Use of Insecticide-Treated Nets (ITN) Against Diseases Vectors and Sucking Blood Arthropods

 

Introduction

Sucking Arthropods and Related Families in the World are

Mosquitoes (Culicidae), Sand flies (Psychodidae), Black flies (Simuliidae), Biting Midges (Ceratopogonidae), Tabanids (Tabanidae), Stable fly (Muscidae), Tsetse fly (Glossinidae), Kissing bug (Reduviidae), Bedbug (Cimicidae), Flea (Pulicidae), Head and body louse (Pediculicidae), Crab (Phthiridae), Mite (Trombiculidae), Hard Ticks (Ixodidae), Soft ticks (Argasidae). They transmit deferent diseases to human. World Health Organization listed the main vector borne disease in the world (Table 1). Vector-borne diseases are illnesses caused by pathogens and parasites in human populations. Every year more than one billion people are infected, and more than one million people die from vector-borne diseases including malaria, dengue, schistosomiasis, leishmaniasis, Chagas disease, yellow fever, lymphatic filariasis and onchocerciasis. For many vector-borne diseases, there are no vaccines, and drug resistance is an increasing threat. Vector control plays a vital role and is often the only way to prevent disease outbreaks. Many existing interventions, such as insecticide treated bed nets and indoor spraying, are simple and proven. Insecticide-treated bed nets are one of the most. WHO therefore recommends that everyone who is at risk of malaria sleeps under a long-lasting insecticidal net every night?

Table 1: Patients with tendon and ligament injury according to age and sex.

International donors funded over 700 million bed nets to protect families against malaria in sub-Saharan Africa. Nets should be checked regularly for holes and replaced every 2-3 years (Figure 1). The use of insecticide in impregnation of bed nets against sucking arthropods is due to these creatures are attracted to contact occupied nets by the odor of the occupants. This equipment is being used as personal protection for high-risk groups. If 80% of the entire population is coverage, it has mass killing effect. At the total coverage, ITN effect on the vector density and survival.

Figure 1: Global death from vector-borne diseases.

Advantages of Mosquito Nets

Low cost, lack of need for special equipment, fewer organization and logistical problems, less insecticide needed, compatibility with local customs, suppressed on the population nuisance insects, protection against cold, dust and snake.

Disadvantages Mosquito Nets

Several factors are involved including: culture, community acceptance due to the lack of awareness, sustainability, allergic effect, Feasibility, accessibility, misuse, not compatible with vector behavior, less coverage, program of distribution, ventilation problem, house design, restrictions of the community movement, -side effect on the pregnant women and child, -shape and design of net, re-impregnation, difficult to evaluate the impact of net.

Efficacy of Impregnated Bed Nets Depend on

Bed net types (Type of bednets can be determined through KAP study), Fabrics (cotton, nylon, polyester, polypropylene, polyethylene (Figure 2). World Health Organization recommended several insecticides for impregnation of bednets (Table 2).

Different Formulations for Impregnation of Bed Nets are: (SC = aqueous suspension concentrate, EW= emulsion, oil in water, WT= water dispersible tablet, CS = capsule suspension (microencapsulated), EC = emulsifiable concentrate.

Figure 2: Types of Fabrics of bednets.

Table 2: Pesticide recommended for impregnation of bednet.

Ways of Impregnation

Soaking, spraying, colour (green, grey, brown, black, white), coding, skirting, insecticides (killing effect, deterrent effect, packaging, safety, registration, cost, social acceptances. Shape could be rectangular, conical, pyramid (Figure 3).

Figure 3: Different type and shapes of impregnated bednet nets commonly used

Current Insecticide Impregnate Bednets Against Insect Resistant to Insecticides are

Olyset® Plus (Permethrin + PBO incorporated into polyethylene, all panels) , PermaNet® 3.0 (Combination of deltamethrin coated on polyester with strengthened border (side panels), and deltamethrin + PBO incorporated into polyethylene roof)), Tsara® Boost (Deltamethrin + PBO incorporated polyethylene, all panels) , Tsara® Plus (Combination of deltamethrin coated on polyester (side panels), and deltamethrin + PBO incorporated into polyethylene (roof)) , Veeralin® (Alpha-cypermethrin + PBO incorporated into polyethylene, all panels) , Interceptor® G2 (Alpha-cypermethrin and chlorfenapyr coated on polyester) , Royal Guard® (Alphacypermethrin and pyriproxyfen incorporated into polyethylene, all panels).

Basic Information for Evaluation of Efficacy of Impregnated Bed Nets are

Ventilation, insecticide, vector susceptibility to insecticides, efficacy of insecticides, availability of insecticides, cost of insecticide, demographic data, population estimates, target groups (children, pregnant women), socioeconomic data, sleeping pattern (outside, inside), current use of nets, cultural attitudes, colors, sizes, vector bionomics, exophilicity and endophilicity, vectorial capacity, vector density, feeding pattern, species, zoophiloicity and anthropophilicity.

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Science: Scarcity Versus Plenty

 

Introduction

Managing in a context of scarcity is radically (and can go up to the level of rupture, in the kuhnian sense of the term) different from managing in a world of plenty.

In order not to stick to the slogan, we are concise and:

1. Of the Objectives: scarcity imposes the objectives on us within the necessary (sometimes only the essential, the basic); in the context of plenty we must find, among the many possible, the desired objectives;

2. From the Strategy (which way): we have the adjustment of the possible paths (naturally tight) and the demand (or impositions) of the necessary resources versus avoiding waste and maintaining the focus on the action (or multiple actions) defined as desired, although, of course, within the available resources;

3. From the Tactic (where we seek to give body, to make reality, to the previous points): we have the economy of means in order not to waste resources so that we are not blocked by the faults versus the saving resources so that we do not have to reduce the target objectives or the quality with which each of them can be achieved;

4. Of Technology: we have the lowest possible costs, saving resources and restricting to the indispensable versus the investment in quality, knowing that technology has a reproductive sense and sometimes investing in routes that have no immediate utility allows saving, in the medium / long term, because there are solutions “in portfolio” that can be made available and that show alternatives that would not otherwise even be thought of (as well as, the demand carried out beyond the needs of the immediate allow identifying costs and collateral risks that, in this way, can be avoided);

5. From Operationalization: we are looking to meet the partial objectives in a parsimonious way, versus seeing how far we can go with the available resources, in search of the possible quality / quantity.

The basic structures, let’s say “logistics”, may even be identical in one case as in the other, but face very different challenges in how they have to combine the coherence and balances between the impositions and needs of the five points presented above.

A couple of examples:

A. In Education: the focus will be placed on the case of scarcity in points 3, 4 and 5 above presented, while in the case of abundancy, points 1 and 2 should be privileged, which open doors to the multiplicity of possible options;

B. In Research: the debate should focus on points 1 and 2, as there will be resources for the other points to materialize.

Let us leave science for a moment and look at what is happening in our daily life in trivial situations such as:

i. Feeding: in which we have “starved” versus “obesity”. Two sick ways, but of contrary senses;

ii. Clothing and other robes versus “unique clothing”: with the need and indecision of choice, on the one hand and the difficulty of customizing on the other. For some time, men’s “suit and tie” outfits were opposed to women’s clothing that allowed other freedoms, but also concerns and costs. The uniforms, in addition to the sense of uniformity (uniform) also have this simplifying sense in the choice, being still an image of organization and structuring power by the image of “order”, which they gave (gave for a while and in some contexts);

iii. Gadgets: which, when there is a shortage, are practically standardized, but abundance causes them to be used in a profuse way in which, often, the goals to be achieved are not even defined and, possibly, do not matter because the possession of a gadget is an end in itself;

iv. Toys: in which lack can restrict the richness of experiences, but can simultaneously stimulate imagination and wealth can foster curiosity, the tendency to seek novelty, but which can also lead to a superficiality in the exploitation in which it leads to an inconstancy and a “blasé” attitude in which everything loses the value (the values) that, in fact, it has;

v. Knowledge: that can be a tool, which is not an end in itself and is used in a parsimonious way. But can also be a mean of exhibition in which erudition is nothing more than a (sometimes even nozzle) way of projecting onto others of a verborrhea that in a position of power project onto their surroundings.

We are not defending any of these positions, not even the easy position to assume that a balance between them is necessary (which, to facilitate, we would still not need to try to define). We believe, however, that it is important to understand the alternatives of one position and another, to facilitate options and open visions of choice (which means preferring points 1 and 2, therefore defending the wealthy, within what we defend above). But, we think, plenty and scarcity have the same problems in the level of moving to operationalization, because it does not allow us to see, grasp, the possibilities that exist, since even if we can define desired objectives, we do not have the means to obtain them.

In Science

Today we have plenty of information and means to disseminate it. In other words, we have a situation of affluentity in which, however, the previous points 3, 4 and 5 are still privileged. But we should have already started to focus on points 1 and 2, focusing on the definition of objectives and strategies. We live, therefore, times of transition between the shortcomings that until recently (twenty or thirty years ago) we felt in which definitions are sought in coherence and balances between the five points indicated above, so that we can move from what Thomas Kuhn defined as “the crisis”, to times of “normal science”. If this passage takes place again, because the speed at which the changes (at the structural and deep level and not the mere incidents of the very current journey in the media and in social networks – and which we believe are simply swipe of the ambiguity in which we live at the level of the essential, the essential that was and the essentials that we need to be) are giving what may lead us to be permanently in crisis. However, the position we are defending is that the permanence of the crisis is a “passing thing”, like always happens when we have not yet become accustomed to using new references and their consequences, the search for new balances and coherences.

We are living what we have pointed out in the “examples of our daily life”, for food, toys, gadgets, etc.. The transition is not made progressively, but by rupture, in which the “world changes” and suddenly we find ourselves in a new framework, not even remembering what happened before. But in the framework of science, we have a “sui generis” product, as any researcher will recognize, although it often does not identify the specific characteristics that define that product. It is that knowledge, the product of science, is similar to a well-known Swiss cheese, the more product we have, more “holes” we have to manage. Since the function of science is advancing through the unknown, the questions from which we start lead us to more questions and even more questions, as it is visible in the conclusions of any research work (worthy of that name and not simply nicknamed in this way). Which puts us facing paradoxes, that we will give some examples:

Rationality Versus Decision-Making Ability

The “rational” (?) leads us to think that to decide, and decide well, we must have all the necessary information, have the time to work and then, calmly, make the decisions that are imposed. This is, however, the best way to make mistakes. Of making mistakes ... of all shapes and sizes. Because we will never have all the necessary information, neither the time to work all this information, nor the calm to decide when we try to solve really important things. Recently, this problem of incompleteness of the framework in which understanding of problems, decision-making and evaluation of the actions that are carried out and the results obtained has begun to gain weight (see, for example, the works of Herbert Simon).

At the root of the problems due to the need to act (in the most diverse institutional frameworks, from companies to states, from military structures to research organizations, from space agencies to large industrial organizations, from banks to planning institutions, that is, the most powerful institutions within which a mistake can be fatal at an economic level or even cause the death of many of its agents) without complete information on the issues on which they have to decide and make choices, obviously results from the limits we have set for any phenomenon, their borders, always being arbitrary (sometimes unconscious, even), leading to the need, in the best cases, to opt for a conditioned rationality (limited), which leads to decision-making being made considering: a) the time to decide; b) the relationship between the costs/benefits of obtaining more information; c) the lethality and importance of the risks taken; d) incomplete and false information on which the decision needs to be based; e) similar previous experiences; f).... However, deciding is always a situation in which there is never a “transparent” support, in which there is a percentage (greater or lesser) of luck, in which there is an important intervention of intuition. This is only acceptable because phenomena are always complex, not isolated and constantly changing.

Managing Holes Versus Managing Matter

The questions are unoccupied spaces (which, apparently, seek answers to fill them out), which, as in a kind of maze give way to more questions. However, this ambiguity is the most achieved way to satisfy those who are in search of uncertainty and the unknown. In the time of the “navigators and discoveries”, ships went in search of new lands, of unknown worlds. But if they did find wonderful lands (on a trip that fulfilled their objectives fully) the tendency would not be to go back to where they were in the old days, but to take advantage of the better possibilities offered to them. Which was not, of course, the initial goal of the trip.

The different Stages of Knowledge Development do not Represent a Continuum, but Imply Ruptures in the Evolution of the Process

The information in its evolution gives rise to the ability to understand / explain, in view of the ability to choose and decide (see point I). Desirably this process will lead to the production of a knowledge (which is not to know). A knowledge that, we intend, is not specific and local, but is generic and as universal as possible and that will lead (if we are lucky, ingenuity and digestion/reflection capacity) to the domain of a wisdom, which is still less material and more universal than the forms available in the previous phases (ground, for example, the five points with which we mark scarcities and plenty’s at the beginning of this work).

In the face of these paradoxes, and the immensity of all the others with which we could illustrate the positions we have taken and defend here, we believe that we can affirm that a rupture (Kuhn again) is imposed, one that frees science from the shackles that drags from the past, a past, perhaps still recent (some would say current) in which we gain coherences and balances that free us from the need to permanently stumble on the cultures of the past (not those that are old but those that belong to the past and “passed the deadline”), the mentalities of the past (not those that are old but those that belong to the past and “passed the deadline”), the structures of the past (not those that are old but those that belong to the past and become “outdated”), the objectives and strategies of the past (not those that are old but those that belong to the past and become “outdated”). Huge challenges. What is good (or great?) for those who like reps, but bad for those who want stability (which is the reverse of movement).

Teaching / Education / Training has prepared us for integration into what exists, but not for the construction of futures, however desirable (and affirmed as desired) as they may be. Conflicts are increasingly imminent and evident. Let us hope that it is not decided and arbitrated by artificial intelligence (on the one hand and by natural stupidity on the other) or by a virus, (or both), that puts man and his social structures in a corner, because they consider them outdated (not because they are old but because they belong to the past and “passed the deadline”.

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Impact of Intrauterine Exposure on Fetal Brain Development and Brain Injury

 

Introduction

Human prenatal brain development after fertilization is usually classified into four periods: 0–7 gestational weeks (GW) and neuronal proliferation during 8–15 GW, 16–25 GW, and > 26 GW [1]. In humans, neurons are mostly produced in the first trimester of gestation. The rapid development of the fetus’s cerebral cortex from the day of fertilization occurs for a period lasting from 8 to 15 weeks, and by 16 weeks, the number of neurons in the cerebral cortex reaches the adult level [2,3]. Abnormal brain growth may result from an unsuitable intrauterine environment. Adverse intrauterine environments that may have a negative effect on the fetal brain include maternal diabetes, undernutrition, infection, hypoxia, stress, alcohol, smoking, toxins, and anemia; hypertensive disorders in pregnancy; high-altitude pregnancies; and placental insufficiency. These adverse environmental factors may trigger epigenetic alteration and have a significant impact on fetal brain development through genome-wide changes of epigenetic regulation. The common epigenetic modifications include acetylation of histone and methylation of DNA, in addition to non-coding RNA epigenetic regulations [4,5] and chromatin modification [6,7], which are vulnerable to the maternal environment [8]. The purpose of this review is to summarize articles on the deleterious effects of some types of intrauterine exposure on fetal brain development and brain injury. The hope is to provide the impetus for further studies to delineate the function of the intrauterine environment on fetal brain development, through evidence from premature and term infants, as well as the role of the intrauterine environment in lifelong brain injuries and the pathologic mechanisms by which these injuries occur.

Fetal Brain Development

Synapse Development: Synapses connect billions of neurons during intrauterine fetal brain development, which is important in all functional neuronal circuits [9]. Synaptic plasticity is characterized by the removal and insertion of amino-3-hydroxy- 5-methy1-4-isoxazolepropinic receptors (AMPARs) into the postsynaptic membrane, and by the shrinkage or enlargement of dendritic spines, where the majority of excitatory synapses are positioned [9,10]. Synapse formation exceeds elimination, leading to a surplus of immature excitatory synapses during early brain development. Subsequently, synapse elimination and destabilization diminish the number of synapses, thus refining neural circuits that generate cognition and behavior [11]. Cell surface receptors such as metabotropic glutamate receptors (mGluRs), NMDA-type glutamate receptors (NMDARs), and tyrosine kinase (TRK) receptors activate mTOR signaling through the AKT pathway and the phosphoinositide-3 (PI3K) pathway, and MAPK via the ERK pathway. The ERK/MAPK pathway plays a key role in synaptic plasticity, consolidation of memory, and the transition from pluripotent stem cells to neuronal progenitors [12]. The myocyte enhancer factor (MEF2) family of transcription factors can regulate synapse elimination during brain development [13,14]. Synaptic strength is mainly influenced by changes in synaptic structure that depend on instruction of local protein synthesis, structural remodeling of the cytoskeleton, and receptor signaling [15,16]. Glutamate serves as both as a key neuromodulator to control synape and cirruit function and the mammalian brain’s primary excitatory neurotransmitter over a wide range of temporal scales and spatial.The group metabotropic GluRs (mGluRs) are abundant at excitatory synapses throughout the brain, where they are speculated sited to adjust to glutamatergic signaling [17]. They are vital to synaptogenesis and the shape of neural circuitry during the period of brain development [17]. Some evidence has demonstrated the important function of signaling lipids in mediating signal transduction and membrane traffic at pre-and post-synapses. For example, phosphoinositides can conduct ion channels, regulate exocytosis and endocytosis of synaptic vesicles and postsynaptic receptors, and signal from activated neuroreceptors such as NMDARs and mGluRs to allow plastic adjusted function of synapse [18,19].

Oligodendroglial Cells: Oligodendroglial cells in the central nervous system (CNS) synthesize myelin, transform from progenitor to the mature oligodendrocyte, and play a key role in salutatory conduction of action potentials [20-22]. After 20 GW, oligodendrocyte progenitor cells (OPCs) are shaped in the ventricular zone [23]. OPCs are generated in the brain and spinal cord from multipotent stem cells, and then they proliferate and differentiate. Neurogenesis and oligodendrogliogenesis progress at different rates in the human brain. OPCs first emerge in the ganglionic eminence at approximately 9 GW in pregnant women [24,25]. In humans, cortical oligodendrogenesis begins at around 10 GW, but it progresses well into adulthood [26]. Olig2-positive stem cells from early fetal development exist in the germinal matrix of the brain and transfer from the original regions in the brain to the axon-dense zones of the neocortex, spinal cord, diencephalon, and brainstem.

Gliogenesis: Gliogenesis is often generated during the last trimester of gestation in humans [27]. As mentioned above, the timing of an insult in pregnancy is critical to compare and estimate the neurodevelopmental response of offspring. While early insult in pregnancy is related to structural brain abnormalities such as neural tube defects, late-gestation insults may disturb the migration progression of postmitotic neurons and cause deviant cortical development [28]. Later insults have been demonstrated to be associated with more with behavioral, cognitive, and psychiatric disorders, such as autism, obsessive compulsive disorders, and schizophrenia [29,30]. The regulation of oligodendrocyte differentiation and myelination in the fetal brain involves negative and positive regulators [23]. There are three negative regulatory pathways for oligodendrocyte differentiation, including the BMP signaling, Notch signaling, and Wnt/β-catenin pathways. These and Wnt pathways are involved in oligodendrocyte maturation. Some studies showed that white matter disorders are associated with dysregulation of the BMP and Wnt/β-catenin signaling pathways [31,32]. The maturation of oligodendrocytes relies on ATP through oxidative phosphorylation in mitochondria [33]. Mitochondria support oligodendrocyte differentiation and survival [34]. It is commonly found that after hypoxia-ischemia, mitochondrial dysfunction occurs in the developing brain [35]. Studies have demonstrated that microglia have an effect on the maturation of oligodendrocytes during normal brain development. Activated microglia discharge high levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-2, and IL-17; tumor necrosis factor-alpha (TNFα); and excitotoxic factors such as glutamate, nitric oxide, and hyaluronan, or endothelial growth factor, which impair immature oligodendrocyte differentiation and proliferation and assist in decreasing the number of oligodendrocytes [36- 39]. Mitochondria are very important in the developing brain and throughout life in energy phosphate tasks such as regulating the cellular redox state, maintaining organelle function, cellular proliferation, mediating the DNA or protein responsible for transcription, excitotoxic injury, translation and assembly of the enzyme complexes of the respiratory chain, and apoptosis. These mitochondrial functions in cellular proliferation rely on mitochondrial dynamics. Mitochondria are extremely plastic and mobile, altering their shape through fission and fusion to reach sites of high energy demand in cells [40]. Mitochondrial impairment results in deregulation of calcium homeostasis, bioenergetic failure, mitochondrial permeabilization with release of proapoptotic proteins, and production of reactive oxygen species (ROS), leading to cell death [41].

Myelination: The myelination of mature oligodendrocytes continues especially in late gestation and is susceptible to excitotoxic and damage associated with premature exposure to the extrauterine environment without neuroprotection. Neonatal or fetal brain injury may occur as a result of thrombosis, infection, hemorrhage, trauma, or hypoxia and can lead to lifelong cognitive, sensory, or motor dysfunction. Defining the type and range of brain damage is not as simple as it would seem. Magnetic resonance imaging (which requires dangerous ionizing radiation) and transcranial ultrasound (which has limited sensitivity) can only be used to examine the damaged fetal brain, not to predict function.

Placenta and Fetal Brain Development: The placenta is the maternal-fetal interface that has an essential role in the transfer of nutrients and oxygen to the fetus and provides and secretes growth-regulating factors to ensure the neurodevelopment of fetal brain. In addition, the placenta functions as an immuno-defender to protect the fetus from maternal infection and inflammation. The placenta, which controls the intrauterine environment, is of fetomaternal organ. It is well-known to secrete neurotransmitters, which are associated with abnormal neurodevelopment and normal fetal brain development. The maternal component of the placenta is the decidua. The fetal placental tissues include the umbilical cord, chorionic villi, amniotic membrane, and chorionic membrane [42,43]. Placental metabolism, placental hormone production, and substrate transport are all essential for fetal development. Normal development of the placenta includes two concurrent and complex processes: the cytotrophoblast (CT) cells invade the endothelium of the maternal spiral artery and then the fetal vascular tree develops. Endothelial cell invasion initially leads to the formation of a trophoblast “plug,” resulting in a hypoxic milieu environment within the intervillous space (oxygen partial pressure [PaO2] < 20 mm Hg) [44]. After 10 GW, the CT plug dissipates, which results in increased placental blood flow and PaO2 [45,46]. Several mechanisms affect placental function. The sustained high-pressure flow through the intervillous space (2–3 m/s, while normal dilated vessels are 10 cm /s) leads to increased shear stress and damage to the trophoblast cells of the chorionic villus, thereby damaging the capacity of the villi for nutrient and gas exchange [46,47]. Unsuccessful spiral arterial conversion makes these vessels prone to adrenergic stimulation and vasoconstriction, which leads to intervillous PaO2 fluctuations and placental hypoxic perfusion injury [48]. Dysregulation of angiogenesis and anti-angiogenic factors in the placental interface results in abnormal development of the fetal vascular tree in the placenta [49], subsequently impairing the function of the placenta, and has been relevant in the development of preeclampsia, gestational diabetes-related pregnancy, fetal growth restriction (FGR), placenta early exfoliation, intrapartum fetal compromise (IFC), and preterm birth [50-52].

Risk factors of arterial disruption involve trauma, preeclamptic arteriopathy, uterine rupture, abruption placenta, and vasoactive drugs, such as nicotine or cocaine. Marginal retroplacental hemorrhages mostly occur at the margin of venous drainage of the placenta [53,54]. Many other events, such as malnutrition, genetic abnormalities, and infection can also disturb placental function and alter the fetal brain’s environment. The failure function of placenta can directly injure the developing brain or raise its vulnerability to injury, result in lasting neurological disabilities [55,56].

Fetal Brain Injury

Intrauterine Fetal Brain Injury: Chorioamnionitis, hypoxia, fetal inflammatory response, and preterm birth can contribute to brain injury and progression of the subsequent neurological deficits [57]. Hypoxia and inflammation mediate neuropathology, acting to induce neuroinflammation and breakdown of the blood brain barrier (BBB), resulting in oligodendrocyte cell damage [58]. The activated immune cells such as mast cells, microglia, and neutrophils release the key cytokines IL-1α, IL-1β, IL-6, and IL- 18, which sequentially stimulate the discharge of TNF, ROS, and excitatory amino acid agonists, including glutamate, which work together to initiate neural cell apoptosis [59,60]. The substances above can also directly influence the differentiation of neurons and OPCs by inducing apoptosis and can cause mitochondrial failure [61,62]. Neighboring reactive astrocytes, by releasing TNF-α and IL-1β, cause proliferative inhibition of oligodendrocytes and downstream activation of apoptotic pathways [63].

Impact of Intrauterine Infection: Many microorganisms, which include certain viruses, bacteria, and protozoa, have been linked to intrauterine infection. These infections can result in clinical syndromes, including TORCH infections, referring to infections caused by toxoplasma, other microorganisms, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses (HSV) [64]. Other common infections in women are caused by aerobes, such as group B streptococcus (GBS) (15%); and gram-negative rods, including Escherichia coli (8%), anaerobes, including Bacteroides sp. (30%) and Gardnerella vaginalis (25%) [65]. These microorganisms are associated with preterm birth [66]. Further studies demonstrated that a persistent intrauterine inflammatory exposure may also result in fetal brain injury [67]. The characterization of chorioamnionitis is an intra-amniotic infection in which bacteria invaded the amniotic cavity, resulting in acute inflammation of the fetal membranes and/or the placenta [65]. Chorioamnionitis, which results in spontaneous preterm birth and premature rupture of membranes (PROM), is defined as a feto-placental environment of acute inflammation [68]. Chorioamnionitis often leads to fetal inflammation and damage to the immature brain, raising the possibility of diffuse white matter injury and intraventricular hemorrhage [69]. Fetal inflammatory response syndrome (FIRS), resulting from systemic immune activation, is characterized as inflammation of multiple fetal organs in utero [70]. Infections can trigger inflammatory pathways, causing the discharge of diverse proinflammatory biomarkers, such as interleukins, cytokines, and other molecules. Proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) from microglia and astrocytes may directly insult neurons and oligodendrocytes. The injection of IL-1β in neonatal rats leads to delayed myelination and neuronal death [71]. TNF-α induces apoptosis in developing oligodendrocytes and cell death in mature oligodendrocytes [72].

Toxoplasma: Primary infection of congenital toxoplasmosis in pregnant women is uncommon, but it remains as a latent, chronic, cryptic brain infection throughout the life of the host, often with severe consequences [73]. Some studies have demonstrated that infection of the toxoplasma may alter cognitive functions and human behavior and may cause headaches, the onset of schizophrenia, and cryptogenic epilepsy [74]. Chronic, adultacquired Toxoplasma gondii infection in outbred mice can cause behavioral and neurologic abnormalities secondary to the loss of brain parenchyma and inflammation [74]. There is also improved expression of message for synaptic remodeling and markers of neuronal cell death and mediators of inflammation in brains of chronically infected mice, comparing to uninfected control mice [74]. Synaptic transmission underlies vastly complicated instruction by protein networks assembled at the presynaptic location of neurotransmitter discharge and the postsynaptic device for neurotransmitter reception. Haroon and colleagues have indentified that T. gondii–-activated cytokines disturb synaptic signaling [75]. Chronic T. gondii infection brings dissimilar changes in synaptic protein composition, which downregulate a huge number of proteins occupied in synaptic plasticity and pose a danger for neuropsychiatric disorders [75].

Rubella: During the Rubella epidemic in the U.S, in 1964-1965, thousands of infants were infected and subsequently suffered lifelong problems. During this epidemic, 8–13% of cases were congenital rubella syndrome (CRS) occurring in early pregnancy. Rubella virus has a particular affinity for the central nervous system, resulting in mental retardation, encephalitis, cataracts, central auditory imperceptions, glaucoma, and cochlear atrophy [76]. Fetal damage associated with rubella is inclined to occur only when an infection occurs in the first 16 weeks of pregnancy. In general, the earlier the infection begins, the more severe the malformation that is observed [77]. The later sequelae of rubella in early pregnancy include diabetes and autism [78-81].

Cytomegalovirus: Human cytomegalovirus (HCMV) infection is the main cause of congenital viral infection and brain disease in developed countries. HCMV is also a major pathogen in congenital illness and can lead to permanent disabilities, including hearing loss, mental retardation, and vision loss. It was reported that 50% of children with congenital HCMV infection in Japan developed hearing loss 6 months after their diagnoses [82]. HCMV in fibroblasts acquires its covering by budding into exosome-like vesicles, which subsequently combine with the plasma membrane to discharge mature virions from the cell. Compared to the infected cells, the glycerophospholipid component of HCMV virions is strikingly different. The liposome of virions has been found to be similar to that of synaptic vesicles via comparing Monica the published results [83]. These similarities showed that HCMV in fibroblasts obtains its envelope by budding into vesicles, which can fuse at the plasma membrane to discharge mature versions of this cell. Synaptosomalassociated protein of 25 kDa (SNAP-25), a constituent of the SNARE complex, which mediates exocytosis of synaptic vesicles in exocrine cells and neurons, has been found to be involved in the exit of HSV-1 from neurons [83,84].

Herpes Simplex Viruses: The rate of neonatal herpes simplex virus (HSV) infection ranges from 1 in 2,500 to 1 in 20,000 live births. Manifestations of congenital HSV include hydranencephaly, chorioretinitis, skin lesions, scars, and microcephaly. The condition of neonates who have HSV infection can deteriorate rapidly due to encephalitis, disseminated intravascular coagulopathy, shock, or respiratory distress. Infants who survive neonatal HSV encephalitis have high rates of neurological sequelae, including mental retardation, visual or motor deficits, Alzheimer’s disease (AD), and seizure disorders [85]. HSV-1–infected neurons also have shown considerably reduced expression of the presynaptic proteins synaptophysin and syanpsin-1 and depressed synaptic transmission. In mice, these effects rely on intraneuronal accumulation of Aβ and GSK-3 activation [86].

Bacterial Infection: Group B Streptococcus and E. Coli: GBS is the leading reason for congenital bacterial infection in developed nations. The incidence of transmission to newborns in GBS-positive women is about 21% [87]. No direct evidence has shown that GBS infection plays a function in cerebral palsy (CP), but nearly 50% of infants who survive GBS meningitis experience longterm neurodevelopmental sequelae [88]. In addition, mediation of extensive cortical neuronal injury through reactive oxygen intermediates was observed in GBS-infected neonatal rats [89]. The association of cellular response of the fetal brain with perinatal inflammatory or infectious damage reflects activation of astrocytes and microglia with oligodendrocyte dysfunction and neuronal loss. In developing countries, E. coli is one of the major pathogens leading to early-onset infections in preterm neonates. In human newborn infants, cerebral white matter injury has been observed by MRI following an episode of E. coli meningitis [90].

Hypoxic-Ischemic Injury

Unpredictable and severe events that involve placental abruption, cord prolapse, uterine rupture, or eclampsia are strongly associated with a high risk of catastrophic fetal hypoxia [91]. Hypoxic-ischemic injury that leads to mental retardation, motor impairment (CP), hypoxic ischemic encephalopathy (HIE), and seizures is a considerable contributor to morbidity and mortality in infants [92]. The fetal brain of prematurity before 32 GW is immature, and the white matter is especially susceptible [93]. The susceptibility of the immature CNS to hypoxia-ischemia is mainly dependent on regional status and the timing of decisive developmental processes, for example, proliferation, differentiation, migration, programmed cell death, and myelination, as well as on the instruction of metabolism and cerebral blood flow. The fetal brain is hypersensitive to hypoxic damage and oxidative stress because of its high oxygen consumption, lack of glucose stores, high lipid content [94,95], and considerably low concentrations and activity of antioxidant enzymes [96,97]. The upregulation of IL-1 and TNF-R1 can result from periods of hypoxia in the brain. Pro-inflammatory cytokines mediate the immune response to inflammation and infection and influence a wide range of physiological action that involves cell survival, fever, acute-phase response gene expression, glial activation, hypotension, T- and B-lymphocyte stimulation, and leukopenia [98-101]. Hypoxia, which damages OPCs by activating the enzymes caspase-3 and caspase-9, leading to cell death, is also related to calcium influx after inflammation-induced glutamate discharge from immune cells, which causes excitotoxicity and results in bax translocation to the mitochondria on OPCs and release of cytochrome-c [102]. The exact mechanisms underlying hypoxic cerebral damage are multifarious and are not totally mediated by the initial hypoxic injury, but instead are compounded by insults happening during the reperfusion stage [103] because of toxicity from ROS and activation of N-methyl-D-aspartate-type glutamate receptors [104]. In fact, the severity of the secondary injury happening during the reperfusion phase associates best with the severity of neurodevelopmental disability at 1 and 4 years of age [105]. There is a strong connection between hypoxia and hypotension with fetal injury, mainly fetal death and neuronal damage. During hypoxia, the blood flow of cerebral hemispheres is reduced, whereas perfusion to the thalamus, brainstem, and basal ganglia is increased [106]. Cerebral ischemia has a dramatic and rapid effect on synaptic function and structure [107].

Seizures

Seizures are one of the most common neurological emergencies in newborns. A reduction in the normal environment of fetal neurosteroids is associated with undesirable outcomes, such as episodes of potentially destructive seizures, which can cause destructive and permanent conversion in neurodevelopment [108,109]. Premature birth is related to an increased rate of seizure disorders [110]. Neonatal seizures create a long-term increase in seizure susceptibility and change in inhibition/excitation balance of synaptic transmission in layer II/III neurons of the somatosensory cortex [111]. In summary, neonatal seizures have enduring effects on synaptic plasticity in the somatosensory cortex [112].

Cerebral Palsy

CP is defined as a disorder of posture and movement that includes abnormalities in reflexes, tone, movement, and coordination, and delays or aberration in primitive reflexes and in motor milestone achievement that is enduring, and is caused by a lesion, nonprogressive interference, immature brain, or abnormality of the developing fetal and infant brain [113,114]. CP is also defined by type (dyskinetic, dystonic, or spastic), topography (limb involvement), and descriptors of the extent and pattern of involvement (quadriplegia, hemiplegia, diplegia, and monoplegia) [114]. Autopsy of the brain of a preterm child with CP showed white matter atrophy, dysmyelination, ventriculomegaly, and reactive gliosis [115].

Autism Spectrum Disorders

Autism spectrum disorders (ASDs) are characterized by a complex and strong genetic component with broad familial inheritance patterns and have been found to be related to mutations in as many as 1,000 genes [116]. Environmental factors, including maternal diabetes, prenatal infections, prenatal and perinatal stress, zinc deficiency, and toxins, can also contribute to the risk of autism during early life [117,118]. Some evidence shows that the placenta plays a key role in ASD pathogenesis [119]. That the architecture of placenta from ASD patients consists of smaller branch angles than in population-based counterparts, fewer branch points, better extension to the surface boundary, and thicker and less tortuous arteries may indicate that both environmental and genetic factors have an impact on vascular branching morphogenesis in pregnant women [120,121]. A recent study of the placenta from patients with ASD demonstrated considerably higher incidences of fetal inflammation, maternal vascular mal-perfusion, and acute generalized inflammation, suggesting that these conditions are deleterious to fetal brain development [119]. Some forms of intellectual disabilities and syndromic autism are linked to mutations in genes that regulate protein synthesis and influence transmission, plasticity, and structure of synapses [12]. Failures to sustain RNA-binding protein levels and the accurate number of mRNA molecules are critical access points of synaptopathies [122].

Schizophrenia

Schizophrenia is a greatly polygenic disorder, involving hundreds of genes. Genes implicated in synaptic plasticity and glutamatergic function figure prominently among genes associated with schizophrenia [123]. A deficit in glutamatergic synapses can provoke schizophrenia [124]. Both neurochemical alterations and structural changes may lead to defective neuronal transmission in schizophrenia [123]. The uterine environment may have a significant influence on later development of schizophrenia [125-127]. Influenza infection during early gestation that has a strong correlation with schizophrenia in offspring can result in overexpression of tumor necrosis factor-α (TNF-α) and IL-6, probably through changing either epigenetic modification or gene expression [128]. Schizophrenia has been associated with exposure that may happen in early life and might be linked to pregnancy (hyperglycemic conditions, hemorrhage, or preeclampsia), labor (uterine rupture, birth asphyxia), or fetal conditions (genetic anomalies or intrauterine growth restriction) [56,129].

Stress Or Mood Disorders

Many maternal stressors such as trauma, depression, and malnutrition can have an effect on the placenta and change maternal glucocorticoid levels, which play a major role in programmed cell death and neuronal maturation and to which the developing brain is extremely susceptible [130]. 11βHSD2 is expressed at very high levels in the placenta, which protects the fetus from the normal increase in maternal cortisol occurring during gestation. Maternal mood disorders have a relationship with disruption of the placental barrier, in part through suppressing 11βHSD2 expression, resulting in abnormal neurodevelopment in the offspring [131]. Human placental lactogen expression was considerably decreased in placentas from women diagnosed with depression and who had high depression scores [131].

Premature Birth and Fetal Brain Development

Preterm And Fetal Brain Development: Steroid precursors generate from the placenta that maintain the neuroprotective and trophic functions of neuroactive steroids in the fetal brain [132]. In preterm birth, the loss of neuroactive steroid precursors leads to disruption of the normal track of fetal brain development and delays the progress of myelination [133]. The GABAA receptors that play a key role in late gestation are vital to interaction with the placenta-derived neuroactive steroids [134,135]. Research studies showed that tobacco smoke during pregnancy may result in chronic hypoxia and be associated with increased placenta resistance and carboxyhemoglobin and decreased uterine blood flow [136]. Some scientists have also found the connection between elevated levels of serotonin and altered oligodendrocyte development and myelination [137]. Recent studies showed that extracellular vehicles (EVs) including proteins, nucleic acids, and lipids are a mechanism for communication between fetus and mother [138]. How EVs influence the maternal response to pregnancy and fetal development is currently an area of vigorous exploration [139,140].

Premature Birth and Neurodevelopmental Disorders: Preterm birth can result from maternal/fetal inflammatory responses and intrauterine infection and result in fetal brain damage with a negative effect on the function and structure of the entire brain [141]. Serial MRI examinations have shown that the gray and white matter volume of premature infants is reduced compared to full-term control groups [142,143]. Loss of neurons as a result of apoptosis may partly explain the reduction in gray matter volume of the basal ganglia and cortex in both humans and mice. This loss of neurons is the most common form of cerebral abnormalities in premature infants, which include hippocampus and gray matter abnormalities and diffuse white matter injury [144,145]. However, focal necrotic lesions of cystic ventricular leukocyte softening are seldom seen in preterm infants [146]. Prematurity can also result in CP and visual and hearing impairments [147]. The common forms of white matter injuries in preterm birth occur as diffuse white matter injury, periventriclular leukomalacia (PVL), and germinal matrix hemorrhage [148]. The less frequent forms of injury are cerebral sinus vein thrombosis, primary intraparenchymal hemorrhage, hyperbilirubinemiainduced kernicterus, and infectious meningitis/encephalitis [149]. PVL lesions have been demonstrated that have a relationship with the loss of pre-oligodendrocytes and OPCs [150].

Prospective: Extracellular vesicles provide a promising strategy for early prediction of intrauterine brain development EVs, including microvesicles and exosomes, participate in signal transmission between neurons, play a fundamental role in activity of the nervous system, and facilitate communication of the CNS with all body systems [151]. EVs may be produced in almost all cells of the body, function to transport biologically active molecules to target cells, and provide intercellular communications [152,153]. EVs are secreted by numerous cell types in the brain, including microglia, astrocytes, oligodendrocytes, and neurons [154-158]. Neuronal communications with glial cells are mediated via EVs by the transport of mRNAs, miRNAs, and proteins, where vesicles’ discharge into the extracellular space is taken up through recipient cells [154,159-161]. Synaptic pruning was performed through neuronal EVs via neuron-specific signal transduction between microglia and neurons; it was not improved via non-neuronal EVs [162]. Some evidence indicates that synaptic dysfunction is an essential role in the pathophysiology of neurodegenerative disorders. Exosomal miRNAs have also been demonstrated to play a latently neuroprotective function in subsequent ischemic brain injury. Exosomes from multipotent mesenchymal stem cells (MSCs) mediate miR-133b transfer to neurons and astrocytes, which modify gene expression in charge of functional recovery and neurite remodeling after stroke [163]. EVs provide an apparatus of communication not only between glial cells and nerves, but also permitting the interconnection of the CNS with all body systems [151,164]. The pathology of neurodegenerative disorders is a result of intercellular spreading and aggregation of proteins in the brain [165]. In recent years, the decrease of EV production through an nSMase-ceramide pathway resulted in the alleviation of AD in a mouse model of this disease [166]. α-synuclein of the Parkinson’s disease gene encapsulated in neuron-derived EVs is present not only in the membranes, but also in the extracellular space of EVs and are secreted from neurons [167,168].

Conclusion

This review has addressed the dysregulated synaptic function and plasticity, receptors, molecular signaling cascades, and spine architecture that underlie cognitive deficits and the behaviors associated with other forms of syndromic ASDs. Synapse dysfunction is linked to the pathophysiology of diverse neurodevelopmental disorders such as intellectual disability, schizophrenia, and autism [12,169]. EVs are membrane-bound nanoparticles discharged into the extracellular space through most types of cells. Many CNS cells can release EVs, including exosomes, which may play a key role in the spread of pathogenic agents in various diseases. EVs have been studied extensively in pathologies including neurodegenerative disorders, such as prion protein in prion diseases, α-synuclein protein in Parkinson’s disease, tau and amyloid-β peptide in AD, mutant huntingtin in Huntington’s disease, and superoxide dismutase-1 and transactive response DNA-binding protein 43 kDa (TDP-43) in amyotrophic lateral sclerosis [166,170-175]. MSCs show homing abilities, which make it possible for them to travel to sites of inflammation or brain injury and to be used in treatments of various neurological disorders [176]. It may be difficult for clinicians to detect subtle injuries in the fetal brain. With the recognition of novel vesicle biomarkers, we hopefully will develop the ability to use EVs as a tool in clinical practice for treatment of nervous system diseases in the future.

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High Throughput Chemical Quantification of Pyruvate in Sweat in Response to Modulation by Nutritional Supplementation and Exercise

 

Introduction

Pyruvate is a commonly occurring organic keto-acid found in various food-associated items and many biological fluids. In particular, pyruvate is responsible for imparting distinct flavor attributes to food and is recognized for its association with pungency in onions and garlic, and the enhanced flavor profiles in common fruits [2-5]. Interestingly, pyruvate quantification in onions is of central importance for the selection of breeding stock that imparts lower pungency and enhanced sweetness, which correlate to consumer preference [6-8]. The determination of pyruvate concentration is also of central importance in diagnostics and represents a useful and easily quantified biomarker present in various human biological fluids (sweat, saliva, and urine), or cell culture supernatants. For example, it has been used in conjunction with lactate levels to infer cellular redox state in vitro and in vivo, it has been evaluated in saliva as a quantitative biomarker for head and neck cancers and thus simplifies patient monitoring for individuals at risk [9].

Pyruvate levels have also been used to identify mitochondrial metabolism impediments as reflected by an altered pyruvate to lactate ratio [10,11]. Concordantly, pyruvate levels in blood are modulated by exercise, generally increasing during exertion and decreasing post-recovery [12]. Modulation of pyruvate in other body fluids, particularly sweat, has not been addressed or considered as reflecting intracellular or blood metabolite levels. Pyruvate ingestion influences blood lactate parameters during and post-exercise [13,14, and reviewed 15]. Johnson and Edwards [13] further demonstrated that urine exhibited a similar profile of lactate and pyruvate increase during exercise, both of which then remained elevated 90 minutes post-recovery [13], although sweat or other bodily fluid levels were not considered in this study. As such, various enzymatic, analytical, and chemical methods have been used to quantify the abundance and distribution of pyruvate [6,16]. High performance liquid chromatography (HPLC) and capillary electrophoresis (CE), represent gold standard techniques for the separation, detection, and quantification of this molecule [5,17,18].

Although reliable, HPLC instrumentation may be of limited availability in certain research or educational settings. In addition, such specialized instrumentation is expensive to acquire, run, and maintain. Fluorescence methods are also prevalent and offer analyte sensitivity. Fluorescence methods often couple the reaction of pyruvate to the formation of lactate in the presence of lactate dehydrogenase and fluorometrically follow the change of NADH+H to NAD+ according to the following reaction:

Pyruvate + NADH → L − lactate + NAD+ [19,20].

Again, this is a sensitive and specific reaction, but it requires a fluorimeter and expensive enzymes to drive the reaction. To address the shortcomings of the methods described above, a reliable and sensitive assay utilizing chemical detection to determine pyruvate levels in sweat, a readily available biological fluid, was initially proposed by Maclean [16] and subsequently modified by Schwimmer and Weston [1]. This assay was further optimized in terms of sample and reagent volumes and implemented to follow the changes in pyruvate concentrations in sweat samples derived from a group of athletes consuming a Health Canada approved onmarket health supplement that contains pyruvate. This enabled the rapid and sensitive detection of pyruvate level modulation in sweat with simple high throughput spectrophotometric detection of the colored product and may be suitable for use with other biological fluids or matrices.

Procedures

Sweat Collection

Informed consent was obtained from each athlete following Regulatory Ethics Board approval which included the consumption of a Health Canada approved on-market nutritional supplement (NPN80070757) containing a pyruvate as described by Badulescu, et al. [15]. Sweat pyruvate concentrations were determined chemically according to Sharma, et al. [4], which is a modification of the method proposed by MacLean [17]. This chemical approach was further modified to accommodate a sweat sample matrix obtained from athletes following a prescribed exercise protocol as described in Figure 1. Both the sample and reagent volumes were miniaturized and optimized to accommodate a 96-well plate assay format. Additionally, the linearity and performance at specific wavelengths were determined to enable sensitivity within the pyruvate concentration ranges relevant to the sample matrix.

Figure 1: A representative pyruvate profile in sweat obtained from a pyruvate supplemented (Dosed) athlete following the prescribed Dosed exercise protocol.

The general profile of pyruvate levels tended to increase over the course of exertion and decrease towards the end of the assessment period, likely reflecting uptake of available pyruvate to meet metabolic demands and foster recovery. The lower complexity of metabolites in sweat relative to blood or serum permits accurate quantification using chemical quantitative techniques. It was determined that the simple collection technique used, a BandAidTM absorptive pad, offered a substantial recovery volume (400 - 1000 μL) and was determined to be void of interfering substances.

Pyruvate Chemical Determination

Pyruvate concentration was determined using freshly prepared reagents according to the following setup in a 96 microwell plate using 8-channel pipettes for additions and mixing. To each well was added either 50 μL sweat or water and 125 μL of 0.0125% v/v 2,4-dinitrophenyl hydrazine (DNPH) prepared in 2 M HCl. The components were mixed and incubated at room temperature for 10 minutes. Subsequently, 63 μL of 3 N NaOH was added and mixed. The plate held at room temperature for 5 minutes before performing spectrophotometric assessment at the following wavelengths: 420 nm, 450 nm, and 515 nm. Optical densities at each wavelength were compared to a standard curve to obtain corresponding pyruvate concentrations. Pyruvate standards in the range of 0 nM - 500 nM were prepared fresh in milliQ-water and used on the same plate as the experimental samples to ensure consistency. Three replicates for each sample and control were performed.

Results and Discussion

The small volume, high throughput, and low-cost assay presented enables the direct chemical determination of pyruvate concentrations in sweat associated samples and may be suitable for other sample types such as saliva or cell culture supernatants if unpigmented. The assay exhibits linearity at different wavelengths as reflected by the absorption maxima assessed at 420 nm, 450 nm, and 515 nm (Figure 2). Interference from commonly encountered matrix associated compounds such as sugars do not impact accurate quantification [2,21], but it is anticipated that pigmented matrices such as blood and potentially urine may be influenced in a manner akin to the interference of pigments in plant-derived samples [22]. In such cases, alternative, albeit more labor intensive, methodology can be implemented [19]. Alternatively, a suitable wavelength maxima may be selected to minimize interference from pigmented substances. For example, for serum or urine derived samples, wavelengths of 450 nm or preferably 515 nm can be used for standard curve generation.

Figure 2: Standard curve for pyruvic acid as determined by assessing various absorption maxima peaks at 420 nm, 450 nm, and 515 nm.

All three wavelengths assessed exhibited linearity across a concentration range of 0 nM - 500 nM pyruvate. Replicates n = 3 for each concentration.

Generally, for sweat samples, a wavelength of 450 nm was used (Figure 3) which permitted the evaluation of timed sweat collected samples to be effectively analyzed from various athletes (Figure 1) as well as the assessment of pyruvate supplementation to be observed over the collection periods, pre- and postpyruvate supplementation (Figure 4). Volume optimization for plant-, specifically onion-derived samples has been proposed [21], but the assessment of pyruvate from mammalian samples has not been attempted. The simple chemical methodology is readily applicable to various settings, scalable, and can be used in a teaching environment with appropriate precautions in place. Additionally, the utility of assessing sweat as a suitable biomarker to infer metabolic status was determined to be implementable and useful post-pyruvate intervention by supplementation and may be extended to the use of pyruvate assessments in tissue extracts [23] once solids have been removed by centrifugation.

Figure 3: Standard curve for the chemical determination of pyruvate at 450 nm.

Pyruvate levels were determined chemically as described in the text in the range of 0 nM - 500 nM and represented by the mean and standard deviation of n = 3 replicates.

Figure 4: Differential pyruvate concentration profile in sweat collected from a female athlete monitored during the course of exercise.

Sweat was collected at various time points as indicated and the pyruvate concentrations assessed using the chemical method described. As shown, pyruvate concentrations in a representative female athlete were elevated during supplementation with a pyruvate containing nutraceutical supplement (Health Canada NPN80070757), and under both baseline and supplemented states the level would increase with increasing exertion (exercise) time.

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Effectiveness of Shock Wave Therapy in Injuries of Tendons and Ligaments of the Osteomyoarticular System

 

Introduction

For more than 20 years, medical technology with great potential to improve or replace some invasive procedures has been successfully applied in the world, such is the case of Extracorporeal Shock Wave therapies. In 1997 the European Society for Muscleskeletal Shock Wave Therapy was established in Vienna, due to the rapid diffusion of the method, in 1999 it was renamed the International Society for Muscle-skeletal Shock Wave Therapy [1]. The application of this therapy has proven to be safe and effective, as it has avoided surgical procedures. Shock wave therapy is acoustic waves present in everyday situations (the sound of thunder, clapping in an auditorium, or an airplane breaking the sound barrier). The wave generates a sudden pressure variation that propagates in the three planes of space; it goes from ambient pressure to the maximum pressure peak at the wave front. In the case of its therapeutic application, the wave is transmitted through a coupling pad that is a liquid medium that, having an acoustic consistency similar to that of the human body, favors its transfer. It is essential that there is a transitional medium between the docking pillow and the body, such as ultrasound gel. The shock waves are directed towards a focal point in the tissue to be treated. For the shock wave to have an adequate therapeutic effect, the energy must be focused on the point to be treated. The depth of penetration of the shock wave focus into the tissues can be varied by modifying the thickness of the coupling pillow [1,2]. At present in Cuba the number of elderly people has increased, this brings a series of progressive physiological and functional deteriorations with the consequent acquisition of chronic degenerative diseases. Diseases that cause joint pain are chronic and often disabling. Between 50-80% of the population over 65 years of age present pain [3]. Medical care for osteomyoarticular conditions that end in a surgical procedure is high, every day the number of patients who need specialized medical assistance in search of a solution to their health problem is greater.

Thus, it is necessary to use a new technology that manages to improve, replace or replace some old invasive procedures compared to new technologies, such is the case of Extracorporeal Shock Wave therapies, with the aim of improving the quality of life of patients. the Cuban population and treat conditions of the osteomyoarticular system. In Cuba, at the “Frank País” International Orthopedic Scientific Complex, it began to be applied in 2001. This therapy has been used until now as a method of treating chronic pain in patients who do not improve with other conservative treatments. The use of this equipment in musculoskeletal conditions enables a wave disintegrating effect to treat calcifications, has analgesic effects and allows stimulation of the repair process in tendons, soft tissues and bones [4]. The treatment unit produces, by means of an external piezoelectric source, high-energy sound waves, which have a great depth of penetration. This maximum energy in the affected area allows exact location of the area to be treated, low risk of bruising and very little irritation to the skin. It facilitates the outpatient treatment of the patient, short sessions [3-5], without risk of allergy or the need for anesthesia [5].

The number of patients who have received physiotherapeutic treatment with shock waves for this cause has increased in recent years at our institution. The objective then of our research was to evaluate the effectiveness of extracorporeal shock wave therapy in patients with injuries to the tendons and ligaments of the osteomyoarticular system.

Methods

A descriptive, cross-sectional study was carried out with patients who presented tendon and ligament injuries (supraspinatus tendinis, epicondylar insertions, calcified achillean tenosynovitis, calcaneal spur and plantar fasciitis). For the therapeutic treatment, the Well Wave equipment (extracorporeal shock waves) was used, in the International Orthopedic Scientific Complex “Frank País”, in the period from March 2019 to April 2020. The selection of patients in the sample was carried out through a convenience sampling and was made up of 107 cases. To determine the effectiveness (real benefit), the medical and physiological effects that occur when applying this therapy were analyzed.

Inclusion criteria

a) Patients of both sexes, aged over 18 years.

b) Patients with persistence of pain in a period of six months or more.

c) Patients undergoing failed previous surgery.

d) Patients who received at least three of the following treatments:

e) Medications

f) Infiltrations

g) Laser

h) Therapeutic ultrasound

i) Magnetotherapy

j) Supports

Exclusion criteria

k) Patients who refuse to continue in the study.

l) Patients with decompensated chronic diseases (severe cardiovascular disorders, neurological disorders).

m) Patients with bleeding disorders.

n) Pregnant patients.

o) Patients with polyneuropathies.

p) Patients with epiphysiolysis.

q) Patients with pacemakers.

r) Patients with primary or metastatic malignant tumors.

s) Patients with acute or chronic tissue infections.

t) Patients with severe arthritic changes.

In the initial consultation, all patients underwent a detailed interrogation, physical examination, radiographic study in anteroposterior views and ultrasound of the soft tissues of the affected area. Once the clinical radiological diagnosis was made that they had some injury to the tendons and ligaments (supraspinatus tendinis, epicondylar insertions, calcified achillean tenosynovitis, calcaneal spur and plantar fasciitis) and taking into account that the patient had used other conservative and surgical methods and had not presented improvement, he began with the therapeutic treatment of extracorporeal shock waves in the affected area with the Well Wave equipment, consisting of a piezoelectric shock wave source mounted on a mobile arm with a full range of motion. All patients were asked for their informed consent to participate in the study (Annex 3).

Process

a. Patient lying or sitting in right or left lateral decubitus, depending on location, on a stretcher in the shock wave unit.

b. Localization of the painful point by palpation and lubrication of the treatment area with gel on the skin and on the coupling membrane of the equipment for the transmission of shock waves.

c. Energy density from 0 mj / mm2 to 20 mj / mm2 . Progressive application of shock waves from low intensity to maximum intensity according to tolerance.

d. Frequency 0 - 4

e. Maximum pressure 6 to 126 Mpa.

f. Depth of penetration 0 mm to 165 mm

g. Sessions: 3 to 5 (once a week).

h. Duration of treatment: 20 to 30 min.

i. No sedation or pain relievers

The patients were evaluated by the authors before and after treatment. The following variables were taken into account: age, sex, pain and disability. In addition, specific scales were used for musculoskeletal diseases, supported by studies collected in the scientific literature. For the assessment of pain (VAS analog scale) (Annex 1). The DASH scale (arm, shoulder and hand disabilities) (Annex 2) was used for a global assessment of symptoms and disability; This measures the ability to carry out activities of daily life and work, composed of 30 items, measures different dimensions: functionality, symptoms, social role and psychological state. The score ranges from 0 in those patients in the absence of disability to 100 total disabilities. Its authors proposed a criterion for the qualitative interpretation of the results (Absence: 0, mild disability: 1-10, moderate disability: 11-40, severe disability: 41- 80 and total disability: 81-100) that, despite having received some criticism, it is still used.

The criteria for evaluating response to treatment:

1. Good evolution when there is remission of pain (EVA-0), restoration of joint mobility and incorporation of patients to their usual activities.

2. Regular evolution when there is a conspicuous improvement in pain (EVA ≤3), improvement in joint range of motion, requirement of some conservative treatment and incorporation to their usual activities.

3. Poor outcome when there was no remission of pain (EVA >3), no improvement in mobility and no incorporation to usual activities.

The information processing was carried out in EXCEL and using the statistical package SSPS 11.5. The frequency analysis of the variables contemplated in the study was carried out, the absolute and relative frequencies were obtained. In addition, measures of central tendency (mean, median) and dispersion (standard deviation) were used. Likewise, the Chi square test of independence was performed to determine the existence of statistically significant differences between the proportions obtained. In each case, the value corresponding to the probability of occurrence p; an alpha error of 0.05 and a confidence of 95% were prefixed. It was determined, as a critical or rejection region, when the value associated with p was less than 0.05 and, in this case, the null hypothesis of independence was rejected, and it was concluded that the variables were dependent on each other.

Ethical Considerations

The study was carried out following the ethical principles set out in the Declaration of Helsinki. The Ethics Committee for research in humans, of the International Orthopedic Scientific Complex “Frank País”, ensured compliance with these requirements and approved the research. The information obtained was kept confidential and was only used for investigative purposes. Similarly, to obtain personal information from each patient, their consent was requested, and the reserved nature of the information provided and its scientific use was explained (Annex 3).

Results

As can be seen in Table 1, in the sample there was a predominance of females with 77 patients (71.9%) and the age group of 51-60 years (28%). The median age of the patients seen was 58 years of age. There were no significant differences in terms of age and sex distribution (p = 0.253).

Table 1: Patients with tendon and ligament injury according to age and sex.

p= 0,253

Table 2 shows the distribution of patients with tendon and ligament injury according to sex. 40.2% of the patients were treated for presenting supra spinous tendonitis, followed by patients who were diagnosed with a calcified Achillean Tenosynovitis, 22.4% of the sample. There were no significant differences (p = 0.345).

Table 2: Patients with tendon and ligament injury according to sex.

AF: Absolute frequency p = 0.345

As can be seen in Table 3, all the patients had pain before the application of the shock wave, inclusive, it was the main indication for performing this non-invasive technique. After treatment, this situation was reversed, 78.5% of the patients were without pain. Only 8.4% had pain while walking and 7.5% at rest. These differences in pain before and after therapy were statistically significant (p = 0.0000).

Table 3: Patients with tendon and ligament injury, according to visual analog scale, before and after treatment.

AF: Absolute frequency p = 0.0000

Table 4 shows the results obtained after applying the DASH Scale. 43% of the patients studied had total disability before starting treatment. Only 4.7% were found in the category of absence of disability. After five sessions of therapy, according to the procedure described, 71% had no disability and only 5.6% remained in the category of total disability. Significant results were obtained (p = 0.0000).

Table 4: Patients with tendon and ligament injury, according to the DASH scale, before and after treatment.

AF: Absolute frequency p = 0.0000

Table 5 shows the analysis of the evaluation criteria for response to treatment, where good and fair results were considered satisfactory and bad, unsatisfactory. There was a higher percentage of satisfactory results (56% and 23.4%). Only 20.6% of the sample had a poor response, persisting symptoms of pain and functional limitation. The results were significant (p = 0.0000).

Table 5: Evaluation criteria of the response to the treatment given to the patients.

Discussion

According to the literature reviewed, tendinopathies of the shoulder injury to the supraspinatus, tennis elbow (epicondylitis) are common between 40 and 60 years of age. The literature states that 2 to 50% of the population have shoulder pain, accompanied by common symptoms such as atrophy of the muscles and limitation of movements. It is common in both sexes, with a 4: 1 ratio, in favor of women associated with jobs such as seamstresses, housewives, hard workers, athletes and musicians. In the case of Epicondylitis, its prevalence is 10% [6]. Calcaneal spur, plantar fasciitis and calcific achillean tenosynovitis are diseases that have a high prevalence that increases with age. It is of multifactorial origin, although a history of repetitive microtraumas is collected, being more common in runners, overweight people and tasks that require standing for long periods of time. It affects 10% of the population throughout their life between the fourth and sixth decade of life, also causing functional disability. The aforementioned diseases are common conditions in women, which coincided with our study, including age [7]. Age can be considered a risk factor in itself for the suffering of these conditions, since in the aging process itself changes occur in our body that favor the appearance of these diseases.

According to Mirallas Martínez, pain, limited movement and disability is a frequent symptom, characteristic of all these conditions and can be present in all cases [8]. This result could be corroborated in our investigation. The pain can be present, even in a state of rest, and it can make it impossible to sleep at night if you sleep on the affected side. Night pain can be severe enough to prevent sleep or wake the patient at night. Extracorporeal shock waves pass through tissues and can trigger absorption, reflection, refraction and energy transmission phenomena (direct effect). The negative phase is the cause of the indirect effects on the cellular tissue. These types of waves increase metabolism in the body and favor the reduction of inflammation in the area affected by the production of endorphins, causing a triggering analgesic action. In this way, the process of stimulation of inflammation mediators by induced hyperemia and the release of free radicals is accelerated.

The reversal of chronic inflammation is another advantage of the use of extracorporeal shock waves, since this persistent inflammation requires components (called mast cells), whose activity increases with acoustic waves, allowing the production of chemokines and cytokines that improve the inflammatory process [9]. The DASH questionnaire was developed in 1994 in English at the initiative of the American Academy of Orthopedic Surgeons (AAOS), as a consequence of this, from 1994 to the present, more than 48 validated and culturally adapted versions of the DASH have been developed (website of Institute for Work & Healt: http://www. dash.iwh.on.ca) is specific for musculoskeletal conditions. Although it is an instrument used to evaluate only disability in the upper limbs, it was of great value to the authors, since a greater number of patients with these conditions were diagnosed in the sample, which was essential to use. In addition, this specific instrument made it possible to detect the clinical changes of interest in the patients’ status, it allowed to functionally assess the joint of the shoulder, elbow, wrist and fingers and the quality of life of the patients [10].

Indications for shock wave therapy encompass a wide range of conditions, including (Supraspinatus tendinis, Epicondylar insertions, Calcific Achillean Tenosynovitis, Calcaneal spur, and Plantar fasciitis), among others. Its effectiveness lies in the physiological effects that occur in the body when applying this wave. It causes a regulation of the inflammatory cascade where it decreases the levels of substance P, bradycin and other local factors of inflammation. In addition, it stimulates the phenomenon of angiogenesis, all these changes finally activate and modulate the healing cascade, thus turning a chronic wound into an acute wound that will have a normal physiological healing process [11]. Wang CJ and others in their clinical studies have shown increased blood flow and growth factors that induce angiogenesis and consequent neovascularization in the calcaneal tendinous insertion [12]. It was manifested in the clinical improvement of the patients after applying it, which coincided with our investigation.

Effectiveness was demonstrated in the treatment of supraspinatus tendonitis and epicondylitis [13]. The improvement is significant in pain intensity, with good or excellent functional gain in 56% of patients treated with extracorporeal shock wave therapy. There are significant differences between patients in the treatment and placebo groups in pain and function, and it is concluded that treatment using this therapy is a pre-surgical alternative. The improvement in pain and function is good or excellent in 48% and acceptable in 42%, with a significant difference in favor of patients in the treated group compared to those in the placebo group. The improvement in pain and function is good or excellent in 52% of those treated compared to 6% of those in the placebo group [14]. Similar results to ours were observed.

In the case of plantar fasciitis and achillean tenosynovitis, Gollwitzer H, et al. [15] Conducted the study that used the largest sample size, with 250 subjects for the trial obtaining satisfactory results. This effectiveness or benefits are reflected in an improvement in the patient’s symptoms, especially in the decrease in pain and improvement in functional capacity, and in a decrease in the thickness of the plantar fascia based on the studies reviewed, as these are the variables more measures together [15]. The main weakness of this study is the small sample size, but with results similar to those found in other studies where a similar response to both treatments could be observed, this fact supports the strength of our findings.

Conclusion

Some of the sociodemographic characteristics of the patients studied do not differ much from those indicated by other authors, such as: the predominance of female sex and age. Treatment with extracorporeal lithotripsy (shock wave therapy), with the Well Wave equipment, was an effective method. It is a modern and noninvasive technique, which has enabled a rapid recovery of patients, their incorporation into daily activities, promotes rehabilitation, early return to work activities and better use of the working day.

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