During the wear-and-tear of aging, that involves the reduction of NS DA neurons, individuals with the 30K number of NS DA neurons will be those most likely to develop PD symptoms and also at an early age (juvenile). This analogy could form the basis for the early-onset to late-onset PD cases. It may also explain the PD-like dispositions that are exhibited by the very old, due to the chronic reduction of NS DA neurons. The population at the right of the bell shape curve may be those that live to old ages without basal ganglia impairments.
4.5. The coincidental involvement of other neuronal sets with the NS neuronal changes
When the NS DA neurons are made susceptible during the early stage of life other neuronal groups may also be harmed by the modifying factor(s) and the coincidence will determine the occurrence of other symptoms with the symptoms of PD. The coincidental involvement may occur if the window of exposure or neurogenesis for the basal ganglia DA neurons overlap the period of neurogenesis for other neuronal sets, or the period of exposure to the interfering factor/factors is long enough to overlap the period of neurogenesis of all neuronal sets. If that is the case all the neuronal sets will be harmed by the interfering factor/factors. For example, if the nucleus basilis of Meynert acetylcholinergic neurons and the mesolimbic or mesocortical catecholaminergic neurons are affected, as proposed for the NS DA neurons, these other neuronal sets will be scared early in life and succumb to the wear-and-tear of aging later in life. Such co-incident may explain the comorbidity of Alzheimer-like dementia as well as depression with the occurrence of PD. It is of interest, therefore, that the Guam amyotrophic lateral sclerosis-parkinsonism-dementia that may be caused by toxins from the cycad plant (Spencer, 1987), may involve the early damage to upper motor and lower neurons, NS DA neurons and nucleus basalis of Meynert neurons and that the failure of the neuronal sets later in life precipitates the triage of symptoms. This may involve a longer time for the early exposure, which is reasonable because the toxin in cycad was taken in as food. So, the impairments of various neuronal sets during the stage of neurogenesis and neuronal development may help to explain the variations and complexity of the PD related syndrome.
4.6. Agents that may cause neuronal susceptibility
Parkinson’s disease was described by James Parkinson in 1817, almost two centuries ago. So, if external factors are involved in the cause of PD they were in the environment during those early times and the factors would be widely distributed since the occurrence of idiopathic PD is universal. Moreover, since aging is the key risk factor for having PD, PD can be seen as the outcome of the changes that occur during the wear-and-tear of aging. As mentioned above, the best scenario is that the changes in aging coupled with early events that render the nigrostriatal neurons susceptible. Several agents or conditions may be involved in causing the NS DA neurons to be susceptible because all that is required is for the factor to cause damage to dividing and developing neurons, and for the factors to be available during the critical stage of the birth of the NS DA neuronal phenotype. The deficiency and excesses of otherwise normal metabolites, such as momentary fetal hypoxia during the development of the NS DA neurons may be all that is required to trigger the sensitization, susceptible or vulnerable stage. There may also be excesses of normal metabolites, since high activity of cyclic AMP can block the induction of dopamine neurons (Hayes et al, 1995).
It is highly likely that the susceptible phase occurs over a short period, which may help to explain the relatively low incidence of PD. We have used the toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to model the sensitization stage in the mice (Muthian et al, 2010), so structurally similar agents to MPTP that occur in nature could affect the basal ganglia long before the synthetic MPTP became available as a toxicant. It is proposed, also, that agents such as colchicine and vincristine that have been in use as medicine for over 2000 years could have played a role as a sensitization factor for PD. Colchicine is an alkaloid from the Lily family, including Autumn lily or Colchicum autumnale and of the saffron family, that is still used today, as food coloring and cosmetics. Vincristine is an alkaloid obtained from the periwinkle plant. These two compounds are not known to target the nigrostriatal dopamine neurons, however, they bind to tubulin and prevent the polymerization of tubulin to form microtubules. By doing so, they interfere with cell division and are known to arrest cell division in the metaphase stage. It means that these agents will interfere with the division of the newly proliferating nigrostriatal dopamine neurons if they are administered during the period of neurogenesis. They will also interfere with cellular transport, cell polarization, cell growth and axonal extension that depend on the integrity of cytoskeleton proteins. These features are especially important for a group of cells, such as the basal ganglia DA neurons that require their long axonal reaches to the striatum for their actions and effectiveness. By interfering with the assembling of the microtubules of the cells, colchicines and vincristine and now MPTP, via MPP+, (Capelletti et al, 2005), will also impede and/or retard the new neurons from migrating to their place of destination in the substantia nigra, pars compacta. The phenomenon will also prevent the cells from extending their axons to their targets in the striatum. Since colchicines have been found to abolish retrograde transport in neurons resulting in the withdrawal of presynaptic terminals (Schwartz, 1991), these alkaloids will eventually result in cell death due to the lack of contact or contact inhibition. Today colchicines are used as a research tool and as a drug and the range of their toxicity is well known. Toxins, such as colchicines and vincristine are not disease specific, but they can cause a specific disease outcome based on the timing of their toxic effects to coincide with the vulnerable stage of a cellular substrate that underlie a specific disorder. For example, if a fetus is exposed to colchicines or vinblastine during the period of the neurogenesis and development of cells to produce the nigrostriatal dopaminergic phenotype, these neurons will be selectively harmed, and likely will result in PD later in life. If the effect of the toxin coincides with the birth of the nucleus basalis of Meynert neurons, Alzheimer’s type dementia will occur. However, if the exposure time is extended to overlap both the birth of the nigrostriatal and acetylcholine neuronal sets the final symptoms will show parkinsonism and Alzheimer’s like dementia.
4.7. Testing the prenatal sensitization, susceptibility or vulnerable concept
In studies designed to test the effects of toxin on the development of the midbrain neurons that are destined to become the nigrostriatal phenotype, we administered MPTP during the stage of neurogenesis, proliferation, migration and development of these DA cells. In the mouse, this period occurs during gestation day 9 - 11 and is marked by the appearance and maturation of TH-containing immunoreactive nigrostriatal neurons. The pregnant dams were treated with various dosages of MPTP or with phosphate buffered saline (PBS), as the control. We found that the dams treated with the 20 mg/kg and 30 mg/kg levels of MPTP, amounts that did not caused marked acute toxicity in the dams, caused very low to no full term pregnancy, suggesting that the higher dosage of MPTP may cause the pups to be aborted. For the 10 mg/kg of MPTP, however, the dams delivered normal looking pups, and this dosage was used to test the prenatal effects of MPTP.
4.7.1. Prenatal effects of MPTP on body weight, motor activity, TH and DA.
The outcome showed that the birth weights of pups born to dam that were exposed to prenatal 10 mg/kg of MPTP lagged behind the PBS control, but caught up within 4 weeks (Muthian et al, 2010). This recovery in birth weight and the appearance of the offspring indicated that they were in good physical health. The prenatal exposure to MPTP also reduced motor activity, measured as the total distance travelled, the movement time and the number of movements (Muthian et al, 2010) and Western blot detection showed that the exposure of the pregnant dams to MPTP at G9-11, that targeted the developing nigrostriatal dopamine neurons, reduced striatal tyrosine hydroxylase (TH) protein by 38%. DA and the metabolites of DA were also studied in the brain of the 12 week old C57BL/CJ mouse offspring following the prenatal exposure to10 mg/kg of MPTP or to PBS (Muthian et al, 2010). As shown in table 1, the prenatal exposure to MPTP reduced the concentrations of striatal dopamine (DA), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) by 13.80%, 16.48% and 66.25%, respectively (Muthian et al, 2010). The level of dihydroxyphenylacetic acid (DOPAC) showed a slight increase (table 1).
Dopamine and metabolites (ng/mg protein)
Prenatal Treatments
DA[%]
DOPAC[%]
HVA[%]
3-MT[%]
PBS
157.3 ± 17.30[0.0]
5.2 ± 0.76 [0.0]
18.2 ± 0.80 [0.0]
1.60 ± 0.20 [0.0]
MPTP
135.6 ± 4.80[13.8]
5.9 ± .88 [+13.46]
15.2 ± 0.80[16.48]
0.54 ± 0.12 [66.25]
Table 1.
Effects of prenatal MPTP on striatial DA, DOPAC, HVA and 3-MT. C57BL/6J dams were treated with 10 mg/kg MPTP or with PBS during G8-G12 to target the developing nigrostriatal dopamine neurons in the fetus. The table shows the levels of DA, DOPAC, HVA and 3-MT in the striatum of the 12 weeks old offspring. MPTP reduced DA, HVA and 3-MT, as compared to the values for the PBS group.
Figure 1.
Substantia nigra, compacta of mice showing tyrosine hydroxylase immunoreactivity. The figure shows tyrosine hydroxylase (TH) immunoreactivity (I) in the substantia nigra compacta of a 12 weeks old mouse that was exposed to PBS (left) and one that was exposed to MPTP (right) in utero. The pregnant dam was treated during gestation days 8-12 and TH-I was determined in the 12 weeks old offspring.
Figure 2.
Nissl staining of the substantia nigra of mice exposed to prenatal PBS or MPTP. The Nissl staining highlights the cells (dots) of the substantia nigra, pars compacta. The overall morphology is closely similar, but the cellular composition of the PBS exposed mice are more concentrated within a defined zone in the compacta and with larger cells, as compared to the mice exposed to MPTP in which the smaller cells, especially within the rostro-medial (R-M) zone, are more abundant.
4.7.2. Prenatal MPTP on the in situ TH immunoreactivity in the substantia nigra
Figure 1 shows the effects of the prenatal exposure to MPTP on midbrain TH immunohistochemistry. Polyclonal antibodies against tyrosine hydroxylase (TH) were used to detect the changes that occurred in 12 weeks old mice offspring that were exposed to 10 mg/kg of MPTP, in utero, during G8-12 of the dam’s pregnancy, when the midbrain neurons are developing the tyrosine hydroxylase phenotype. The results show that TH-like immunoreactivity was reduced in the midbrain substantia nigra of a mouse exposed to MPTP. The rostroventral section of the substantia nigra compacta was taken from horizontal slice of the mouse brain. The left section shows the TH immunoreactivity from a mouse offspring that was preexposed to PBS during G8-12 of the pregnant dam. The right section shows the TH inmmunoreactivity of a mouse offspring that was exposed to 10 mg/kg of MPTP during G8-12. The study shows that marked reduction of TH-I occurred in the mouse that was exposed in utero to MPTP (right).
4.7.3. Prenatal effect of MPTP on the Nissl Stained substantia nigra
The effect of prenatal exposure to MPTP on cellular distribution pattern in the substantia nigra, compacta of C57BL/CJ mice is shown in figure 2 as low magnification Nissl stained section of the 12 weeks old mice offspring. The differences in the cellular patterns for the PBS and the MPTP exposed animals were not marked, but cellular pattern seems to occur in the compacta zone for the PBS control as compared to the mouse that was exposed to MPTP, in which more scattered smaller cells can be seen in the medial (M) to rostral (R) zone of the substantia nigra (figure 1). The proportion of neurons to glia cells are unknown and are yet to be determined.
5. The inducing, precipitating or superimposing stage of the hypothesis
PD shares some characteristics with aging and the incidence of PD is higher in the aged individuals, but only a relatively small number of elders (about 0.3%) developed full-blown PD, therefore, since PD is sporadic it would appear that a predisposition exists for the disorder. The individuals that developed PD may have been predisposed or susceptible throughout their lives, and they develop PD symptoms when metabolic changes associated with getting older caused further harms to the nigrostriatal DA neurons and reduced the number of neurons. The precipitating effects may be due to various factors, such as changes that allow molecules that serve normal functions early in life to become toxic via direct or indirect ways, such as the production of toxic byproducts, for example. The exposure to exogenous toxic insults may also occur. This is represented by the outbreak of the 1919 encephalitis lethargic epidemic (Ravenholt et al, 1992) that precipitated PD symptoms among some of those that were affected by the encephalitis virus. Whether the inducing, precipitating or superimposing stage is due to metabolic changes or exposure to toxins, it should be noted that the effects do not have to be specific to cause the expression of the specific symptoms of PD, since the incidence during the first stage marks or sensitizes the nigrostriatal system, accordingly, any toxin or any change that can cause further harm to neurons, even in a general way, will affects those neurons that were made fragile.
DA and Metabolites (ng/mg protein)
Prenatal Exposure.
Postnatal MPTP Challenges (mg/kg)
0 (PBS)
10
20
30 mg/kg
DA
PBS
MPTP 10mg/kg
157.3 ± 17.3 [0.0]
135.6 ± 4.80 [13.80]
141.0 ± 5.50 [10.35]
48.0 ± 7.10 [69.96]
34.5 ± 1.7 [78.06]
28.0 ± 2.0 [82.20]
16.40 ± 2.0 [89.57]
3.95 ± 1.0 [97.49]
DOPAC
PBS
MPTP 10mg/kg
5.2 ± 0.76 [0.0] 5.9 ± 0.88 [+13.46]
6.00 ± 1.00 [15.38] 1.04 ± 0.96 [80.0]
3.3 ± 0.4 [36.53] 0.46 ± 0.58 [91.15]
1.95 ± 0.41 [62.5]
0.41 ± 0.33 [92.11]
HVA
PBS
MPTP 10mg/kg
18.2 ± 0.80 [0.0] 15.2 ± 0.80 [16.48]
17.5 ± 1.00 [3.85] 9.4 ± 0.66 [48.35]
9.84 ± 0.6 [45.93] 8.3 ± 2.1 [54.39]
6.0 ± 0.47 [67.03] 4.7 ± 0.70 [74.17]
3-MT
PBS
MPTP 10mg/kg
1.6 ± 0.20 [0.0]
0.54 ± 0.12 [66.25]
1.2 ± 0.15 [25.0] 0.45 ± 0.11 [65.38)
0.75 ± 12 [53.22]
0.32 ± 0.05 [80.0]
0.54 ± 0.11 [66.25]
0.32 ± 0.06 [80.0]
Table 2.
Postnatal effects of MPTP in mice offspring exposed to in utero MPTP or PBS. Effects of postnatal MPTP (10, 20, 30 mg/kg) on striatal DA, DOPAC, HVA and 3-MT in 12 weeks old mice offspring exposed to prenatal MPTP or PBS. The percent changes based on the normal PBS population levels are enclosed by brackets below the respective concentrations. The results show that postnatal MPTP was more effective in reducing DA and its metabolites in the offspring that were exposed to prenatal MPTP. However, for the 20 and 30 mg/kg doses of MPTP the significance of the postnatal, precipitating concept was masked because those doses of MPTP also markedly reduced DA and its metabolites in the prenatal PBS offspring.
5.1. Testing the inducing, precipitating or superimposing stage
We have shown that MPTP can be used to model the inducing, precipitating or superimposing stage. This was demonstrated in our studies in which we found that the postnatal administration of MPTP to 12 weeks old offspring, that were exposed in utero to MPTP earlier, during the developmental stage of the NS DA neurons, showed dramatically reduced levels of DA and its metabolites, as compared to similar mice that were exposed to the PBS treatment. The magnitude of the changes matches the level seen in PD, when compared with the normal population, or the PBS controls (table 2). The 10 mg/kg dosage of MPTP given to the mice that were exposed to prenatal MPTP caused the most dramatic reduction of DA and its metabolites, as compared to the PBS control (Table 2, column 3 vs. 4 showing values for prenatal PBS vs. prenatal MPTP). The 20 and 30 mg/kg of postnatal MPTP markedly reduced DA in the prenatal exposed MPTP mice, but these dose levels of MPTP also caused dramatic reductions of DA and its metabolites in the prenatal PBS mice, as well, so the differences between the prenatal MPTP and the prenatal PBS were not as dramatic (Fig 2, column 3 vs. 5 and 6 showing values for prenatal PBS vs. pre natal MPTP).
6. Analogy that depicts the two stages of affliction hypothesis
The two stages of affliction hypothesis for PD may be best illustrated by an analogy of a motor vehicle tire that was manufactured with a specific defect due to poor quality steel cords imbedded in the carcass or the body of the tire, during a critical period in the manufacture of the tire. The tire shows all of the characteristics of normal tires, but on exposure to the roadway the frictions that cause normal wear in tires turn out to cause serious failure in the defective tire. An inspection of the failed tire will show specific failure of the steel cords. The subtle imperfection that occurs during the manufacture of the tire may be seen as the sensitization factor that tags the tire for the specific type of failure that occurs under normal usage. In this scenario, such a normal tire usage may constitute the period for the precipitating stage, the tire serves to depict the human brain, the cords depict the nigrostriatal dopamine neurons with their far-reaching axonal projections, and the roadway-frictions represent the wear-and-tear of living that increases as a function of age. The two stages of afflictions or the sensitization-precipitating hypothesis for PD may also explain the discordance for PD in monozygotic twins. The life-long personality difference between monozygotic twins discordant for Parkinson\'s disease suggests that the process responsible for the disorders of PD has its inception early in life (Ward et al, 1983). The developmental personality of the member of the monozygotic twins who developed PD was found to be more introvert but since being an introvert is not usually abnormal within the population, it may be deduced that at least a second factor should be involved in causing the PD in the affected twin. The primary factor could be the early changes that render the nigrostrital DA neurons susceptible and also reflected or coincide with personality difference. The second factor for the disorder expression may be related to the regression in dopamine cells that occurs during aging (see McGree et al 1977).
7. Special cases of PD may involve early-life and multiple neuronal groups
The Guam amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) may represent an incident of PD in which wide-scale neuronal damage occurred during the sensitization stage, and the wear-and-tear of living or the aberrations associated with aging take their toll later in life. In other words, the nigrostriatal dopaminergic neurons that were impaired during the fetal development degenerate to the threshold level that causes PD symptoms. Above threshold neuronal death also occurred for the nucleus basalis of Meynert acetylcholinergic neurons and cortical neurons involve in memory and cognition and caused the dementia phase of ALS-PDC syndrome (Oyanagi, 2005). The lower and upper motor neurons systems that control skeletal muscle contraction also died to cause the amyotrophic lateral sclerosis phase of the disorder. The theory is based on the report that the ALS-PDC or otherwise PDC-ALS is essentially the convergence of three disorders. Patients with PDC showed the signs of rigidity, tremor and bradykinesia (Oyanagi, 2005), the classical signs of Parkinson’s disease as well as dementia (Oyanagi, 2005), the main sign of Alzheimer’s disease. The ALS phase of the Guam ALS-PDC disorder has been reported to be essentially similar to those of classic ALS. Moreover 5% of the patients with ALS subsequently developed the total clinical symptoms of the ALS-PDC and 38% of the patients with PDC eventually developed the PDC-ALS syndrome (Elizan, et al, 1966; Oyanagi, 2005). So the PDC syndrome may be based on the exposure of the fetus to the cycad toxin during the period of the neurogenesis of both nigrostriatal DA neurons and nucleus basalis neurons. The duration of the toxic exposure of the patients may have been long enough to coincide with the neurogenesis and migration of the nigrostriatal DA neurons as well as the nucleus basalis of Meynert acetylcholinergic neurons. For the ALS patients, it is proposed that the exposure to the prenatal toxin coincides with the birth of upper and lower motor neurons and causing deleterious effects early in life that sensitized them to stress that occurred later in life. The higher 38 percent of patients with ALS may be matching to the longer neurogenesis and proliferation period for the related motor neurons and therefore longer fetal exposure time.
7.1. Proposed fetal basis for the Guam ALS-PDC disorder
The proposition that beta-methylaminoalanine (BMAA), a toxin found in flour produced from the Cycad plant and eaten as food, caused ALS-PDC (Spencer et al, 1987), is of interest. It was also claimed that the basal ganglia symptoms were produced in monkeys fed BMAA (Spencer 1966), but this claim was disputed on the basis that the dosage used was far too high to represent the amounts that are eaten by human (Ince and Codd, 2005; McGree and Steele, 2011), and the disease produced in the monkeys was a classic acute toxicity model (Ince and Codd, 2005), rather than the progressing model of the ALS-PDC seen in the Guam patients. Moreover, the disease occurred in patients who had not used cycad products for many years (Sacks 1998), again suggesting the fetal basis for this ALS-PDC disorder. The risk of ALS-PDC was carried by migrants who had resided on Guam for the first 18 years of life (Ince and Codd, 2005), suggesting that early exposure is important for those who developed the ALS/PDC disorder, and the disorder takes over 35 years to develop, which is a very long time for a metabolic toxin to cause direct toxicity, and this also deviates from the short-term toxic models that have been presented.
It would be surprising that a major toxin consumed as a major source of food by several families would be so limiting in the number of individual within a family who were affected. In other words, if the ALS-PDC syndrome is due to a single-stage bout of toxic exposure, it would be expected that the toxin, which is ingested regularly as food, would affect a larger proportion of the group. So, it is apparently more reasonable to propose that the individuals that developed the ALS-PDC in Guam were exposed during the period of vulnerability of the nigrostriatal dopaminergic neurons, the nucleus basilis of Meynert acetylcholinergic neurons and the upper and lower motor neurons. They bourne the scar of the early exposure that pair with the changes that occur during aging to precipitate the ALS-PDC syndrome later in life. The sensitization-precipitation concept may be true also for the PD-like toxicity caused by MPTP in the later years of the 70s to the 80s. This may be so because not all individuals who were exposed to intravenous MPTP eventually developed full blown PD symptoms. Those that developed the symptoms of PD were probably predisposed with less resilient nigrostriatal neuronal set, and those that were spared had highly resilient nigrostriatal dopaminergic neurons. It means therefore, that most cases of PD may be caused by encounter made during the stage of neurogenesis and development of the nigrostriatal dopamine neurons, and that aging, the key risk factor for PD, precipitates idiopathic PD. The progressive nature of idiopathic PD may be based on the fact that aging is relenting and progressive in its own right.
8. S-adenosyl-L-methionine (SAM): A model precipitating factor for Parkinson’s disease
S-adenosyl-L-methionine (SAM) is presented as a likely precipitating factor for PD. SAM is a naturally occurring and ubiquitous molecule derived from methionine and ATP (Cantoni 1953). It is one of the most reactive and important biochemical (Kotb and Geller, 1993), but its activity seems to be harnessed by the limits and the control placed on its synthesis. SAM is apparently synthesized on demand and rapidly utilized by several enzymes, as the biological methyl donor (Cantoni 1953), for trans-sulfuration reactions and in the synthesis of polyamine (Andres and Cederbaum 2005). As the biological methyl donor, SAM is the co-factor for several methyl transferases, including catechol-O-methyl transferase (COMT) and indole amine methyl transferase. COMT transfers the methyl of SAM to dopamine (DA) to produce 3-methoxytyramine and to norepinephrine (NE) to produce normetaphrene and by doing so SAM terminates the synaptic activities of DA and NE, via irreversible reactions. SAM also serves to methylate N-acetyl-serotonin, via indoleamine methyltransferase to form melatonin and in the process may deplete serotonin (5-HT). These are major metabolic processes since DA, NE and 5-HT are important in synaptic transmission and in behavior (Agnoli et al, 1976) and are reported to be depleted in PD. So, SAM is a highly reactive endogenous molecule.
The injection of SAM into the cerebral ventricle of rodents produced symptoms that are similar or identical to those described for PD, including hypokinesia, rigidity, tremors (Charlton and Way 1978), the loss of DA, loss of striatal and substantia nigra tyrosine hydroxylase (Charlton, 1990; Charlton and Crowell, 1995; Crowell et al, 1993) and loss of neurons in the substantia nigra (Charlton and Mack, 1994).The PD-like changes that occurred following the cerebral ventricular administration of SAM are based on very logical and mechanistic grounds, since SAM reacts avidly with L-dopa and DA and reduced DA. More importantly, the loss of DA is the hallmark of PD disease, and the methylation of DA at the synapse (Axelrod, 1965) terminates the neurotransmitter activity of DA; a process that irreversibly destroys the dopamine molecule by covalently converting it to 3-methoxytyramine. SAM also drives the synthesis of phosphotidylcholine (PTC) (Hirata et al, 1981) that is accompanied with increases in lyso-PTC (Lee and Charlton 2001), a potent membrane damaging surfactant. It has been shown also, that SAM interacted with and methylated DA receptor protein and inhibited DA receptor binding (Lee and Charlton, 2004). In addition, the carboxylmethylation of protein, including DA receptor protein, by SAM, generates methanol (Axelrod and Daly, 1965), formaldehyde and formic acid (Lee et al 2008), reactive byproducts that can cause irreversible and accumulative damaging changes to cells and cellular constituents. Although the biological role of methanol, formaldehyde and formic acid are not viewed with much significance, these molecules are likely to be of primordial origin, helping to shape the destiny of life. They are produced in the body and are extremely reactive. The activity of SAM is also increased during aging (Mays and Borek 1973; Stramentinoli et al, 1977; Gharib et al, 1982; Sellinger et al, 1988), a critical period for cellular attrition and a stage of life during which the symptoms of idiopathic PD are seen. Today SAM is well studied as the major driver of the epigenetic modification of various genes. The biochemical control that SAM exhibited is remarkable on the basis that SAM is the limiting factor for dozens of methyltransferases, so any increase or decrease in the level of SAM serves as a key driving force for most methylation reactions.
8.1. Common markers exist for methylation and parkinsonism
A review of the results from various laboratories, include our own, shows that various biochemical, functional, anatomical and other markers are common to PD and to the methylation process (Table 3). Metabolites and byproducts of SAM, such as N-methyl dopamine, 3,4-dimethoxy-dopamine, N-methylsalsolinol (Maruyama, et al, 1996; Naoi et al, 2002; Matsubara et al, 2002) and harman and norharman (Kuhn, et al, 1996) are elevated in the CSF of PD patients and homocysteine (Lee et al, 2005) may cause PD like toxic changes. In addition, methyl-beta-carboline was reported to cause PD-like changes (Collins, et al. 1992; Gearhart et al, 1997). Furthermore, it has been shown that the tissues of PD patients methylate nicotinamide greatly higher than tissues of the control patients (Willams et al, 1993); and that nicotinamide methylation is proposed to be a key factor in the development of degenerative diseases (Williams and Ramsden, 2005). The enzyme, nicotinamide-N-methyltransferase, that transfers the methyl group from SAM to nicotinamide, was shown to be high in the CSF of PD patients (Aoyama et al, 2001) and N-methyl-nicotinamide was also higher in the brain of PD victims as compared to the control (Williams and Ramsden, 2005). So, as shown, many biological changes seen in PD correspond with the effects of SAM, its enzymes and its metabolites (table 3)
More prevalent Alleviates Aggravates Causes/in PD brain Causes Causes Found in Found in Found in Aggravates Aggravates PD-like effects High in CSF
Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes
Yes Yes
High activity of SAM Depletes SAM Increased SAM SAM metabolite SAM metabolite Enhances methylation SAM metabolite SAM metabolite SAM metabolite Increased SAM activity Increased SAM activity Increased by SAM SAM is the cofactor
Table 3.
Many biological changes seen in PD correspond with the effects of SAM. The table shows the parallel relationship between changes associated with Parkinson’s disease and with the effects and biochemical activities of S-adenosyl-L-methionine and its metabolites. A one-one relationship is shown in the activities listed.
8.2. Actions and effects that support the role of SAM as a precipitation factor in PD
If a secondary precipitating factor is associated with PD, it would more likely fits as a toxic metabolite that is associated with aging. Such a metabolite would be expected to be very reactive. It would show age-related increases in activity, would have a narrow index of safety so that even slight increases would cause toxic reactions. It should react with normal biochemicals that are critically needed on a moment-by-moment basis for the maintenance of essential functions. Moreover, the metabolite should react with biochemical that are found to be modified during the course of PD, for example, DA that is depleted in PD and which is an avid methyl acceptor. In addition, the mode of reactivity of the metabolite should explain others changes that are related to the degenerative disease process, such as the effective therapy for PD and the development of tolerance to the therapeutic agent. So, an evaluation of S-adenosyl-L-methionine (SAM), the biological methyl donor, based on the above criteria, indicates that it fits the role of a precipitating factor for PD. Again, it is an endogenous molecule, its activity is increased during aging, it is very reactive, it has a narrow index of safety, it controls the metabolism of specific chemicals that are modified in PD, the major drug for PD, which is L-dopa, reacts avidly with SAM and L-dopa, in turn, induced methionine adenosyl transferase, the enzyme that produces SAM (Benson et al, 1993; Zhoa et al, 2001). Moreover, as mentioned above, several SAM-induced changes seem to be associated with the neuronal degeneration and many of the biochemical changes that occur in PD.
8.2.1. Age-dependent increases in SAM-dependent methylation
The activities of SAM, denoted by increases in its synthesis and utilization, are increased during aging. This has been reported as, an age-related increase in methionine-adenosyl transferase, the enzyme that produces SAM, increases of various methyl transferases, and the accumulation in products of SAM-dependent methylation reactions, including homocysteine and adenosine (Mays et al 1973; Stramentinoli et al, 1977; Sellinger et al 1988; Gharib et al 1982). It should be noted that a decrease in the absolute concentration of SAM in rats was reported to be related to aging (Baldessarini and Kopin, 1966) but the reduction was apparently due to increases in the turnover of SAM that also occurred during aging (Stramentinoli et al, 1977).
8.2.2. SAM depletion of biogenicamines may occur in PD
In the presence of catechol-O-methyltransferase and other transferases SAM serves as a cofactor in the methylated metabolism of several biogenic amines, including DA and norepinephrine, by donating its reactive methyl group mainly to receptive hydroxyl of the molecular ring and the nitrogen of the ethylamine side chain (Axelrod, 1965). SAM dependent methylation is the most important mechanism in mammals for the inactivation of catecholamine (Lambrosse et al 1958, Axelrod et al, 1965), consequently SAM is an important factor in controlling the neuronal levels of the biogenic amines. The decreased levels of DA (Hornykiewicz, 1966), norepinephrine (Erhinger and Hornykiewicz, 1960) and serotonin (Bernheimer et al, 1961) observed in PD could be explained by an increase in the methylation of DA, norepinephrine and of N-acetyl-serotonin. The methylation of DA may also explain the increase ratio of homovanillic acid (HVA) to DA (HVA/DA) in PD and the increased level of 3,4-dimethoxyphenylethylamine, the dimethoxy metabolite of DA, that was reported to be contained in the urine of PD patients. More importantly, the DA derived alkaloid, N-methyl-(R)-salsolinol, was shown to occur in the human brain, accumulates in the nigrostriatal system and may play a role in PD (Naoi et al, 2002). An increase SAM-dependent methylation may also help to explain the pharmacology of L-dopa, in treating the symptoms of PD, because L-dopa is not only converted to DA, but it also reacts avidly with SAM, and depletes SAM. SAM dependent regulation of biogenicamines is achieved by methylated catabolism as well as by increasing synthesis, because it has been shown that preincubation with SAM caused activation of tyrosine hydroxylase in the corpus striatum of rats (Mann and Hill, 1983). These and other outcomes suggest that SAM is functioning both intra- and extra-neuronal, therefore its bio-availability at specific sites should be critical in determining the up or down regulation of the activity of biogenicamines. SAM activation of tyrosine hydroxylase (Mann and Hill, 1983) may help to explain the increase in DA turnover that occurs in PD. An increase in the methylation of L-dopa and DA will shunt tyrosine toward the production of L-dopa and L-dopa toward the production of DA, thus, tyrosine will be shunted away from the synthesis of melanin, a process that may help to explain the reduction of melanin in the substantia nigra of PD patients: noting that melanin is a product of tyrosine. Likewise, SAM also methylates phosphotidylethanolamine to produce phosphotidylcholine and phosphotidylcholine, in turn, is metabolized to generates choline molecules for the synthesis of acetylcholine. So, an increase in methylation could conceivable increase the level of acetylcholine and acetylcholinergic activity that occurred in PD, and which may form the basis for the utility of anticholinergic agents in the treatment of PD symptoms.
8.3.3. Mechanisms and selectivity of SAM for the basal ganglia
Conditions that increase the rate of methylation, for example aging (Sellinger et al 1988), may precipitate PD in individuals with susceptible DA neuronal population. In individuals with the normal complement of substantia nigral DA neurons the same level of methylation may represent an age-dependent normal regression of cell population, because the critical cell level that will result in PD would not be reached. Thus, the final effects of an increase in methylation in persons with normal populations of DA neurons would be different degrees of aging. Besides aging, other factors that facilitate an increase in methylation ought to be emplaced. It turns out that (i) the chemistry of the basal ganglia, (ii) the anatomical and physical state of the basal ganglia and (iii) the functions that are controlled by the basal ganglia coexist in a cooperative way to facilitate the uniqueness of SAM as the methyl donor and as a putative precipitating factor for PD.
For the chemistry of the basal ganglia, the methylation of DA and the methylation of phosphotidylethanolamine may be of major importance. First, the methylation of DA by SAM depletes DA at the synaptic cleft. This is an irreversible reaction that also generates 3-methoxytyramine, a metabolite that has been shown to competes with DA for its receptor binding (Charlton and Crowell, 2000). So, the reaction of SAM with DA and the generation of an competing metabolite will not only depletes DA, but also will interfere with the binding of DA to its receptors, which is consistent with a SAM-induced dopaminolytic state. SAM also methylates phosphotidylethanolamine to produce phosphotidylcholine, and, as mentioned above, to produce choline for the synthesis of acetylcholine. In addition, phosphotidylcholine is readily hydrolyzed to form the toxic surfactant, lyso-phosphotidylcholine (Lee et al, 2001; 2005). The reaction is also relevant on the basis that lyso-phosphotidylcholine is a potent surface-active agent that will damage cellular vesicles and nerve ending, and can contribute to the progression of the degeneration that occurs in PD. The biochemical peculiarity of the basal ganglia, therefore, includes the fact that the neostriatum contains large quantities of L-dopa, DA and norepinephine that are avid methyl acceptors, so they utilize high levels of SAM. SAM is also required for the methylation of phospholipid and the synthesis of acetylcholine, so the neostriatum is a high utility site of SAM, or a chemical ’sink’ for, SAM.
The precise functions of the basal ganglia marked it for visible impairments. The basal ganglia dopaminergic system controls precise articulation of the hands, finger, lips and whole body to support emotional expression, gesture and feelings. Therefore in the awaking human the neostriatum is constantly under stress to maintain the delicately balanced and fine-tuned processes that it controls, so slight impairments of the nigrostriatal system will upset the postural balances and precise muscle regulations and will cause visible impairments, that are seen as PD, even when such a degree of impairment or degeneration would not be physically obvious if occurred in other systems. SAM-related age-related changes may also affect vision and hearing, but the changes in the quality of life are not of the same magnitude as seen when the basal ganglia is impacted.
The anatomical or physically states of the basal ganglia also make this structure very accommodative to the effects of an increase in SAM, because SAM, which is very water soluble, will accumulate in the cerebral spinal fluid (CSF). In the CSF SAM is in close proximity to the neostriatum, which courses along and protruded into the lateral ventricle and contains the sensitive dopamine nerve terminals. Studies have shown that the administration of SAM into the lateral ventricle damaged the delicate ependymal cell barrier that separates the CSF from the caudate nucleus neuronal environment. By doing so, SAM gained access to the neostriatum, where it can deplete DA (Crowell et al, 1993), can methylate phospholipids (Lee and Charlton 2001) and DA receptor protein (Lee et al, 2004) and generate methanol, formaldehyde and formic acid (Lee et al, 2008) that are damaging to nigrostriatal dopamine nerve endings. These metabolites, especially formaldehyde will result in permanent changes to the dopaminergic neurons. Interestingly, in a more recent study, we found that the co-administration of a retrograde neuronal tracer with SAM into the lateral ventricle caused the labeling of cells in the substantia nigra, indicating that molecules placed in the lateral ventricle can gain access to the caudate nucleus DA nerve endings.
The increase in methylation can caused other significant changes, for example, the utilization of SAM imposes a great demand on ATP, because for every mole of DA methylated at the 3-OH and 4-OH positions 2 moles of ATP are utilized to replenish the utilized SAM and for every mole of phosphotidylethanolamine that is methylated to form phosphotidylcholine 3 mole of ATP are required to replenish SAM. Furthermore, the carboxyl methylation of protein by SAM will increase the isoprenylation of the proteins and each farnesyl molecule that is utilized requires 3 moles of ATP for its synthesis and each geranyl-geranyl requires 4 moles of ATP for its synthesis. So, an increased methylation will require increased production of ATP, which increases oxygen utilization and the probability of generating reactive oxygen species. In addition, 1 mole of potentially toxic homocysteine and 1 mole of adenosine may be produced for every mole of SAM utilized, and huge amounts of adenosine will be produced as a result of the metabolism of ATP to replenish SAM. The depletion of ATP may be relevant in this connection, because inhibition of mitochondrial oxidation and ATP reduction are proposed to be involved in the actions of MPTP or MPP+. It is well understood that SAM-dependent methylation is a normal physiological process, so for one to imagine how SAM may be involved in PD it should be understood that the symptoms of PD are due directly to dopamine biochemical deficiency and indirectly to the neuronal degeneration. This is so because drugs, such as L-dopa and DA receptor agonists relieve the tremors and other symptoms of PD, in spite of the fact that the permanent neuronal degeneration remains. Furthermore, the syndrome of PD wax-and-wane, which, cannot be explained by the existence of a permanent degenerated neuronal set. These examples show that the symptoms of PD, such as tremor and freezing, are striatal biochemical deficiency symptoms, due to the loss of dopamine as a result of the neuronal degeneration.
In spite of the doubts about the methylation concept, it is of interest that most of the other hypotheses concerning the genesis of PD cannot explain many of the changes that are seen in PD. One-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxyl-dopamine (6-OHDA) serve as the most important chemical models for PD. Their efficacies are mostly related to the targeted nigrostriatal cell death, but these agents do not cause changes that reflect the whole spectrum of PD symptoms. For example, MPTP does not cause PD-like symptoms in the rat, which also has a nigrostriatal dopamine system, but SAM does (Crowell et al, 1992; Charlton and Mack, 1994).
9. Conclusion
The abberrations that cause the nigrostriatal degeneration that result in Parkinson’s disease are unknown. Since about 90-95% of all cases of PD are not due to genetic changes, it means that the environment plays a major role in the cause of PD. The environment is not restricted to the toxins that might be involved, but includes the biochemical melieu that the nigrostriatal cells encounter from their origin to the outcome that causes them for die. So, the encounter with inappropriate biochemicals and inappropriate levels of the appropriate biochemicals may occur, and the outcome will vary and will be restricted to the nigrostriatal neurons or will involve other neuronal sets. This type of encounter will produce the syndrome that are eventually expressed and may include symptoms related to nigrostriatal damage only, but may be accompanied with other syndrome. So the expression of symptoms in addition to the classical PD other symptoms, suggests that nigrostriatal neuronal impairment may be accompanied with the impairments of other neuronal groups. These may include the basal nucleus of Meynert acetylcholinergic neurons that are degenerated in Alzheimer’s disease (AD) and the upper and lower motor neurons that are involved in the cause of amyotrophic lateral sclerosis (ALS). So, the existence of the Guam amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC, suggests that the factors that cause PD are not specific for the nigrostriatal neurons, but will affect other neuronal groups, as well.
For PD, it is suggested that the nigrostriatal dopaminergic neurons were exposed by chance encounter during a vulnerable stage of development of the neuronal set. Since aging is the key risk factor for PD, it also means that at least two stages of afflictions are involved in the cause of PD. Evidence and circumstance suggest that the first stage occurs in utero during the neurogenesis and development of cells to form the substantia nigra dopaminergic phenotype. The neuronal set is harmed in a subtle way that does not cause visual symptoms, but the sub-threshold effects weakened the resilience of the neurons so that the stress encounter during the course of living causes further harm to the already affected neurons and precipitates the symptoms of PD. So, the first impairment may occur during the neurogenesis and development of the nigrostriatal dopamine neurons by inappropriate levels of regulatory molecules or by toxins. An increased activity of cyclic-AMP-dependent protein kinase A, for example, may antagonize the signal for sonic hedgehog protein and blocked the induction of dopamine neurons (Hayes et al, 1995). The exposure to alkaloids, such as colchicine or vinblastine may also occur, and these alkaloids may interfere with the development of the cytoskeleton, with long-term and sub-threshold levels of effects. The stress of aging that causes globally deteriorating change will then take a toll on these low resilient neuronal sets to precipitate the symptoms of PD. The prenatal and postnatal effects can also explain the occurrence of juvenile PD, which would involve the substantia nigral dopamine neurons that were affected in ways that make them less resilient and more sensitive to age-related stress, so a short course of living would be enough to precipitate the symptoms of PD in the young individual. The Guam ALS-PDC cases are proposed to be caused by the exposure to the Cycad toxin during the neurogenesis and development of the nigrostriatal dopamine neurons, the basal neucleus of Meynert acetylcholinergic neurons and upper and lower motor neurons. The exposure caused subthreshold harms to those neuronal sets and they failed before other major groups of neurons during the course of aging.
The hypothesis that neurodegenerative disorders, such as PD and others have their origin in the womb is in line with normal physiology, since the lives of all mammals have their origin in the womb. If the hypothesis is tested to be true further investigation will identify the specific agents and/or the mechanisms that may be involved in the sensitization stage and measures could be adapted to protect the vulnerable neuronal groups during critical stages of fetal development.
Acknowledgement
The author wishes to thank Gladson Muthian, Ph.D., Lemuel Dent, MD., MS; Veronica Mackay, B.S., Marquitta Smith, B.S. and Brenya Griffin, B.S. for their support of science in our laboratory. Supported by NIH NINDS R21NS049623, RO1xlink8432 and R01NS31177 and Bernard Crowell, Jr. MD, Ph.D., Little Rock AR.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/41743.pdf",chapterXML:"https://mts.intechopen.com/source/xml/41743.xml",downloadPdfUrl:"/chapter/pdf-download/41743",previewPdfUrl:"/chapter/pdf-preview/41743",totalDownloads:2703,totalViews:156,totalCrossrefCites:0,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:13,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"December 1st 2011",dateReviewed:"October 3rd 2012",datePrePublished:null,datePublished:"January 2nd 2013",dateFinished:"December 27th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/41743",risUrl:"/chapter/ris/41743",book:{id:"2604",slug:"basal-ganglia-an-integrative-view"},signatures:"Clivel G. Charlton",authors:[{id:"145066",title:"Dr.",name:"Clivel",middleName:null,surname:"Charlton",fullName:"Clivel Charlton",slug:"clivel-charlton",email:"ccharlton@mmc.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Major symptoms and the proposed causes for Parkinson’s disease",level:"1"},{id:"sec_2_2",title:"2.1. Aberrations in non-basal ganglia systems.",level:"2"},{id:"sec_4",title:"3. The fetal basis hypothesis for Parkinson’s disease. ",level:"1"},{id:"sec_4_2",title:"3.1. Chance encounter of the nigrostriatal neurons with harmful factors. ",level:"2"},{id:"sec_5_2",title:"3.2. High workload may explain the vulnerability of the nigrostriatal neurons.",level:"2"},{id:"sec_7",title:"4. The predisposing, sensitization, susceptible or vulnerable stage of the hypothesis ",level:"1"},{id:"sec_7_2",title:"4.1. The involvement of cytoskeleton and alpha-synuclein as axonal constituents",level:"2"},{id:"sec_8_2",title:"4.2. There may be a window of vulnerability for nigrostriatal dopamine neuronal sensitization",level:"2"},{id:"sec_9_2",title:"4.3. The susceptible stage may set the age of onset of PD and the severity of PD symptoms",level:"2"},{id:"sec_10_2",title:"4.4. The number of NS DA neurons may also determine the susceptibility to PD",level:"2"},{id:"sec_11_2",title:"4.5. The coincidental involvement of other neuronal sets with the NS neuronal changes",level:"2"},{id:"sec_12_2",title:"4.6. Agents that may cause neuronal susceptibility",level:"2"},{id:"sec_13_2",title:"4.7. Testing the prenatal sensitization, susceptibility or vulnerable concept",level:"2"},{id:"sec_13_3",title:"Table 1.",level:"3"},{id:"sec_14_3",title:"4.7.2. Prenatal MPTP on the in situ TH immunoreactivity in the substantia nigra",level:"3"},{id:"sec_15_3",title:"4.7.3. Prenatal effect of MPTP on the Nissl Stained substantia nigra",level:"3"},{id:"sec_18",title:"5. The inducing, precipitating or superimposing stage of the hypothesis",level:"1"},{id:"sec_18_2",title:"5.1. Testing the inducing, precipitating or superimposing stage",level:"2"},{id:"sec_20",title:"6. Analogy that depicts the two stages of affliction hypothesis",level:"1"},{id:"sec_21",title:"7. Special cases of PD may involve early-life and multiple neuronal groups",level:"1"},{id:"sec_21_2",title:"7.1. Proposed fetal basis for the Guam ALS-PDC disorder",level:"2"},{id:"sec_23",title:"8. S-adenosyl-L-methionine (SAM): A model precipitating factor for Parkinson’s disease",level:"1"},{id:"sec_23_2",title:"8.1. Common markers exist for methylation and parkinsonism",level:"2"},{id:"sec_24_2",title:"8.2. Actions and effects that support the role of SAM as a precipitation factor in PD",level:"2"},{id:"sec_24_3",title:"8.2.1. Age-dependent increases in SAM-dependent methylation",level:"3"},{id:"sec_25_3",title:"8.2.2. SAM depletion of biogenicamines may occur in PD",level:"3"},{id:"sec_26_3",title:"8.3.3. Mechanisms and selectivity of SAM for the basal ganglia",level:"3"},{id:"sec_29",title:"9. Conclusion",level:"1"},{id:"sec_29_2",title:"Acknowledgement",level:"2"}],chapterReferences:[{id:"B1",body:'AgnoliAAndreoliVCasacchiaMand CerboREffect of S-adenosyl-L- methionione (SAM-e) upon depressive symptoms. J. Psychiar. Res. 1319764354'},{id:"B2",body:'AlimM. AHossainM. SArimaKTakedaKIzumiyamaYNakamuraMKajiHShinodaTHisanagaSUedaKTubulin seeds alpha-synuclein fibril formation.J. Biol. Chem. 2772002321122117'},{id:"B3",body:'Alvord JrEC., Forno, LS., Kusske, JA., Jaufman, RJ., Rhodes, JS., Goetowski, CR. The pathology of parkinsonism: Comparison of degeneration in cerebral cortex and brainstem. Adv. Neurol. 51974175193'},{id:"B4",body:'AndresAand CederbaumA. 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1. Introduction
1.1 Clinical pathway in hospital
Clinical Pathway [1] is an effort made in order to:
Outlines the steps in detail:
Outlines the important steps that must be taken;
Describe services to patients;
Estimate possible clinical problems.
The description above provides directions to make it easier to discuss and try to get the same understanding, thus further formulation can be carried out to find clinical problems that may occur and provide directions for possible solutions, so that optimal conditions or the best conditions can be considered in existing conditions. This will be important for the following 3 things:
Provide an overview of the optimal service quality conditions;
Linkage with the best activity steps of cost-related services;
Clear activity as part of the steps that an algorithm can make, so that software can be made for computer or smartphone applicants.
Now with more advanced and superior computerization advancements, help simplify the complex problems of the Clinical Pathway, thus providing a discussion space for clinicians and hospital management to:
The use of the Clinical Pathway, its components and relationships that are clinically correct and in optimal management, an understanding that has often become difficult;
Provide steps, problems and optimal solutions, so that cost calculations can be carried out and rationally accepted.
The following are examples related to the role of clinical pathways in effectiveness [2]: clarity of admission, interventions, comparison of old and new therapies and clearer outcomes of clinical pathways. In this condition, the use of computerization makes it easier to explain and simulate events. The relationship of the above becomes clearer as described, as follows.
Components-relation to clinical pathway
Components in the right and correct clinical pathway are important, because it determines the appropriate diagnosis and is associated with appropriate clinical reasoning [3], otherwise it will be very dangerous related to misdiagnosis. The existence of various components that can be replaced or substituted is a challenge to keep choosing the right and right choice, as well as linkages that remain in the right and precise order according to Clinical Resioning while still guided by the flow of diagnosis as well as the correct therapy. Any mistake in the association will be dangerous to diagnosis and therapy, which can be dangerous for the patient. In the use of algorithms in the use of information systems in the Clinical Pathway, components and relationships play an important role in maintaining compatibility between clinical Reasioning and computational logic. The role of the fields of Information Technology, Medical and Medical Informatics is to jointly guard the condition of the components and their activities correctly and correctly.
Step-problem-optimal solution
Actually the best is the ideal or maximum, this is one that is intact from the world of medicine which is classified as an art, although some things have been replaced by tools and computerization. Determination of Step-Problem-Solution requires clinical reasoning, judgment, and experience so it is necessary to have an alternative companion, including still considering any possible side effects. Again, the role of Medical, Information Technology and Medical Informatics [4] or Information System experts is important to guard not only accuracy-truth, also Step-Problem-Solution, it is also necessary to consider the existence of patient safety [5].
1.2 Linkages clinical pathway with quality improvement and cost containment
The existence of Component-Linkage and Step-Problem-Solution is a necessity that needs to be considered in order to achieve an optimal Clinical Pathway, so the importance of being considered is related to things like the following.
Quality Improvement [6] is the existence of service conditions related to the ideal or optimal quality that can be achieved, or meets the minimum or optimal quality standard requirements, thus it must be protected from decreasing quality or achieving low quality of service.
Cost Containment [7] must actually consider services that remain of quality, should not decrease below the minimum standard required, so it is important that Cost Containment can be carried out while maintaining the quality that does not decline. 3. Adequacy of Quality Improvement and Cost Containment in Clinical pathway, must be pursued with repeated simulations, which will be facilitated by the use of software or smartphone applications using appropriate and supportive algorithms.
It is important to note things like the following:
(1) It is necessary to pay attention to and select the quality that can be improved, related to examination, diagnosis and therapy as well as rehabilitation, in real terms with scientific developments, technology and community development, (2) so that components and steps that lead to costs are selected, and can be carried out without reducing the quality of service, related to science and technology, as well as the substitution and new sophisticated equipment at a higher or lower cost.
Thus the selection must be carried out by means of a formal and written review, so that the success rate can be measured. Described as follows, Figure 1.
Figure 1.
Linkages clinical pathway with quality improvement and cost Cotnaimnent.
In computerized technology, software development [8] and mobile phone applications [9] have many sophisticated technologies and procedures, but there is still a need for close cooperation between medical, information technology, hospital management and medical infromatics in order to manufacture form algorithm [10], so that it can be made faster and in accordance with the integrity and in harmony with the use of the application in the field with optimal results that can be achieved while still being used easily, simply and user friendly.
2. Clinical pathway for services quality improvement
2.1 Clinical pathway for service quality
The example of the Clinical Pathway algorithm for the management of malnourished patients in elderly patients, shows: clarity of steps, clarity of risk, clarity of size, clarity of time, which allows clinicians to collaborate with management; has demonstrated one quality improvement strategy [11]. Examples of the effectiveness of clinical pathways in infection disease [12], algorithms on diagnosis and therapy provide good pathways for quality improvement and also cost savings, because there are:
Clear and measurable steps, diagnostic steps that show a basis for the diagnosis accompanied by a measure of the likelihood of that basis;
Stages from beginning to end, this stage is important to develop clinical reasoning that is important in the algorithm for clinical pathways, this is important for improving service quality;
There are types and doses of drugs, which can be selected on the basis of the level of the type of diagnosis, in this case the therapy becomes a clear choice and can be calculated the cost burden, so at the same time cost containment efforts can be carried out.
The 3 important things above provide evidence that a Clinical Pathway can provide simultaneous direction between:
Quality, between components-linkages and Step-Problem-Solution, which will specifically differ for each disease diagnosis, which needs to be considered in order to maintain the quality;
Quality Improvement, which is the hope of the clinician, management is the patient, because it will provide improvements in the efficiency and patient satisfaction.
The relationship between Clinical Pathway and Quality Improvement [13], with its accompanying components, is illustrated as follows, Figure 2.
Figure 2.
Clinical pathway for quality improvement.
The figure above shows:
Related to Quality and Quality Standard [14], which will provide an overview of the extent to which must be done and especially services that meet the minimum and optimal standards;
Related to procedures [15] that must be carried out and the most important thing is related to patient safety, because it will allow services that save the patient, it will include simultaneously saving doctors and hospitals;
Prioritization in order to improve can be done simultaneously, but the fulfillment of patient safety first and then the quality standard;
Quality Improvement so that it is endeavored simultaneously with different levels and simultaneously achieving an optimal level.
2.2 Patient safety for service quality improvement
One of the ways of Service Quality Improvement is to use accreditation, accreditation is an effort to periodically assess the Quality Standard as the highest reference, so that our achievement is assessed against that standard. Service Quality Improvement which is important and must be a concern is Patient Safety [16], because it is one of the main goals of health services. Patient safety which is important in the hospital is the expected outcome as follows:
Significantly increased patient safety;
There is a reduction in risk and accidents;
There are health outcomes that are better than before;
There is an improved patient experience.
The four things above are related to the Quality Improvent of the service so that it will be clear what processes, outputs and outcomes will be achieved, and this effort needs to be carried out continuously and continuously, and is always a fun daily activity.
Optimal cost, in connection with this the existence of Cost Containment is required, it is proposed to do the following:
Create a clear clinical pathway component-Linkage and Step-Problem-Optimal Solution, and can be tracked for costs;
Make efforts to carry out a clear and directed Quality Improvement towards the expected quality standard;
Work on Cost Containment which takes into account the quality of service, service procedures, unit costs which are simultaneously reviewed in order to create an optimal cost condition without reducing the specified quality.
2.3 Algorithm usage
The following is an example of an algorithm, which is the basis for making diagnosis and therapy, with this algorithm it can be used as a software or smartphone application. Like the following example, Figure 3.
Figure 3.
Example of algorithm [17].
The figure below shows:
The existence of certain steps in accordance with the direction of the signs and symptoms, in this case Heat in Adults;
There is a Differential Diagnosis guide;
There is a flow for yes and no choices;
If the yes path is selected it will lead to the further path-Tets-Diagnosis-Therapy.
This simple algorithm image will provide an opportunity for programmers to create software and smartphone applications, which can then be developed to examine in each of the steps which allows for quality improvement, so that it is easier to analyze shortcomings and their relationship with other steps to be improved.
Research process in the context of making APSIS (Aplikasi Pembelajaran Alur Diagnosis dan Terapi Kedokteran = Learning Application Flowchart of Medical Diagnosis and Therapy) in Smartphone Application, related to algorithm development can be sown as above Figure 4.
Figure 4.
Flowchart of APSIS [17].
The figure above shows:
There is direction about the beginning of the start,
There is a division of groups which contains relatively similar indicators,
There are continuous steps in the form of a flowchart,
Provide a final description of the series, in the form of tests, diagnosis and therapy.
3. Clinical pathway in cost containment
3.1 Link of components
Cost Containment is done by maintaining the quality of service, because that is the first and important value of medical services, so the thought of costs is the next thing to consider, not the other way around. This effort can be done in terms of: [18].
Rates that reflect costs, with the help of Clinical Pathway and software algorithms, will easily provide remedial options, and better still provide easy possibilities for simulations by performing simulation at various costs, so that lower costs will be found while still maintain quality;
On investment, tools and instruments can now be selected which results in an easier and cheaper basis for diagnosis and therapy.
Procedure is a series of activities that have been directed and specific in order to carry out the service, so that the service achieves the objectives as determined, in accordance with the competence of the specified executor, as Figure 6.
Figure 6.
Link of procedure for cost containment.
The figure below shows:
Procedure, will be related to equipment, material and infrastructure so as to enable services to run smoothly;
Related to operations, namely: time, schedule and service implementation, as well as operators to enable services to run according to their destination and time;
The existence of certain service specifications, which are related to available funds and determined service rates, are considered in the context of cost containment.
The 3 things above must be considered with the standard of optimal cost, and the quality of service still occurs without a decrease in quality, this is a characteristic of cost containment that is carried out properly.
3.3 Unit cost
Description related to Unit Cost [19] which is the basis for Cost Containment, related to Billing for existing Services in accordance with Quality Standards and Coding in Clinical Pathways. The figure is as below, Figure 7.
Figure 7.
Link of unit cost for cost containment.
Furthermore, the Unit Cost, as a breakdown of Cost in accordance with the required cost details, will be the basis for determining the tariff and the charging of investment, so that a complete loading will occur; thus the optimal efficiency conditions will be calculated. In this case, it will be a part that provides a limitation so that the Quality Standard does not decrease by keeping the Unit Cost from decreasing drastically which causes the Quality Standard also decline too.
4. Clinical pathway in new era
4.1 New era in pandemic Covid-19
There are 4 important things related to the Covid-19 Era Pandemic: [20]
Pandemic atmosphere, anxious atmosphere, lots of information circulating and often confusing, mainstay information centers are often late in reporting, so there is an atmosphere that is at least unsettled and unpleasant.
Daily behavior, work and trying behavior are limited and there is a health protocol, providing a new, limited atmosphere and additional rules.
Patients with chronic diseases, such as hypertension, diabetes, chronic lung disease and others are known as comorbid people, a label that is very susceptible to infection, so there must be special protection and treatment.
This is invisible to the eye, the prominent patient being treated is only limited stress [21] which can be handled alone, an iceberg phenomenon that requires special treatment which currently only focuses on physical activities. The proof is that the health protocol is very difficult to implement, it must be violent until the threat of punishment, it does not develop automatic and natural awareness.
In connection with the matters above, how is the condition of the hospital: [22]
Outpatient visits decreased dramatically, so admissions were reduced;
Additional costs for the implementation of the health protocol, required immediately and cannot be delayed,
Protection for medical personnel, paramedics and other personnel related to hospital services, requires extra efforts to maintain a balance of quality services with protection of health workers so that they do not become infected.
Throughout the current journey, no hospital has gone bankrupt, apart from being supported by the government with social assistance, also because the hospital can make good adjustments, or postpone the burden into the future. In this connection:
There is an effort to maintain quality, it remains an important task that must be carried out without adjustments that can reduce quality;
The existence of cost containment is an option that must be done, with all the risks and consequences, which must be done right now;
There is an effort to give a big role to clinical pathways and the use of computerized analysis [23] to simplify complex problems and prepare new efforts quickly and easily, in this case when normal is only an option for later, then now inevitably have to be selected and worked on now, using computerized assistance.
There are 3 important things that will immediately be used as important references in ministry in the new era, as below:
Clinical Pathway in Non Curative Service [24], is a service that needs attention, as part of reducing contact and cost containment, which is promoted as a service that tries to reduce curative services which are usually more expensive, which of course can only be done at certain diseases and stages of therapy only;
Clinical Pathway in Technology Services [25], services designed with the support of mechanical technology and information systems, thereby reducing doctor-patient contact and providing better accuracy, which may be lacking in compassionate contact;
Clinical Pathway in Technological Related [26], is a service that from the beginning relied on technology as a mainstay, thus the presence of doctors will be made more efficient and on matters that are important and that are not harmful.
4.2 Clinical pathway in non curative service
The application of the Clinical Pathway now and in the future requires adjustments related to earlier approaches and prevention, not just therapy, because technological advances and awareness of healthy living are being promoted. Advance clinic and treatment to an earlier direction, such as Promotive, Preventive and Rehabilitation which is more aggressive and earlier.
The current palliative approach still needs to be developed towards older and more productive patients who can still enjoy an optimal quality of life, requiring hard work and continued development.
The next explanation is as follows.
Promotive [27] is an effort to increase knowledge and behavior in order to have a basic knowledge in dealing with disease with 3 main activities:
Awareness, is an effort to make people aware, especially those who are still healthy or slightly ill, have an awareness of the dangers that lead to disease;
Health education, which aims to increase knowledge and society or prospective patients, or have become patients so that the prevention is more severe;
Education, is an effort to encourage the community or patients to improve their abilities that previously could not be, bad behavior becomes good;
Consulting, is an effort to help the community or patients to be able to solve existing problems, and together find solutions.
This condition is often mixed up so that efforts do not produce optimal results, the best way to suggest is to select the required picture, then adjust the handling according to need.
Preventive [28] is an effort to prevent the disease from occurring, not getting worse, not getting worse, a common example is the use of immunization. This effort will be calculated the value of the cost that is cheaper when compared to treatment.
Rehabilitation [29] is an effort to make improvements to a condition that is already damaged or there is already an abnormality, so that as much as possible it can be restored as before. The current rehabilitation, many use tools and some are computerized, what is needed is a careful study so that it is sorted according to needs and the use of cost containment can be done.
4.3 Clinical pathway in technology services
The era of Telemedicine [30], with the Covid-19 Pandemic, the need to maintain distance makes it imperative to use more massive telemedicine, it is necessary to develop algorithms that are in accordance with the following: (1) there is a standard procedure and still meets clinical reasoning, (2) services that can be carried out gradually Quality Improvement, (3) services that can be simultaneously carried out cost Contaiment optimally but reduce quality. This presents a challenge, not only for doctors, hospitals, Information Communication Technology and Medical Informatics experts, to collectively achieve the above expectations.
The robotic era [31] will be greatly stimulated by the Covid-19 Pandemic by trying to avoid contact between doctors and patients in order to prevent transmission. The differences that occur are: (1) the procedure will be relatively the same, dealing with the patient is a robot, (2) the doctor controls the robot, not the instrument, also the time and sequence will be clear and can be calculated. Increasingly sophisticated computer performance with large capacities, supported by Artificial Intelligent, provides challenges, and at the same time, care must be taken with regard to patient safety, not according to good tools, still violating the patient safety principle.
The era of the Internet of Things [32] is a challenge now in various countries with a large number of elderly people, several countries have happened, some countries are not less than 10 years old will be a heavy burden. Thus the use of: Clinical Pathway, Quality Improvement, Cost Contaiment and the Internet of Things will be the way out that is needed. An example illustration is as follows as Figure 9.
Figure 9.
Clinical pathway in technology services.
The description above provides options and accelerates the use of advanced technology and with large capacities more quickly and relatively forced, due to the Covid-19 Pandemic which requires maintaining distance, avoiding contact and avoiding relatively long trips. Anticipation must be developed immediately with the following standards:
Keep following Clinical Reasoning and Clinical Pathway which are based on service quality standards;
Developing Quality Improvement and Cost Containment that are relevant and balanced, so that the perspective is accepted by doctors, hospitals, patients and insurers.
4.4 Clinical pathway in technological related
Heath Electronic Record (HER) or Medical Record (MR) [33] related to electronic medical records, which is getting more and more advanced with regard to voice recognition which provides direct recording of the history, and video recognition which records examination conditions using video in an integrated manner. The importance of an integrated and electronically based Medical Record (MR) provides:
Higher speed;
Clearer accuracy, greater capacity and high access, also with completeness, will help Quality Improvement;
Conditions that will impose large costs, which require Cost Contaiment to achieve optimal efficiency and cost load; with the Direct Consultation tool, the patient can consult a doctor or a robot, for several diseases that have been standardized first.
Tele-device [34], is a device that can be controlled remotely, or performs remote inspection, so that examinations that use certain tools do not need people to come from a distant city, just at the initial place, the results of the examination can be sent including the description. This is important for reference and preparedness in the context of Covid-19.
Self Service [35] with a standardized algorithm, a Guidance Commission Support System can be used to make diagnosis and therapy of diseases. In this case, Quality Improvement and Cost Contaiment is important in giving choices, because the decision is made by the patient, it may need to be limited to chronic disease and regular control and options that are not feasible.
A simple example illustration as follows as Figure 10.
Figure 10.
Clinical pathway in technological related.
The above description is broader as below.
Consultations, with real doctors, with robots that use voice or video can be carried out, which requires an unbeatable Clinical Pathway Algorithm, so the Quality Improvement role is very important and must be made from the time the services and software are used.
Examinations such as laboratories, methods, reagents and result criteria must be clear about the normal and maximum or minimum standards that apply, this is related to so that patients do not need to think a lot and do not need to learn clinical reasoning, but precisely in a safe corridor. This Cost Containment becomes important, especially in choosing a relatively cheap and safe examination.
Self-medicating, determining the usual diagnosis and therapy and in a safe category, can be done as long as it is normally done, without complications and there are new diagnoses and therapies. Quality Improvement and Cost Containment simultaneously to ensure high quality at optimal cost.
5. Conclution
Clinical pathway in hospital is an effort made in order to: outlines the steps in detail, outlines the important steps that must be taken, describe services to patients and estimate possible clinical problems; it can be used as a system for Quality Improvement and Cost Containment. The effectiveness of clinical pathways in algorithms on diagnosis and therapy provide good pathways for quality improvement and also cost savings. Cost Containment is done by maintaining the quality of service, because that is the first and important value of medical services, so the thought of costs is the next thing to consider, not the other way around. The Cost Containment effort can be done in terms of rates that reflect costs, with the help of Clinical Pathway that lower costs will be found while still maintain quality. Clinical Pathway that is used on investment, tools and instruments can now be selected which results cheaper basis for diagnosis and therapy. There are important things that will immediately be used as references in the new era that related to New Era in Pandemic Covid-19, Non Curative Service, Technology Services and Technological Rerelated, biside that Clinical Pathway will be made more efficient and on matters that are important and that are not harmful.
\n',keywords:"clinical pathway, quality improvement, cost containment, pandemic covid-19, non curative service, technology services, technological rerelated",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/77302.pdf",chapterXML:"https://mts.intechopen.com/source/xml/77302.xml",downloadPdfUrl:"/chapter/pdf-download/77302",previewPdfUrl:"/chapter/pdf-preview/77302",totalDownloads:93,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 18th 2020",dateReviewed:"May 27th 2021",datePrePublished:"June 29th 2021",datePublished:null,dateFinished:"June 24th 2021",readingETA:"0",abstract:"The explanation begins with the Clinical Pathway in Hospital which describes how the Clinical Pathway is used in relation to 2 things: Components-Linkages and Step-Problems-Optimal Solution, followed by Linkages Clinical Pathway with Quality Improvement and Cost Containment, which describes the relationship of each. Followed by the Clinical Pathway for Service Quality: which consists of: (1) Clinical Pathway for Service Quality, (2) Patient Safety for Service Quality Improvement, (3) The role of alogarithm, thereby clarifying the form of clinical pathways in quality improvement efforts that ensure service improvement by still maintain the quality that is maintained during the cost containment. The Clinical Pathway in Cost Containment describes the roles of: (1) Link of Components, (2) Procedure, (3) Unit Cost, so that cost containment efforts can be made in the form of cost containment optimally while maintaining quality does not need to decrease. Clinical Pathway in New Era is a newly developed algorithm related to current and future conditions. This is related to: (1) New Era in Pandemic Covid-19, (2) Clinical Pathway in Non Curative Service, (3) Clinical Pathway in Technology Services, (4) Clinical Pathway in Technological Rerelated while continuing to carry out quality improvement and cost containment simultaneously. Concluton: clinical pathway in hospital can be used as a system for Quality Improvement and Cost Containment, related to New Era in Pandemic Covid-19, Non Curative Service, Technology Services and Technological Rerelated.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/77302",risUrl:"/chapter/ris/77302",signatures:"Boy Subirosa Sabarguna",book:{id:"11068",type:"book",title:"Contemporary Issues in Information Systems - a Global Perspective",subtitle:null,fullTitle:"Contemporary Issues in Information Systems - a Global Perspective",slug:null,publishedDate:null,bookSignature:"Dr. Denis Reilly",coverURL:"https://cdn.intechopen.com/books/images_new/11068.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83969-464-6",printIsbn:"978-1-83969-463-9",pdfIsbn:"978-1-83969-465-3",isAvailableForWebshopOrdering:!0,editors:[{id:"105509",title:"Dr.",name:"Denis",middleName:null,surname:"Reilly",slug:"denis-reilly",fullName:"Denis Reilly"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"200387",title:"Ph.D.",name:"Boy Subirosa",middleName:null,surname:"Sabarguna",fullName:"Boy Subirosa Sabarguna",slug:"boy-subirosa-sabarguna",email:"sabarguna08@ui.ac.id",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Indonesia",institutionURL:null,country:{name:"Indonesia"}}}],sections:[{id:"sec_1",title:"1. 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However, only thermal treatment triggers many unwanted biochemical reactions, which leads to undesirable sensorial and nutritional effects. Therefore, a number of nontraditional preservation techniques are being developed to satisfy consumer demand with regard to nutritional and sensory aspects of foods. Ensuring food safety and at the same time meeting such demands for retention of nutrition and quality attributes has resulted in increased interest in emerging preservation techniques. These emerging food preservation technologies can extend the shelf life of unprocessed or processed foods by inactivating the enzymes, reducing the food spoiling microbial growth rate or viability without altering the food quality attributes including flavor, odor, color, texture, and nutritional value. On the emerging technology, sphere promising results have been attained by the radiation processes. Ionizing radiation has been widely used in industrial processes, especially in the sterilization of medicals, pharmaceuticals, cosmetic products, and in food processing. Nonionizing radiation has been used in surface decontamination, as on the packaging sector. Although radiation techniques, as the other traditional or emerging techniques, can impair alterations that can modify the chemical composition and the nutritional value of foods, these changes depend on the food composition, the irradiation dose and factors such as temperature and presence or absence of oxygen in the irradiating environment. The aim of this chapter is to discuss retention or loss of vitamins and minerals in several food products submitted to a radiation process (gamma irradiation, short wave ultraviolet, microwave, and pulsed electric fields).",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Fabiana Lima, Kássia Vieira, Miriam Santos and Poliana Mendes de\nSouza",authors:[{id:"246696",title:"Dr.",name:"Poliana",middleName:null,surname:"Mendes De Souza",slug:"poliana-mendes-de-souza",fullName:"Poliana Mendes De Souza"},{id:"267120",title:"BSc.",name:"Fabiana Regina",middleName:null,surname:"Lima",slug:"fabiana-regina-lima",fullName:"Fabiana Regina Lima"},{id:"267121",title:"BSc.",name:"Kássia Héllen",middleName:null,surname:"Vieira",slug:"kassia-hellen-vieira",fullName:"Kássia Héllen Vieira"},{id:"267122",title:"BSc.",name:"Miriam Aparecida",middleName:null,surname:"De Aguilar Santos",slug:"miriam-aparecida-de-aguilar-santos",fullName:"Miriam Aparecida De Aguilar Santos"}]},{id:"63207",doi:"10.5772/intechopen.79434",title:"Agrifood By-Products as a Source of Phytochemical Compounds",slug:"agrifood-by-products-as-a-source-of-phytochemical-compounds",totalDownloads:1477,totalCrossrefCites:4,totalDimensionsCites:7,abstract:"In last years, food by-products and waste valorization practices have gained importance because these processes are sustainable and can increase the profit for local economies. Many compound families of phytochemicals like carotenoids, tocopherols, glucosinolates and phenolic compounds can be obtained through plant by-products coming from agroindustries, such as citric peels, tomato wastes or wine pomace. A number of novel methods like pressured liquid, microwaves or supercritical CO2 are being used for the extraction of compounds, affecting them in different ways. Phytochemicals obtained can be used in cosmetics, medical uses and dietary supplements or reused in agrifood industries among others, as natural pigments, antioxidants or antimicrobials.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Sara Martillanes, Javier Rocha-Pimienta and Jonathan Delgado-\nAdámez",authors:[{id:"193962",title:"Ms.",name:"Sara",middleName:null,surname:"Martillanes",slug:"sara-martillanes",fullName:"Sara Martillanes"},{id:"193963",title:"Mr.",name:"Javier",middleName:null,surname:"Rocha-Pimienta",slug:"javier-rocha-pimienta",fullName:"Javier Rocha-Pimienta"},{id:"247371",title:"Dr.",name:"Jonathan",middleName:null,surname:"Delgado-Adámez",slug:"jonathan-delgado-adamez",fullName:"Jonathan Delgado-Adámez"}]},{id:"61595",doi:"10.5772/intechopen.77973",title:"Ultrasound Application to Improve Meat Quality",slug:"ultrasound-application-to-improve-meat-quality",totalDownloads:1681,totalCrossrefCites:5,totalDimensionsCites:7,abstract:"High-intensity ultrasound offers an alternative to traditional methods of food preservation and is regarded as a green, versatile, popular, and promising emerging technology. Ultrasound generates acoustic cavitation in a liquid medium, developing physical forces that are considered the main mechanism responsible for the observed changes in exposed materials. In meat, ultrasound has been successfully used to improve processes such as mass transfer and marination, tenderization of meat ,and inactivation of microorganisms. It is also an alternative to traditional meat aging methods for improving the quality properties of meat. Moreover, the combination of ultrasonic energy with a sanitizing agent can improve the effect of microbial reduction in foods. This review describes recent potential applications of ultrasound in meat systems, as well as physical and chemical effects of ultrasound treatments on the conservation and modification of processed meat foods.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Alma D. Alarcon-Rojo, Esmeralda Peña-González, Iván García-\nGalicia, Luis Carrillo-López, Mariana Huerta-Jiménez, Raúl Reyes-\nVillagrana and Hector Janacua-Vidales",authors:[{id:"114470",title:"Dr.",name:"Alma D.",middleName:null,surname:"Alarcon-Rojo",slug:"alma-d.-alarcon-rojo",fullName:"Alma D. Alarcon-Rojo"},{id:"194015",title:"Dr.",name:"Hector",middleName:null,surname:"Janacua-Vidales",slug:"hector-janacua-vidales",fullName:"Hector Janacua-Vidales"},{id:"228859",title:"Dr.",name:"Luis",middleName:null,surname:"Carrillo",slug:"luis-carrillo",fullName:"Luis Carrillo"},{id:"252001",title:"Dr.",name:"Esmeralda",middleName:null,surname:"Peña-Gonzalez",slug:"esmeralda-pena-gonzalez",fullName:"Esmeralda Peña-Gonzalez"},{id:"252003",title:"Dr.",name:"Iván",middleName:null,surname:"García-Galicia",slug:"ivan-garcia-galicia",fullName:"Iván García-Galicia"},{id:"252004",title:"Dr.",name:"Mariana",middleName:null,surname:"Huerta-Jimenez",slug:"mariana-huerta-jimenez",fullName:"Mariana Huerta-Jimenez"},{id:"252005",title:"Dr.",name:"Raul",middleName:null,surname:"Reyes-Villagrana",slug:"raul-reyes-villagrana",fullName:"Raul Reyes-Villagrana"}]},{id:"62295",doi:"10.5772/intechopen.78796",title:"Chemical Constituents of Fruit Wines as Descriptors of their Nutritional, Sensorial and Health-Related Properties",slug:"chemical-constituents-of-fruit-wines-as-descriptors-of-their-nutritional-sensorial-and-health-relate",totalDownloads:1385,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"Functional foods are foods that provide positive health effects apart from the provision of essential nutrients. Along with nutraceuticals, they represent the top trends in the food industry. Fruit wines are considered functional foods. When assessing the fruit wine quality, a wide range of descriptors are taken into consideration, namely physicochemical and sensorial properties of fruit wine. Furthermore, within the context of the new food products development (e.g. functional products), functional properties of fruit wines are also taken into consideration. Functional properties are determined by the content of the biologically active components, such as polyphenols, vitamins and micro- and macrominerals. It is also important to consider the food-safety issues regarding the fruit wines consummation, that is, the presence of pesticides, mycotoxins and biogenic amines in different fruit wines. This chapter aims to give an overview of various factors used to evaluate the quality and the functional properties of fruit wines.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Darko Velić, Daniela Amidžić Klarić, Natalija Velić, Ilija Klarić, Vlatka\nPetravić Tominac and Ana Mornar",authors:[{id:"147995",title:"Dr.",name:"Ana",middleName:null,surname:"Mornar",slug:"ana-mornar",fullName:"Ana Mornar"},{id:"245704",title:"Prof.",name:"Darko",middleName:null,surname:"Velić",slug:"darko-velic",fullName:"Darko Velić"},{id:"246414",title:"Dr.",name:"Daniela",middleName:null,surname:"Amidžić Klarić",slug:"daniela-amidzic-klaric",fullName:"Daniela Amidžić Klarić"},{id:"246415",title:"Prof.",name:"Natalija",middleName:null,surname:"Velić",slug:"natalija-velic",fullName:"Natalija Velić"},{id:"246416",title:"Dr.",name:"Ilija",middleName:null,surname:"Klarić",slug:"ilija-klaric",fullName:"Ilija Klarić"},{id:"246417",title:"Prof.",name:"Vlatka",middleName:null,surname:"Petravić Tominac",slug:"vlatka-petravic-tominac",fullName:"Vlatka Petravić Tominac"}]}],mostDownloadedChaptersLast30Days:[{id:"63169",title:"The Dairy Industry: Process, Monitoring, Standards, and Quality",slug:"the-dairy-industry-process-monitoring-standards-and-quality",totalDownloads:9071,totalCrossrefCites:12,totalDimensionsCites:27,abstract:"Sampling and analysis occur along the milk processing train: from collection at farm level, to intake at the diary plant, the processing steps, and the end products. Milk has a short shelf life; however, products such as milk powders have allowed a global industry to be developed. Quality control tests are vital to support activities for hygiene and food standards to meet regulatory and customer demands. Multiples of chemical and microbiological contamination tests are undertaken. Hazard analysis testing strategies are necessary, but some tests may be redundant; it is therefore vital to identify product optimization quality control strategies. The time taken to undergo testing and turnaround time are rarely measured. The dairy industry is a traditional industry with a low margin commodity. Industry 4.0 vision for dairy manufacturing is to introduce the aspects of operational excellence and implementation of information and communications technologies. The dairy industries’ reply to Industry 4.0 is represented predominantly by proactive maintenance and optimization of production and logistical chains, such as robotic milking machines and processing and packaging line automation reinforced by sensors for rapid chemical and microbial analysis with improved and real-time data management. This chapter reviews the processing trains with suggestions for improved optimization.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Niamh Burke, Krzysztof A. Zacharski, Mark Southern, Paul Hogan,\nMichael P. Ryan and Catherine C. Adley",authors:[{id:"243276",title:"Dr.",name:"Michael P",middleName:null,surname:"Ryan",slug:"michael-p-ryan",fullName:"Michael P Ryan"},{id:"246153",title:"Prof.",name:"Catherine",middleName:null,surname:"Adley",slug:"catherine-adley",fullName:"Catherine Adley"},{id:"264302",title:"Ms.",name:"Niamh",middleName:null,surname:"Burke",slug:"niamh-burke",fullName:"Niamh Burke"},{id:"264304",title:"Mr.",name:"Krzysztof A",middleName:null,surname:"Zacharski",slug:"krzysztof-a-zacharski",fullName:"Krzysztof A Zacharski"},{id:"264305",title:"Mr.",name:"Paul",middleName:null,surname:"Hogan",slug:"paul-hogan",fullName:"Paul Hogan"},{id:"264306",title:"Dr.",name:"Mark",middleName:null,surname:"Southern",slug:"mark-southern",fullName:"Mark Southern"}]},{id:"62295",title:"Chemical Constituents of Fruit Wines as Descriptors of their Nutritional, Sensorial and Health-Related Properties",slug:"chemical-constituents-of-fruit-wines-as-descriptors-of-their-nutritional-sensorial-and-health-relate",totalDownloads:1380,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"Functional foods are foods that provide positive health effects apart from the provision of essential nutrients. Along with nutraceuticals, they represent the top trends in the food industry. Fruit wines are considered functional foods. When assessing the fruit wine quality, a wide range of descriptors are taken into consideration, namely physicochemical and sensorial properties of fruit wine. Furthermore, within the context of the new food products development (e.g. functional products), functional properties of fruit wines are also taken into consideration. Functional properties are determined by the content of the biologically active components, such as polyphenols, vitamins and micro- and macrominerals. It is also important to consider the food-safety issues regarding the fruit wines consummation, that is, the presence of pesticides, mycotoxins and biogenic amines in different fruit wines. This chapter aims to give an overview of various factors used to evaluate the quality and the functional properties of fruit wines.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Darko Velić, Daniela Amidžić Klarić, Natalija Velić, Ilija Klarić, Vlatka\nPetravić Tominac and Ana Mornar",authors:[{id:"147995",title:"Dr.",name:"Ana",middleName:null,surname:"Mornar",slug:"ana-mornar",fullName:"Ana Mornar"},{id:"245704",title:"Prof.",name:"Darko",middleName:null,surname:"Velić",slug:"darko-velic",fullName:"Darko Velić"},{id:"246414",title:"Dr.",name:"Daniela",middleName:null,surname:"Amidžić Klarić",slug:"daniela-amidzic-klaric",fullName:"Daniela Amidžić Klarić"},{id:"246415",title:"Prof.",name:"Natalija",middleName:null,surname:"Velić",slug:"natalija-velic",fullName:"Natalija Velić"},{id:"246416",title:"Dr.",name:"Ilija",middleName:null,surname:"Klarić",slug:"ilija-klaric",fullName:"Ilija Klarić"},{id:"246417",title:"Prof.",name:"Vlatka",middleName:null,surname:"Petravić Tominac",slug:"vlatka-petravic-tominac",fullName:"Vlatka Petravić Tominac"}]},{id:"64299",title:"Quality of Reduced-Fat Dairy Coffee Creamer: Affected by Different Fat Replacer and Drying Methods",slug:"quality-of-reduced-fat-dairy-coffee-creamer-affected-by-different-fat-replacer-and-drying-methods",totalDownloads:1447,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"This work aims to investigate the effects of inulin (0, 2.5, 5 and 7.5%, w/w) and maltodextrin (0, 15, 20 and 25%, w/w) as wall materials and fat replacers and drying techniques (i.e. spray drying and fluidized-bed drying) on physicochemical properties of regular and instant reduced-fat dairy creamers. The regular reduced-fat dairy creamer was produced by one-stage drying (i.e. spray drying), while the instant reduced-fat dairy creamer was produced by two-stage drying (i.e. spray drying followed by fluidized-bed drying). In this study, control (0% inulin and 0% maltodextrin) and two commercial regular and instant coffee creamers (A and B) were also considered for comparison purposes. The results showed that the regular creamer containing 25% maltodextrin and 7.5% inulin had the largest particle size, highest viscosity and most desirable wettability among all formulated regular creamers. The yield of reduced-fat coffee creamer was significantly increased from 43.55 to 94.60% by increasing the amount of fat replacers to the maximum level (25% maltodextrin and 7.5% inulin). The current study revealed that the application of fluidized-bed drying for agglomeration led to significantly improve the wettability and instant properties of the instant creamer. In this study, the formulated instant creamer containing 25% maltodextrin and 7.5% inulin was the most desirable product as compared to all creamers.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Simin Hedayatnia and Hamed Mirhosseini",authors:[{id:"245735",title:"Associate Prof.",name:"Hamed",middleName:null,surname:"Mirhosseini",slug:"hamed-mirhosseini",fullName:"Hamed Mirhosseini"}]},{id:"63188",title:"Effects of Radiation Technologies on Food Nutritional Quality",slug:"effects-of-radiation-technologies-on-food-nutritional-quality",totalDownloads:2249,totalCrossrefCites:8,totalDimensionsCites:14,abstract:"Generally, foods are thermally processed to destroy the vegetative microorganisms for food preservation. However, only thermal treatment triggers many unwanted biochemical reactions, which leads to undesirable sensorial and nutritional effects. Therefore, a number of nontraditional preservation techniques are being developed to satisfy consumer demand with regard to nutritional and sensory aspects of foods. Ensuring food safety and at the same time meeting such demands for retention of nutrition and quality attributes has resulted in increased interest in emerging preservation techniques. These emerging food preservation technologies can extend the shelf life of unprocessed or processed foods by inactivating the enzymes, reducing the food spoiling microbial growth rate or viability without altering the food quality attributes including flavor, odor, color, texture, and nutritional value. On the emerging technology, sphere promising results have been attained by the radiation processes. Ionizing radiation has been widely used in industrial processes, especially in the sterilization of medicals, pharmaceuticals, cosmetic products, and in food processing. Nonionizing radiation has been used in surface decontamination, as on the packaging sector. Although radiation techniques, as the other traditional or emerging techniques, can impair alterations that can modify the chemical composition and the nutritional value of foods, these changes depend on the food composition, the irradiation dose and factors such as temperature and presence or absence of oxygen in the irradiating environment. The aim of this chapter is to discuss retention or loss of vitamins and minerals in several food products submitted to a radiation process (gamma irradiation, short wave ultraviolet, microwave, and pulsed electric fields).",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Fabiana Lima, Kássia Vieira, Miriam Santos and Poliana Mendes de\nSouza",authors:[{id:"246696",title:"Dr.",name:"Poliana",middleName:null,surname:"Mendes De Souza",slug:"poliana-mendes-de-souza",fullName:"Poliana Mendes De Souza"},{id:"267120",title:"BSc.",name:"Fabiana Regina",middleName:null,surname:"Lima",slug:"fabiana-regina-lima",fullName:"Fabiana Regina Lima"},{id:"267121",title:"BSc.",name:"Kássia Héllen",middleName:null,surname:"Vieira",slug:"kassia-hellen-vieira",fullName:"Kássia Héllen Vieira"},{id:"267122",title:"BSc.",name:"Miriam Aparecida",middleName:null,surname:"De Aguilar Santos",slug:"miriam-aparecida-de-aguilar-santos",fullName:"Miriam Aparecida De Aguilar Santos"}]},{id:"63751",title:"Role of Dietary Carotenoids in Different Etiologies of Chronic Liver Diseases",slug:"role-of-dietary-carotenoids-in-different-etiologies-of-chronic-liver-diseases",totalDownloads:1260,totalCrossrefCites:0,totalDimensionsCites:5,abstract:"Carotenoids are tetraterpenoid organic pigments synthesized by a variety of plants and microorganisms. Dietary carotenoids, taken by animals through food, play an essential role in cell differentiation, morphogenesis, vision, prevention of cancer, atherosclerosis, and age-related macular degeneration in humans due to their potential to suppress oxidative stress. As reactive oxygen species and oxidative damage to biomolecules have been found to be involved in the causation and progression of chronic liver diseases (CLDs), including hepatocellular carcinoma (HCC), which is one of the major causes of morbidity and mortality worldwide. Therefore, dietary antioxidants, which inactivate reactive oxygen species and obstruct oxidative damage, are considered as vital prophylactic strategic molecules. Data from various epidemiological studies and clinical trials strongly validate the observation that adequate carotenoid supplementation may significantly reduce the risk of several liver disorders. This chapter, thus, provides a comprehensive account of dietary carotenoids and includes the recent information with respect to their role in prevention of liver diseases.",book:{id:"6817",slug:"descriptive-food-science",title:"Descriptive Food Science",fullTitle:"Descriptive Food Science"},signatures:"Uzma Latief and Riaz Ahmad",authors:[{id:"249801",title:"Dr.",name:"Riaz",middleName:null,surname:"Ahmad",slug:"riaz-ahmad",fullName:"Riaz Ahmad"},{id:"251098",title:"Ms.",name:"Uzma",middleName:null,surname:"Latief",slug:"uzma-latief",fullName:"Uzma Latief"}]}],onlineFirstChaptersFilter:{topicId:"325",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:320,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:17,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. 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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"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:7,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. 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Kasenga",hash:"91cde4582ead884cb0f355a19b67cd56",volumeInSeries:4,fullTitle:"Malaria",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga",profilePictureURL:"https://mts.intechopen.com/storage/users/86725/images/system/86725.jpg",institutionString:"Malawi Adventist University",institution:{name:"Malawi Adventist University",institutionURL:null,country:{name:"Malawi"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. Rodriguez-Morales",hash:"61c627da05b2ace83056d11357bdf361",volumeInSeries:3,fullTitle:"Current Topics in Neglected Tropical Diseases",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. 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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:301,paginationItems:[{id:"116250",title:"Dr.",name:"Nima",middleName:null,surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/116250/images/system/116250.jpg",biography:"Professor Nima Rezaei obtained an MD from Tehran University of Medical Sciences, Iran. He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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