Iris Publishers-Open access Journal of Yoga, Physical Therapy and Rehabilitation | Yoga Therapy for Rheumatoid Arthritis

 

Authored by Natalie Fortune*

Abstract

As the prevalence and incidence of rheumatoid arthritis continues to rise, and current pharmaceutical interventions offered have been shown to elicit negative side effects, there has been a recent shift in the use of supportive and therapeutic medical modalities. In particular, functional treatments, like yoga therapy show great promise as a complement to traditional medicine. In this review, we provide a brief overview of yoga therapy, present the latest findings between the relationship of yoga therapy and Rheumatoid Arthritis, and discuss the future direction of this promising field.

Introduction

Rheumatoid Arthritis (RA) is a prevalent, chronic, systemic, inflammatory autoimmune disorder that affects more than 2 million adults in the United States and is characterized by swollen, stiff, and inflamed joints [1]. The onset of RA is commonly seen from the age of 30 to 50 and affects women three times more than men [2, 3]. Disease management for RA is predominantly based on drug therapies such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Though these medications have proven clinical outcomes, some patients do experience negative side effects [4]. As the prevalence and incidence of RA continues to rise, it creates a burden on the individuals, their families, and society [5]. Currently, there is a lack of established, no pharmacologic treatment options [6] that can offer support while remaining affordable and minimizing the chance of side effects.

In the last decade, there has been an increase in attention brought to functional therapies as complements to pharmacologics that improve physical function, such as yoga [7,8]. The practice of yoga involves several mind-body exercises including physical postures, breathing exercises, and meditation techniques that have been shown to reduce stress and improve motor functions in various groups of people [9,10]. According to the International Association of Yoga Therapists (IAYT), “Yoga therapy is the process of empowering individuals to progress toward improved health and well-being through the application of the teachings and practices of Yoga” [11]. Yoga therapy is a specific field that integrates the ancient science of Yoga with modern medicine and is an evidencebased approach to support the needs and goals of an individual, while considering their limitations. In this review, we performed a literature search of clinical trials and observational studies involving yoga therapy and rheumatoid arthritis in the last 10 years to evaluate the effectiveness of this discipline.

Discussion

A variety of methodologies have been utilized to observe the effect that yoga therapy has on RA and other inflammatory conditions. A notable study, conducted by Greysen et al. assessed the practice of yoga in community settings [12]. Telephone interviews were conducted with 17 RA patients that regularly participated in yoga. A qualitative approach was implemented to document participants’ practice characteristics and thoughts about yoga and how it relates to RA. It was found that yoga experiences unanimously had components including stretching, physical exertion, breathing, and meditation. Consistent themes found in the interview included: interest in improving physical fitness and psychological health, reduced cost of at-home practice, as well as flexibility in training plans [12]. Interestingly, though it was shown that participants had similar beliefs for practicing yoga and that their routines included similar components, this study highlighted the variance in different routines emphasizing the lack of an effective framework of yoga therapy for RA, a basis for further research.

Though observational studies can show associations, they lack the ability to draw causative conclusions. Middleton et al. performed a pilot study with 30 participants investigating the effectiveness of a yoga intervention on bilingual ethnic minorities, specifically Hispanic and Black/African-American adults, who were diagnosed with osteoarthritis (10%) or rheumatoid arthritis (90%) [13]. They utilized an 8-week yoga program consisting of group intervention which met biweekly for 60-minutes where participants practiced Hatha yoga and were encouraged to continue exercises at home. This type of study design allowed the researchers to draw more definitive conclusions. Significant improvements were seen in values for self-care, self-efficacy as well as physical measurements such as standing on a single leg, functional reach, and upper limb functionality through the DASH index. Results indicated that yoga can be effective in minority communities through improvements in physical and psychological aspects of individuals, and shows promise as a therapy form. Though this study provided insightful information in regards to yoga therapy, it did not separate the participants into groups, and was therefore unable to eliminate the possibility of the placebo effect.

There have been a few clinical research studies conducted that have shown how yoga can be used to support individuals with RA. However, there seems to be a disjointment in the techniques used across studies, and thus poses an issue for validating the effectiveness of the intervention. A randomized controlled trial conducted by Telles et al. enrolled 64 RA patients in a one-week yoga program where they practiced breathing, exercise, and yoga postures and were assessed before and after the one-week intervention [14]. The randomized study design resulted in a reduction in selection bias, that generated results with minimized bias. In this study, subjects reported improvements in dressing, arising, walking and grip strength, but had no changes in reported levels of pain. In addition, there was an improvement in the Health Assessment Questionnaire (HAQ) as well as a decrease in the Rheumatoid factor lab values, suggesting the benefits of incorporating yoga as a treatment option [14]. Yet, with only one week of treatment, this study leaves in question both the potential of yoga therapy as a continuous treatment for disease activity as well as its long-term benefits. Evans et al. investigated the effects of a six-week Iyengar Yoga program where patients were assessed at baseline and at the end of the program, in addition to two months after the program had concluded [15]. Twenty-four participants were split into two groups, with one group receiving yoga treatment immediately for six weeks, and the other group being initially prescribed standard of care followed by the yoga treatment. Researchers found that while the objective measurements of pain reporting did not significantly change through treatment, psychological benefits presented themselves with study subjects reporting more positive well-being directly after the intervention. The psychological benefits did not persist at the two-month post-intervention assessment raising the question of whether the treatment period of yoga may play a factor post-intervention [15]. Together, these studies emphasize the potential of yoga therapy in managing RA, yet more work in this field needs to be done to get a better understanding of the optimum method to implement yoga therapy as well as to solidify psychological and physical benefits of this treatment option.

Current RA and yoga studies have found that long term yoga has psychological benefits, but there have been no findings that support long term physical outcomes. Nevertheless, yoga therapy has been shown to have an analgesic effect in other conditions. Colgrove et al. prescribed a 12 week program to eight subjects who had lower back pain [16]. They found that participants reported significantly lower pain scores post-yoga intervention, suggesting that the therapeutic effects of yoga may emerge after a few months of a program [16]. A short term intervention was used by Ebnezar et al. as 250 participants who had knee osteoarthritis were separated into a control group which received a daily routine of electrical stimulation and ultrasound treatment for two weeks, and an intervention group that received a yoga program in addition to electrical stimulation and ultrasound [17]. Both groups were assessed before treatment, after two weeks, and at a 90 day follow up. Physical benefits, such as reduced resting pain, morning stiffness, blood pressure, and pulse rate were significantly better in the intervention group at both the two week and 90-day assessment [17]. These studies highlight the effectiveness of a yoga intervention to manage physical outcomes and pose the need to further investigate long term, standardized yoga therapy in RA to complement existing forms of standardized care.

Conclusion

Over the last 10 years, the practice of yoga has grown exponentially in the United States and has begun to make itself known as a non-pharmacologic therapy for several diseases. In RA, yoga has been shown to be beneficial with several studies indicating both short term physical and psychological benefits while also being cost-effective, making it a valuable addition alongside primary treatment options and worth promoting. However, across studies, there is a large amount of variability in the reported benefits of yoga which can be attributed to the limited amount of controlled research studies as well as a diverse range of protocols used to administer yoga treatment. Therefore, the future of yoga as a tool for disease management shows promise but more work currently needs to be done to solidify relevant findings. There is a need for well-constructed research studies with good methodology that follow patients for an appropriate period of time, to produce reliable results showing the effect that yoga therapy has on RA and other inflammatory conditions.

Reflection

There is interconnectivity of the mind-body-soul behind every human which translates into the fact that every patient has their own level of complexity. With this in mind, it is key to develop modalities that honor the individuality and freedom of our patients. Given the current published research on this topic, it is evident that there is a need for well-designed clinical trials and observational studies that assess these progressive programs in order to offer the best care to patients with autoimmune diseases.

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Iris Publishers-Open access Journal of Pediatrics & Neonatal Care | Report on Activities of the Kangaroo Mother Care Unit

 

Authored by Kim Chi Luong*

Opinion

Within two months of being officially put into operation, the team of doctors, nurses and midwives at TWG Long An Obstetrics- Pediatrics hospital has successfully managed many premature babies as well as full term babies with difficulty at birth.

Opinion

Within two months of being officially put into operation, the team of doctors, nurses and midwives at TWG Long An Obstetrics- Pediatrics hospital has successfully managed many premature babies as well as full term babies with difficulty at birth.

Two days earlier, TWG Long An Obstetrics-Pediatrics hospital saved the life of a baby with 1000 gram birth weight, born prematurely at 28 weeks gestation, now the mother and baby are monitored at the Neonatology Department, the baby has a stable development, increased more than 300 grams after 3 weeks of care. It is expected that the mother and baby will be discharged from the hospital next week (Figure 5&6).

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Iris Publishers-Open access Journal of Modern Concepts in Material Science | Heat Affected Zone in Welded Metallic Materials

 

Authored by Zakaria Boumerzoug*

Abstract

Welding is used extensively for pipe welding, aerospace, aviation, biomedical implants, fabrication of race cars, choppers, etc. Generally, the metallurgy of the welded joint performed by thermal fusion joining process can be categorized into two major regions, the fusion zone (FZ) and the heat-affected zone (HAZ). The heat-affected zone (HAZ) is a region that is thermally affected by the welding treatment. The main difficulty associated with welding is the prevention of unexpected deterioration of properties as a result of the microstructure evolutions which reduce the resistance to brittle fracture in the heat-affected zone (HAZ). Properties of the HAZ are different from those of the base material. According to the literature, the HAZ is the most problematic area in the high strength steels weld. For this reason, many research works investigated this critical zone in welded joint. The main research questions and results related to the HAZ will be presented.

Keywords: Welding; Heat affected zone; Microstructure; Mechanical properties; Thermal cycle simulation

Abbreviations: HAZ: Heat Affected Zone; Hv: Hardness Vickers; FZ: Fusion Zone; BM: Base Metal; T-HAZ: True Heat Affected Zone; PMZ: Partially Melted Zone

Introduction

Welding is a process of joining materials into unique piece. Welding is an enabling technology applied across almost all industries, from micro-joining of medical devices, electronics and photonics, to larger scale applications such as bridges, buildings, ships, rail, road transport, pressure equipment and pipelines [1]. Welding processes are divided into thermal fusion joining processes and solid-state joining processes. The most common processes of welding are thermal fusion joining processes such electric arc welding. This welding method is performed under high temperature conditions.

Heat generated during welding induces an important temperature gradient in and around the welded area. Generally, the metallurgy of the welded joint can be divided into two main zones, the fusion zone (FZ) and the heat-affected zone (HAZ). The HAZ is a zone which is outside the FZ of the welded joint that is thermally affected by the welding treatment. The HAZ is considered as a transition zone, because it is composed with the microstructure of the BM and the FZ. The properties of the HAZ are very important after performing a weld, because it is considered as a weaker zone, i.e.; the area of failure when the welded metal is submitted to hard conditions. For this reason, it is important to understand this critical zone in welded joint.

Microstructures of HAZ

The HAZ is the unavoidably heat treated area in the parent metal near the fusion zone during welding where structural transformations occur [2]. HAZ formed during welding is an area which some structural changes in the welded material take place as the result of experienced temperature [3]. Figure 1 shows how the HAZ in welded XC38 steel differs significantly from the base metal. There was a development of a recrystallization reaction in HAZ, with the partial dissolution of the colonies of pearlite (dark color).

Depending on the distance from the weld, the different parts of the HAZ can be affected differently during the welding process There are many descriptions of the HAZ, because it can be divided in different subzones and each subzone has its own microstructure. For example, It has been considered that the HAZ can be divided into four different zones [2], as shown in Figure 2, which are subjected to different heat treatments:

• Coarse grain zone

• The normalized zone

• The partially transformed zone,

• The annealed zone

However, according to Lippold [5], the HAZ was subdivided into two regions, the partially melted zone (PMZ) and the “true” heataffected zone (T-HAZ). The PMZ exists in all fusion welds made in alloys since a transition from 100% liquid to 100% solid must occur across the fusion boundary. According to Lippold [5], there are many possible metallurgical reactions in the HAZ: recrystallization, grain growth, phase transformations such as precipitation, and residual stress and stress relaxation.

Mechanical properties of HAZ

The mechanical properties and microstructures of the HAZ have its origin in the thermal heat treatment during welding and depend on the characteristics of the joint (position in the joint, thickness of the joint) and the heat input and the prior-heat treatment before welding (if it is applied) [6].

Controlling of HAZ

It has been concluded that by improving the microstructure of the HAZ, the properties of the welded joint can be improved [7]. The changes of microstructures in the HAZ depend on the level of thermal exposure and are varying with distance from the weld metal zone. High heat input increases the size of the HAZ which induces a low impact strength [8]. As reported by Gu et al. [9], the degradation in strength and toughness of welded joint, is generally happens in HAZ.

As many authors, Parmar and Dube [10] considered HAZ as the most complicated region. It is important to control its effects. HAZ is the most critical region in the welded joint as it affects the microstructure and grain size of weld bead. The main factors for improving welded joint quality are: welding process, material selection, and welding parameters. Concerning the welding parameters, they found that in order to study the heat-affected zone in welded carbon steel, following parameters were considered: welding current, welding speed, and arc voltage. These parameters can influence the Heat input and heat flow.

According to Lippold [5], heat input and heat flow conditions have an effect on the dimensions and nature of the HAZ. These dimensions are controlled by the temperature gradient from the fusion boundary into the surrounding base metal and the nature of the metallurgical reactions that occur over that temperature range. The size of HAZ has been studied by Śloderbach and Pająk [3]. They established an expression for determining the value of x of HAZ for a given time t and knowing diffusivity coefficient κ of given material:

[x/(2√κt )] ≈ 0.61

From this mathematic expression, the size of the HAZ x can be controlled by the time t during the welding. The x can be reduced by reducing the welding time.

Methods of Investigation of HAZ

It has been found that the study of the HAZ of real welded joints is not easy because of the narrowness of the HAZ [11]. Welding simulation is the appropriate technique to determine the different sub-zones in HAZ. This allows the prediction of the microstructure and the properties of these sub-zones [9]. Consequently, thermal cycle simulation in which the HAZ can be geometrically extended is the appropriate method in order to determine the different microstructures, which can be developed in real welded joints [12,13].

Hamza et al. [14] simulated HAZ of the welded stainless steel 304L by the thermal cycle simulation technique and compared it to the HAZ obtained from the real welded joint. They found that the simulated HAZ by the thermal cycle simulation technique has given more information. The HAZ is heterogeneous structure, because it is formed with different subzones. Raouache et al. [15], investigated the HAZ of welded 2014 aluminum alloy by the thermal cycle simulation of the base metal. They found that the HAZ is also a heterogeneous zone, because it is composed with different subzones and each subzone has a specific microstructure.

Conclusion

From the above literature, followings points can be summarized: • The HAZ is the critical zone in welded joint, for this reason it is necessary to control its effects.

• The HAZ is a heterogeneous zone and it can be divided into different subzones

• There are many possible metallurgical reactions in the HAZ

• The mechanical properties and microstructures of the HAZ depend on the heat input during welding

• Main factors for improving weld joint quality such as the welding process, the material selection, and the welding parameters.

• Welding simulation is a suitable technique for the investigation of the HAZ and to determine the various HAZ subzones.

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Iris Publishers-Open access Journal of Modern Concepts in Material Science | The Reproducibility Crisis in Science from the Perspective of Thin Film Deposition: An Unexpected Approach

 

Authored by Carlos Morales*

Abstract

The publication of scientific results in all disciplines, and in particular in Material Science, has geometrically increased in the last decades. Although the quality of the published results seems to follow the same trend, the feeling that we could be facing a reproducibility crisis has become extended within the scientific community. We discuss this issue in relation to thin film deposition techniques such as atomic layer deposition, which should not present deviations on the reported results due to its self-limiting nature. In particular, we put the focus on the necessity of a multipolar approach that takes into account also the global environment in which researchers perform their work.

Keywords: Material science; Reproducibility crisis; Emotional and mental health

Abbreviations: ALD: Atomic Layer Deposition; CVD: Chemical Vapor Deposition

Introduction

The impressive technological development during the last hundred years has become the distinguishing mark of our contemporary era. If the ancient ages were identified by the name of the material that allowed a qualitative jump in terms of nature adaptation and territory control, i.e. stone, bronze and iron, very likely these are the days of silicon. The development of electronics, including its way through the micro and nano scales, has facilitated the greater and faster levels of information sharing and storage of the human history, changing the social uses, the relationships between different communities, our global perception of ourselves and, what particularly concerns us as scientists, the way of doing and sharing scientific results. Indeed, if until the beginning of the XX century the human knowledge was doubled every one hundred years, this time has been decreasing down to thirteen months in 2010. In that same year, the field of nanotechnology was doubling its knowledge every eighteen months [1].

This exponential improvement implies the domain of different bottom-up deposition techniques, most of them developed during the second half of the past century. In spite of the evident control of protocols and the successful results that translate into novel mass devices, there is also an extended feeling in the scientific community: we are within a reproducibility crisis that affects all disciplines, including Material Science [2]. Before moving forward, we would like to stress that this has nothing to do with a proliferation of fake results, but with difficulties on reproducing proper or external reliable results. The following lines will overview briefly the different deposition methods that may be used in thin film deposition. We will pause in atomic layer deposition (ALD), because its self-limiting reaction nature allows to compare and discuss the reproducibility among results from different groups. By extrapolating this reflection, we will discuss the current reproducibility crisis narrative.

Discussion

Thin film (from nanos to microns) deposition techniques can be divided in two large branches: physical and chemical processes [3]. Generally speaking, the first group covers those methods that imply a change on the physical state of the compound (liquid/solid-gas) before its deposition as thin film (gas-solid). The usual examples are sputtering or physical thermal evaporation (using different heating systems, such as e-beam or thermal Knudsen cells). On the other hand, chemical methods imply the formation of thin films by solid/gas or solid/liquid reactions, for instance, chemical vapor deposition (CVD) or ALD. Nevertheless, together with the variation of certain intrinsic parameters of the specific method, combinations of physical and chemical methods are very often used to grow oxides, to achieve film doping or some microstructure control. Reactive sputtering, which consists of standard sputtering under a reactive atmosphere, may well illustrate the former sentence. For example, from pure metallic targets, oxide films can be grown; by controlling the atmosphere composition intrinsic or extrinsic level of doping may be varied; and, finally, by changing pressure and temperature, the microstructure of the film also be tailored [4].

The limited length of the present contribution compels us to stop here the introduction of thin film deposition techniques. However, the aforementioned ALD technique constitutes an excellent example to continue our dissertation. The use of ALD has spread in the last decades due to its conformal growth on 3D structures and excellent control of thickness at the atomic scale, what makes it a very powerful technique in nano-devices production [5]. Although similar precursors to those of CVD are used, the difference between these two techniques is the self-limiting nature of ALD. The sample is alternatively exposed to the different precursors, limiting the reaction of each type with only those active sites available at the surface as a consequence of the previous reaction between the former precursor with the surface, what leads to a well-controlled growth of one layer per cycle (see Figure 1). Therefore, the advantage of ALD lies on the saturation of each one of the reactions that constitute a complete cycle. If saturation is reached, then extra time on the dosage of one precursor should not lead to changes on the deposition rate. Although secondary factors such as temperature or type of oxidant (in case of metal oxide growths) could lead to slight differences on the growth rate for a unique metalorganic precursor, the comparison of deposits under virtually exact conditions should lead to a very low dispersion of results. However, as very recently shown by H.H. Sønsteby et al. [6], there is a wide dispersion on reported growth rates for well-known materials such as Al2O3 (using Trimethylaluminu -TMA, Al(CH3)3- and water), TiO2 (titanium tetraisopropoxide –TTIP, Ti[OCH(CH3)2]4 - and water) or FeOx (ferrocene -Fe(cp)2- and ozone). For example, Al2O3 growth rates between 1 and 3 Å/s are reported. This is a factor of three from the highest to the lowest value for a process that should be self-limiting, whatever the ALD reactor and for the same experimental conditions. Similar data dispersion apparently affects in different grades to the entire field of Material Science.

The perception of the reproducibility crisis that the previous example shows has gained attention in the last decade, as it demonstrates the evolution of records on the Web of Science database that mention this crisis on its title, abstract or keywords [7]. In particular, the survey published in Nature in 2016 by M. Baker drew the attention of the scientific community [2]. That work shows a survey to more than 1500 scientist where 52% of them recognized that there was a strong reproducibility crisis, followed by a 38% that, although recognizing the problem, lowered its depth. Only a 3% of surveyed people denied that such problem exists. Although chemists, physicists and engineers were the most confident regarding the work of their colleagues, more than 60% of them recognized problems in reproducing the results of other research groups. The lack of reproducibility within the same laboratory reached 50%. This value, slightly lower than the former could be explained by the diversity of laboratory equipment. Therefore, it seems clear that there exists a general perception of difficulties to reproduce previous published results and methods.

It is true that doing cutting-edge science may mean moving in the limits of reproducibility, in the sense that developing new lines of research means doing everything new. Therefore, despite describing correctly and in detail (not in all cases) the experimental method, same results may not be obtained because the focus of the description is not placed on important factors that remain hidden. Nevertheless, when scientists were asked in the quoted survey about the possible causes of this lack of reproducibility, more than 60% of them blame to pressure on publishing, selective reporting, low statistical power and non-enough replication of the original lab. In fact, the three last causes may be easily related to limited time and pressure to obtain and publish novel results. In short, the pressure to remain on the funding-publish-funding cycle seems to be the ultimate reason.

Moreover, the accumulative dynamic of such problems should have a high impact on science progress in the middle-long term. For example, the absence of an evident, visible gap between fundamental and more applied research, or the fact that retractions, errata or corrections in journals have not increased relatively to the amount of new publications [8], seems to indicate that this reproducibility crisis has not yet, if at some time should have, consequences. In fact, some authors as D. Fanelli consider that this crisis is not necessarily real, but a narrative put up by projecting personal experiences and idealizing scientific standards and models to all fields [7]. In particular, by metadata analysis from science databases such as Web of Science, this author argues that there are no evidences of an increase of the publications per author if the increase of coauthorship is taken into account, or that there is not a process of multiplication of published works by fractionating or simplifying results [9].

In our opinion, the statistical studies by D. Fanelli are of great interest and should be carefully studied. However, we consider that the wide dispersion of data regarding tests that should not depend on human bias, such as self-limiting ALD, reveals that there exists an important issue of reproducibility. Avoiding generalizations, at least on material science processing. In addition, the issue should be only tackled from an interdisciplinary view that should take into account the environment in which we are doing science. In this regard, we consider essential to relate the Baker’s survey with the multiple studies regarding emotional and mental health of the scientific community, especially PhD students and young researches that carried out most of the laboratory work in many groups. For instance, the study by T.M. Evans [10] on twenty six countries indicates that PhD students are six times more prone to suffer from mental diseases than the rest of the general population, that is, a percentage of 39% versus 6%. When asked about symptoms associated with anxiety and/or depressive disorders, the 3600 participants from an equivalent survey performed in Belgium answered being under constant pressure (41%), feeling unhappy or depressed (30%), lacking confidence or simply useless (16%) [11]. Although it is true that policies on different countries and territories may imply differences on pressure suffered by the scientific community, similar studies have concluded similar trends in different countries. The perception (or narrative) of the reproducibility crisis and its causes cannot be explained without taking into account the whole picture. We believe that behind these two issues it may lie a deeper crisis related to the way by which science production is performed. As diagram of Figure 2 shows, this could especially be related to the accelerations of science times and the temporary and contingent positions of many researches, which contribute to increase the pressure to publish.

Conclusion

Scientific knowledge, and in particular Material Science, are undoubtedly in a golden age. However, in the last years an increasing interest has appeared on the reproducibility crisis in all scientific disciplines. The pressure to publish has been pointed out as the ultimate possible cause. Moreover, the conclusions of different studies regarding metadata of published records show no evidence of such crisis but a narrative built up from personal experiences and erroneous generalizations. We believe that objective experimental techniques, such as the self-limiting ALD, shows the existence of such reproducibility crisis without the critical concurrence of any human bias. Besides, the study of the causes of the reproducibility crisis, that may not yet let to sever consequences, should be related to other facets of the scientists social and labor environment.

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Iris Publishers-Open access Journal of Dentistry & Oral Health | The Modes of Dental Caries Prevention with Xylitol

 

Authored by Jihan Turkistani*

Introduction

The importance of dietary factors in the etiology of dental caries has been acknowledged, and the role of proper nutrition in improving the health of the population cannot be disputed [1]. The American Academy of Pediatric Dentistry (AAPD) acknowledges the benefits of sugar substitutes, particularly xylitol as caries preventive strategies on the oral health of infants, children, adolescents, and persons with special health care needs. Thus, the AAPD has intended a policy about the use of xylitol-based products in caries prevention [2].

The discovery of xylitol is credited to two groups of researchers in 1890, the German chemistry professor Fischer, and the French chemist Bertrand [3]. Xylitol is a natural carbohydrate sweetener that belongs to the pentitols (five-carbon sugar alcohol) [4]. The first trials for xylitol were done in the late 1960s and early 1970s in Turku, Finland [5]. A two-year study showed that subjects who had xylitol in their diets as a substitute for sucrose developed almost no new carious lesions compared to the other groups [6]. Based on Turku study results, several other trials and a large number of laboratory studies ensued. The first significant dental recommendations for the use of xylitol began to appear in the United States’ dental literature in the early 1990s. Anderson et al. presented the medical model approach to dental caries incorporating sealants, antimicrobials, fluorides, and xylitol [7].

Use of Xylitol in Dental Practice

The use of xylitol in caries prevention does not require professionals, clinical visits and treatment, equipment, or repeated indi vidual check-ups. Therefore, one can easily start a preventive pro gram with xylitol, while professionals can use their clinical hours to treat subjects with more acute needs [8]. The use of xylitol in dietary foods has been approved by the United States (U.S.) Food and Drug Administration since 1963. It has been introduced for children in different forms, such as candies, gum, syrups, gelatin, in addition to other products like multivitamins, toothpaste, and oral rinses [9]. Chewing gum has been established as the most effective vehicle for the delivery of xylitol to the oral cavity. However, though this may be an effective means of consuming xylitol for most adult populations, it is a limiting factor for its use in small children and as a public health method of intervention in organized preschool programs [10]. Additionally, dentists should emphasize that xylitol chewing gum is an added measure, not a replacement for other preventive programs like fluoride, consciously applied oral hygiene practices and regular dental visits [11,12].

Xylitol-sweetened gum is not as available in the U.S. as are sucrose- and sorbitol-sweetened gums. Evidence showed that xylitol- sweetened gum offers more caries reduction benefits than did sorbitol-sweetened gum. Still, chewing sorbitol-sweetened gum several times per day is better than chewing sugared gum in reducing caries [11,13,14]. Sorbitol is another sugar alcohol that is frequently used in several sugar-free chewing gums and over-thecounter medicines [13,15]. Due to the relatively high cost of xylitol, sorbitol and xylitol are often combined with a better clinical effect than with pure sorbitol [16,17]. Sorbitol should be considered a low cariogenic sweetener rather than a non-cariogenic one because the consumption of larger amounts increases both the acid production in plaque and the number of sorbitol-fermenting micro-organisms [18].

The long-term effects of xylitol chewing gum have been demonstrated in several studies [19-21]. Teeth erupting after the end of the gum-chewing program showed the most significant long-term caries reductions. For the utmost outcome, chewing xylitol gum should be started at least one year before permanent teeth erupt, i.e., during preschool and early elementary school years [22]. Moreover, several clinical studies provide evidence of the effectiveness of xylitol-sweetened gum in reducing maternal transmission of cariogenic bacteria [23-27]. A range of 6 to10 grams divided into three times per day is necessary for xylitol chewing gum to be useful [19,20,28-30]. The main side effect associated with xylitol consumption is osmotic diarrhea. It usually occurs when consumed in large quantities, four to five times those needed for the prevention of dental caries [31].

Mechanism of Caries Inhibition

Most oral micro-organisms do not ferment xylitol, and its caries- reducing effects have been attributed mainly to this lack of fermentation. However, specific effects on microbial growth and metabolism, on certain salivary factors, and the physicochemical processes of de- and remineralization have also been claimed [32- 34].

Effect on bacteria

Dental plaque formation: Several studies have shown xylitol to reduce the amount of dental plaque formation, adhesiveness, and acidogenic potential of dental plaque when compared with the chewing of sucrose-containing gums or not chewing gum [14,35- 37].

Bacterial metabolism & growth inhibition: Sugar transport into bacterial cells plays a role in the expression of the virulence (cariogenicity) of Streptococcus mutans. The high-affinity phosphoenolpyruvate-dependent sugar: phosphotransferase system (PTS) is the principal route for transporting most sugars in oral streptococci. The other two transport systems are: fructose-specific and sucrose phosphorylase [38]. Some carbohydrate sweeteners are neither taken up nor metabolized to acids by Streptococcus mutans. Since xylitol possesses a 5-carbon sugar alcohol structure, it is taken up via PTS by Streptococcus mutans. Still, it cannot be metabolized to acid and is accumulated as non-metabolizable, toxic xylitol phosphate [most likely xylitol 5-phosphate], resulting in inhibition of both bacterial growth and acid production. Xylitol phosphate is further dephosphorylated to xylitol with the waste of phosphoenolpyruvate potential. This futile cycle can also retard the growth of Streptococcus mutans [34,39,40]. Furthermore, xylitol phosphate inhibits several enzymes of the glycolytic pathway (e.g., phosphoglucoisomerase, 6-phosphofructokinase, and pyruvate kinase) [40].

Most of the mutans streptococci strains tested (e.g., S. mutans, S. rattus, and S. sobrinus strains) are sensitive to xylitol when grown in the presence of glucose plus xylitol [38,41-46]. Sensitivity to xylitol was defined as an inhibition of the growth of wild-type strains in the presence of xylitol and is thus called “xylitol-sensitive” (X.S.) strains [41]. On the other hand, an earlier in vitro study in 1972 showed that when Streptococcus cells were transferred from normal media into xylitol media and the overall bacterial cell metabolism seemed to be retarded. Consequently, the induction of aminopeptidase-like enzymes occurred. It may suggest that the cells were forced to use proteins and peptides to a greater extent for synthetic purposes. After several months of storage in polyol-containing broth, the cells grew almost normally, and the induction of aminopeptidases by xylitol was reduced almost to the level exerted by cells grown in a normal medium. This suggests that xylitol, in long-term use, could be used by oral micro-organisms [47]. Therefore, it is necessary to further investigate mechanisms of effects of xylitol on Streptococcus mutans metabolism, especially at the molecular level [48]. Moreover, other in vitro study showed that xylitol is not phosphorylated by the fructose PTS in the presence of fructose.43 Since fructose competes with xylitol for the fructose PTS and prevents phosphorylation of xylitol by Streptococcus mutans strains. Therefore, no significant growth inhibition is observed when mutans strains are cultured on fructose or sucrose in the presence of xylitol [41,46]. Such competition between xylitol and fructose for the fructose PTS, could result in selective pressure of variable efficiency. This selective pressure indicates that fructose and sucrose may not prevent the uptake and the phosphorylation of xylitol by growing cells, as was thought previously, and enough growth inhibition could occur. Evidence for a selective pressure by xylitol includes:

1) A variation in the inhibition of the growth of a given strain, depending on the nature of the growth sugar, whether a PTS sugar (glucose, fructose, or sucrose) or a non-PTS sugar (lactose).

2) The emergence, or lack of emergence, of xylitol-resistant populations during growth on any given sugar depending on the mutans species or strains.

3) A variation in the time it takes for xylitol-resistant populations to emerge [46].

Some in vitro studies have studied the inhibitory effect of xylitol on acid production at several pH levels under the strictly anaerobic condition found in the deep layer of dental plaque. At pH 5.5-7.0, xylitol inhibited the rate of acid production from glucose. Also, the activity of phosphoenolpyruvate PTS for xylitol was greater at higher pH resulting in the accumulation of intracellular xylitol phosphate. Though these results were not evident at pH 5.0, and it is suggested that xylitol could be incorporated more efficiently at higher or neutral pH [40,49]. Besides, certain strains of salivary lactobacilli, which are involved in the progression of carious lesions, can metabolize polyols resulting in pH drop to values sufficiently low to demineralize the hard tissues of the teeth. Therefore, the limited information available concerning fermentation rate of these polyols and the formation of various metabolic end products by lactobacilli fermenting these polyols necessitates further studies [50].

The emergence of xylitol-resistant mutants: Long-term consumption of xylitol leads to the emergence of xylitol-resistant mutans populations in humans [41,44,46,51,52]. These “xylitol-resistant” (X.R.) mutants are unable to accumulate the toxic xylitol phosphate due to lack of fructose PTS activity responsible for xylitol uptake and phosphorylation [41,43-45]. Two operons encoded the fructose PTS activity. The fru I gene encodes for a protein that transports fructose and xylitol. Its deletion renders the mutant cell’s metabolism and growth resistant to xylitol. By contrast, fru CD gene encodes for a protein that transports fructose but does not transport xylitol. Fru CD deletion does not render the mutant cell’s metabolism and growth resistant to xylitol. In xylitol-resistant strains, the fru I gene was deleted.38 A shift from xylitol-sensitive to xylitol-resistant mutans streptococci populations in the plaque of xylitol consumers does not necessarily indicate a loss of the anti- cariogenic properties of xylitol. Various preliminary results supported the hypothesis that xylitol-resistant mutants are less virulent and less cariogenic than their wild-type parent strains. A study by Tanzer et al. showed that X.R. strains of Streptococcus mutans are of diminished virulence by compromised colonization of the teeth and compromised ability to induce lesions that penetrate dentin [53]. Such characteristics might be beneficial and maybe one of the numerous modes of action of this caries-preventive carbohydrate sweetener. Xylitol-resistant mutants are also persisting many years after the xylitol is removed from the diet [51].

Expression of HSP: Some environmental conditions make living organisms express different adaptive responses that allow survival under the physiological stress created by a new environment. The emergence of mutans populations is not the only way to survive in the new environment. Thermal shock studies led to the discovery of heat shock proteins (HSP), also called stress proteins. 54 Stress proteins are generally divided into families: HSP-60 and HSP-70. They are needed for essential cellular functions and adaptation to the environment [55-58]. A study investigating the effect of a xylitol exposure on the expression of HSP-60 and HSP- 70 proteins in Streptococcus mutans was carried out. The results suggest that xylitol creates a stressful environment that disturbs protein synthesis and reduces the expression of HSP-70 and HSP- 60 proteins in the xylitol-sensitive Streptococcus mutans but not in the xylitol-resistant natural mutant strain [59]. Since the stressing action of a chemical agent is mediated through its incorporation into the cell; then it could be easy to explain the lack of xylitol effect on xylitol-resistant cells by the absence of xylitol uptake by these natural mutants [60].

Glucan-binding protein C induction: Another adaptive response that allows survival under the physiological stress created by a new environment due to the accumulation of non-metabolizable xylitol phosphates was described by the experiments of Sato et al. [48,61] It was noticed that xylitol has other target sites, i.e., induction of a glucan-binding protein C (GbpC) gene expression. The GbpC protein mediates dextran-dependent aggregation (ddag), which mediates adhesion on surfaces such as dental plaque under normal circumstances. Therefore, for Streptococcus mutans, elevated GbpC expression may be disadvantageous to tooth adhesion (i.e., less ability to adhere) depending on how saliva is moving in the oral environment. The results of Sato et al. studies could explain earlier findings by Trahan et al., who observed that the proportion of xylitol- resistant mutans streptococci did not increase in dental plaque but did so in saliva as a result of more easily shedding of xylitol-resistant strains from the tooth surface than xylitol-sensitive strains [51]. Moreover, this explanation is often used to explain reduced plaque formation and reduced colonization of mutans streptococci after frequent use of xylitol [62].

Effect on demineralization and remineralization process

Data analysis from clinical and laboratory studies support the hypothesis that xylitol promotes remineralization and can arrest established dental caries in children [63-65]. Another study showed that histologic and physiochemical changes in dentin caries lesions, which are typical of arrested (rehardened) lesions were more seen in subjects with regular long-term use of xylitol chewing gum than other subjects. The hard, although thin surface layer could be attributable to the precipitation of calcium phosphate salts in the lesion’s outer zone, enclosing the advancing caries process. The propagation of the process requires that the micro-organisms that have invaded the tissue continue to receive nutrients. The availability of nutrients is impaired by the formation of a hard barrier and by the washing action of saliva [66]. This suggests that xylitol, in addition to its non-cariogenic effect, may have therapeutic effects. More studies are needed to support the caries inhibitory benefits of xylitol.

Effect on saliva

Peroxidase activity: Lactoperoxidase belongs to the natural defense mechanisms of the oral cavity; it is attributed to the possible inhibition of lactobacillus and Streptococcus growth. It was found that the overall salivary peroxidase activity was increased fourfold to tenfold in persons receiving a strict xylitol diet for two years. It is suggested that the xylitol-induced elevation of the salivary lactoperoxidase activity and the anticarcinogenic properties of xylitol are partly interrelated phenomena [67].

Salivary flow stimulation: Undoubtedly, increased saliva secretion results in a higher salivary pH, buffer capacity, and glucose clearance. Since saliva stimulation is typical for all chewing gums, it was practically impossible to measure the role of salivary stimulation by xylitol chewing gum in all studies in this field [68]. Aguirro- Zero et al. studied the effect of chewing xylitol gum on the salivary flow rate by comparing four groups: no gum, sucrose, sorbitol, and xylitol gum. The findings did not show any significant effect on the salivary flow [69].

Clearance of oral cavity: Chewing of any gum could have a mechanical cleaning effect, but do not affect Streptococcus mutans counts. In a study by Soderling et al., there was no effect on either the amount of plaque or the numbers of Streptococcus mutans in plaque and saliva in the placebo base group. They concluded that polyols are active ingredients of chewing gums that can modulate the amount of plaque and its microbial composition [35]. However, the importance of chewing would also explain why gum pellets with a harder texture were more effective in caries prevention than were softer gum sticks, as demonstrated in the Belize study [28,70]. Moreover, the frequency of chewing may be more important than the actual daily dose of xylitol. In the study by Isokangas, the chewing of xylitol gums containing 3.5g xylitol three times daily (total daily dose, 10.5g) reduced caries incidence significantly, whereas 7 to 9g of xylitol, chewed fewer than three times, gave no significant reduction in caries increment [71].

Conclusion

Xylitol is a natural sugar substitute with anti-cariogenic properties. Data from earlier studies indicate that xylitol can reduce the occurrence of dental caries in schoolchildren and young children via their mothers. Several mechanisms have demonstrated the anti- cariogenic effect of xylitol: reducing mutans streptococci counts, inhibiting plaque accumulation and enamel demineralization, and enhancing remineralization of early lesions. The effective daily dose of xylitol is 6 to 10g, divided into 3 to 5 times chewed for a minimum of five minutes after meals. There is a demand for providing less expensive xylitol-containing products that should make it more accessible to public health programs directed to high-risk preschool populations.

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