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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Rare earth elements (REEs) are strategic materials in order to facilitate the transition from current economy based on petroleum to an efficient circular economy based on clean energy. Although often needed in small quantities, these metals are essential to produce a huge number of technologically sophisticated products for electronic, optical and magnetic applications. Among other applications, these elements play a crucial role in the development of clean emerging low-carbon energy technologies [1].
In spite of the archaic term, most of rare earths are common elements and some of them are even more abundant than other metals, such as copper or lead. Though moderately abundant in the Earth’s crust, rare earth elements are scarcely concentrated in mineral deposits and this fact complicates its Extractive Metallurgy which is complex and requires economic solutions. The world production of REEs has undergone an exponential growth since its discovery in the 18th century, with a notably increase overtime from 1,000 t in 1930 to 133,600 t in 2010 [2]. The rising REEs production has been the consequence of an escalating demand for REEs as well.
Based on their strong affinity for oxygen, REEs resources are mostly present in oxidic form, mainly as rare earth oxides, phosphates, carbonates and silicates. According to recent estimates, 100 Mt of rare earth oxides are accessible in more than thirty countries all around the world. More than 200 REEs ores have been identified as rock-forming minerals, however, only three are considered mineral ores for economic extraction: bastnasite ((Ce,La)(CO3)F), monazite ((Ce,La,Nd,Th)PO4) and xenotime (YPO4) [3]. Thus, the primary sources of REEs are mineral deposits spread out worldwide, but confined mainly in China, Australia and USA.
Furthermore, REEs are also found in industrial wastes in vast amounts and they have been investigated as potential resources for rare earth metals [4, 5, 6]. Among REEs-bearing industrial residues, phosphogypsum, generated during the wet phosphoric acid process from fertilizer production, and red mud residues from the digestion of bauxites in the Bayer are rich in valuable rear earth metals as to be economically treated.
In addition, end-of-life materials can be recycled due to their significant quantities of REE, among them: magnets (38%), lamp phosphors (32%) and metal alloys (13%), retain more than 80% of REE market. Modern fluorescent lamps typically contain more than 20% (w/w) REE (Ce, Eu, La, Tb and Y) [7].
After ore and/or industrial waste concentration processing, rare earth metals are dissolved selectively from raw materials. Actinides, such as uranium and thorium, with similar chemical properties to REEs, are often co-dissolved during hydrometallurgical processes and this could pose a problem. REE primary ores are leached using acid (H2SO4, HCl, HNO3, H3PO4) or alkaline (Na2CO3, NaHCO3) reagents and NaCl or (NH4)2SO4 for REE-ion adsorbed clays [8, 9, 10]. Nonetheless, the hydrometallurgical treatment is ore-dependent and has been well established in the case of some REE ores, especially monazite, but is less evident for other key minerals with a very complex mineralogy.
Biohydrometallurgy and more specifically its application to the extraction of metals through bioleaching processes have been successfully practiced at industrial level for the recovery of uranium, copper and gold [11, 12]. Biohydrometallurgical technologies could play a fundamental role for the treatment of REE-bearing materials since they offer an alternative to physico-chemically based methods. Bioleaching is connected to the development of more cost-effective, less energy demanding and less polluting metal extraction processes than pyro- and hydrometallurgical processes and is able to treat low-grade mineral ores and a great variety of residues. These biotechnological processes involve interactions between microorganisms and metal-bearing ores that render valuable metals in solution. REE mobilization from solid matrices has been done with a wide range of microorganisms, both autotrophic and heterotrophic, and using both pure and mixed microbial cultures [13, 14, 15].
This chapter provide an insight into the global situation of REEs and the potential application of microorganisms in the extraction of REEs from both REEs-bearing minerals and industrial residues.
The demand of REEs have increased in the past decade because of their extensive use in several fields related to electronics, in renewable energy capture technologies, biomedical devices, and other industrial products. In 2018, a list of 35 critical minerals, including rare earth elements, was published by the U.S. Department of the Interior and other executive branch agencies [16]. Likewise, the European Commission developed a critical assessment on non-energy and non-agricultural raw materials in 2017 including heavy rare earth elements, light rare earth elements and platinum group metals [17].
Global mine production was estimated to be 210,000 tons of rare earth oxide (REO) equivalent, which means an 11% increase in comparison with 2018 (Figure 1a). China dominates the global production of rare earth minerals, separated compounds and metals. China exports REEs to United States (31%), Japan (27%), the Republic of Korea (11%), the Netherlands (9%) and Germany (6%).
World mine production (a) and reserves (b).
Other countries are making efforts to increase their domestic production of mineral concentrates. For example, United States enhanced the production, all of which was exported, a 44% in 2019 compared with 2018 [18].
Rare earths are relatively abundant in the Earth\'s crust; however, REEs resources with minable concentrations are less common. Nowadays, about 85o REE deposits have been identified worldwide, which are mainly located in China, Vietnam, Brazil, Russia, India and Australia (Figure 1b) [18, 19].
Prices for most rare earth products are increasing compared with those in 2016 reversing the falling trend that began after prices spikes in 2011. Gadolinium, praseodymium and neodymium experienced the greatest increase in the price, while the yttrium and dysprosium prices decreased. The estimated unit value of rare-earth compounds was $11.60 per kg in 2017 based on information from the U.S. Census Bureau on imports [20].
The estimation of global consumption of rare earth varies significantly due to the limited data transparency and it generally ranges about 140,000 and 170,000 tons of REO equivalent. Furthermore, the global consumption of scandium was estimated in 10–20 tons per year [21].
The amount of specific REEs used strongly depends on the market sector and application. Lanthanum and cerium, and lower amounts of neodymium, are consumed in the catalysts sector. There are different types of permanent magnets but neodymium-iron-boron magnets are fabricated with neodymium and praseodymium, and samarium-cobalt magnets uses samarium and gadolinium. Batteries contain mainly lanthanum, and ceramics, yttrium. Europium, yttrium and terbium are commonly associated with the phosphors sector.
The global growth rate of REEs consumption is expected to be 5–7% per year through 2022. The magnet materials sector would grow more than other sector such as catalysts, ceramic or phosphors. The increasing global demand of REEs as well as the enforcement of environmental and production legislation beyond 2022 lead to higher prices and, consequently, this situation may drive the mining and processing development outside China.
The application of biohydrometallurgy for extracting REEs offer a green alternative to the conventional methods, which are complex and energy intensive. The main economic REEs-bearing minerals are bastnaesite, loparite, monazite, xenotime, and the lateric ion-adsorption clays. Both autotrophic and heterotrophic microorganisms are capable of solubilize REEs and the selection of these microbes for bioleaching processes depends on the type of mineral. Autotrophic bacteria have been employed for the extraction of scandium from ore minerals containing metal sulfides, whereas heterotrophic bacteria are mostly employed for REEs carbonates and phosphates [22].
Bastnaesite is a rare earth fluoro-carbonate ore (REE(CO3)F) containing commonly cerium, lanthanum or yttrium. REE fluorides from bastnaesite are removed by sulfuric acid roasting (400–500°C) emitting CO2 and HF gases or alkaline pre-treatment (96°C). An alternative method consist on a thermal activation step at 400°C followed by HCl leaching that reduce the release of fluorine but not carbonate [23]. Until now only one attempt has been made to leach biologically bastnaesite minerals. Four actinobacterial strains were able to leach REEs from a bastnaesite-bearing rock and bastnaesite reaching. a total REEs concentration that ranged from 56 to 342 μg/l when grew in a nutrient-rich medium. Only the strain Streptomyces sp. grew in an oligotrophic medium in the presence of the bastnaesite-bearing rock and bastnaesite, leaching 548 μg/l of REEs. The leaching efficiency of total REEs was very low (0.008–0.08%); however, this amount should be due to the REEs precipitation and/or sorption onto residual rock and cell surfaces. Several molecules, such as organic acids, complexing ligands, and siderophores secreted by the actinobacteria, are involved in the mechanism of REEs bioleaching from bastnaesite-bearing rock [13].
Xenotime is a phosphate ore and its content of yttrium is high and the presence of other light rare earths is low. Furthermore, the composition of xenotime is very complicated containing large amount of tungsten and other impurities such as iron and silicon. Generally, xenotime is more difficult to decompose than monazite and the mineral has been treated using concentrated sulfuric acid, alkaline solution at elevated pressure, fusing with molten caustic soda, and mixing with sodium carbonate and roasting [24]. These technological difficulties are probably linked to the fact that there are no biological approaches for REEs leaching from xenotime yet.
Monazite is also a phosphate mineral and is the major commercial source of cerium. Alkali treatment is also used for monazite dissolution and the phosphate is recovered as a marketable by-product, trisodium phosphate, by using caustic soda at high temperature and high pressure.
The bioleaching of REEs has been developed especially on monazite using microorganisms able to dissolve phosphorous from inorganic rocks, named phosphate solubilizing microorganisms (Figure 2). Numerous organisms including bacteria, fungi, actinomycetes and algae mobilize insoluble phosphorous. Bacterial species belonging to the genera
SEM image of phosphate solubilizing bacteria grown on monazite.
Bacteria such as
Several fungal strains able to solubilize phosphate minerals have been also used to leach monazite releasing rare earth elements to the aqueous phase, such as
The fungus
Not only heterotrophic but also autotrophic bacteria has been used for the treatment of monazite. The bioleaching of REEs using
Previous works have determined remarkable alterations in the natural microbial populations during bioleaching of monazite ores. The existence of native
There are a number of mechanisms explaining the inorganic phosphate solubilization. The main mechanism is the production of biological dissolving compounds such as organic acids, siderophores, extracellular polymeric substances, protons, hydroxyl ions and CO2.
The production of organic acids leads to the chelation of cations with their carboxyl and hydroxyl groups and/or to the reduction of the pH releasing phosphorous. The decrease of the pH results in the release of phosporous by substitution of H+ for cations in the rocks [36]. Nevertheless, there is no correlation between pH and the concentration of solubilized phosphate and the cation assimilation is also required in the process [37] or the action of the H+ traslocation ATPase [38].
Gluconic acid is the most common organic acid involved in the mineral phosphate solubilization. This acid is generated by bacteria by direct oxidation of glucose and chelates the cations bound to phosphates [3]. Microorganisms not only produce organic acids but also inorganic acids and siderophores; however, these mechanisms are less effective in the release of phosphorous.
Extracellular polymeric substances have an indirect impact on phosphate solubilization due to their ability to bind metals influencing solubility of metal phosphates in soil. However, further investigation is needed to elucidate the role of high-molecular-weight polysaccharides in phosphate mobilization [39, 40].
Microbial phosphate solubilization can also take place through the liberation of enzymes like phosphatase or phosphohydrolase, phytase, phosphonatase, and C–P lyase. For example, phosphatase enzymes transform high-molecular-weight organic phosphate into low-molecular-weight products by the hydrolysis of ester phosphate bonds, releasing phosphate ions [41].
Despite of the recent work performed in this field, the selection of novel strains and a deeper study of bioleaching mechanisms is required to optimize the extraction of REEs. Biotechnology advances could have a key role in the development of cleaner strategies for the recovery of REEs.
Base metals as well as precious metals recycling have achieved high rates; however, the recycling rates of REEs are still very low (<1%). The low recycling of REEs can be explained by different factors, such as technological difficulties, low toxicities of the REEs, and, until few years ago, low prices and lack of incentives. The technological issues of the recycling of rare earths are due to the low concentrations of these elements in consumer goods.
The growing generation of industrial and electronic wastes and its significant content in critical metals has become these materials in an alternative economic source for the recovery of REE. Recently, secondary sources of REE including industrial wastes, mine wastes, and electronic wastes are being treated using bioprocess technology for the metal recovery. Nevertheless, bioleaching studies of REEs extraction from wastes are yet in their infancy.
Among REE-bearing industrial residues, phosphogypsum is worthy to be mentioned. REEs are often associated with phosphate deposits and phosphogypsum wastes are generated during the wet phosphoric acid process from fertilizer production in large amounts (100–280 Mt per year) with an estimate of 21 Mt of REEs locked into the total of phosphogypsum wastes accumulated to date [2]. A biolixiviant produced by the growth of the bacterium
Other important waste material as REE resource is the red mud from the digestion of bauxites in the Bayer process. According to estimates, about 2700 Mt of red mud residues have been accumulated in Bayer plants all over the world and its generation increases at a rate of 120 Mt per year [43]. These residues are harmful due to its alkalinity, but also are rich in valuable rare earth metals as to be economically treated. Scandium represents about 95% of the economic value of the REEs present in red mud containing between 130 and 390 ppm [44].
Spent cracking catalysts are solid wastes generated in large amounts in oil refining and biocombustible industries. It is estimated that 700,000–900,000 tons of spent fluid catalytic cracking catalyst per year are generated worldwide and the management of this waste and the recycling of rare earth metals have become a challenge [47]. Cerium and especially lanthanum are the main REEs present in cracking catalyst. Cell-free culture supernatants of
Bioleaching of spent cracking catalysts using the fungus
The recovery of REEs from fluid catalytic cracking spent catalyst by biochemical processes using
Compact fluorescent lamps contain on average glass (88 wt.%), metals (5 wt.%), plastic (4 wt.%), lamp phosphor powder (3 wt.%) and mercury (0.005 wt.%). The lamp phosphor fraction contains about 10% of rare-earth phosphors bound in the triband dyes [52]. Consequently, owing to the presence of REEs along with mercury, the disposal of lamp phosphors not only would lead to loss of resources but also to environmental hazards. Some countries collect great amounts of fluorescent phosphors as a distinct fraction from the recycling of fluorescent lamps (175 tons per year in Germany) and thus it is suitable as a secondary resource of REEs.
The most common rare-earth phosphors in these lamps are: Y2O3:Eu3+, LaPO4:Ce3+, (Gd,Mg)B5O12:Ce3+,Tb3+, (Ce,Tb)MgAl11O19 and BaMgAl10O17:Eu3+ [52] and it is possible to dissolve these REE-compounds through microbial processes (Figure 3).
SEM image of the fungus
A symbiotic mixed culture from tea Kombucha, consisting of yeasts and acetic acid bacteria, was used to leach REE from fluorescent powder. The highest leaching yields were achieved using the entire Kombucha-consortium or its supernatant as leaching agent compared to experiments using the isolates
Other study tested a broad spectrum of different microorganisms to evaluate their potential to dissolve REE from the lamps residues. Larger amounts of REE were leached with the strains
The phosphor powder solubilization is probably linked to the carboxyl-functionality or a proton excess. Among the different REE components preferably the red dye Y2O3:Eu3+ was shown to be preferentially solubilized in accordance with the higher solubility of REE-oxides compared to REE-phosphates and –aluminates.
Electronic wastes are discarded devices that are at the end of their economic use and cannot be utilized by consumers anymore. The total global e-waste generation in 2021 is expected to achieve 52.2 Mt. The biggest economic interest is focused on gold with 50% of the possible revenue, but e-wastes contain other metals in significant amounts and still worth to be recovered. Investigations on bioleaching associated to printed circuit boards (PCB) recycling has mostly centered on copper and gold recovery. Ferric iron generated by iron-oxidizing bacteria is involved in copper extraction. Cyanogenic bacteria or fungi have been tested to recover gold from e-wastes [55]. Nevertheless, these processes need to be upscaled and optimized. Recently, a two-step reactor has been developed to separate the production of biogenic ferric iron from the valuable metals leaching reaction achieving a 96% recovery of Cu [56]. Many e-wastes contain magnets with an important amount of REEs, 20–30%. The content of Nd, Dy, and Pr in NdFeB magnets is 259.5, 42.1 and 3.4 ppm, respectively [57].
The growing demand and applications of REEs in many fields lead to an increasing generation of industrial and electronic wastes. Thus, these materials become an alternative economic for REE recovery due to mineral scarcity and the environmental degradation, and the developments in bioprocess technology have a key role in sustainable mining for the green economy.
Rare earth elements possess unique properties that make them useful in a wide variety of applications, such as catalysts, magnets, batteries, phosphors and polishing compounds. Consequently, the demand of these elements is growing and the REEs extraction become an important issue. Biohydrometallurgy is a potential technological solution to conventional chemical processes that employ corrosive reagents with harmful effects on the environment. Bioleaching for the extraction of rare earth metals from mineral ores and industrial wastes can be performed by autotrophic and heterotrophic microorganisms, although the phosphate solubilizing microorganisms have been especially investigated. Several mechanisms are involved in the mobilization of REEs: organic acids, enzymes, bacterial attachment, phosphate regulation, siderophores… Moreover, the application of biotechnological strategies to the treatment of solid wastes might contribute to maximize the amount of resources minimizing the amount of tailings or residues that exert a harmful impact on the environment. Bioleaching of REEs is in its infancy, but the development of global market and the environmental policies as well as the appearance of new drivers such as synthetic biology and digital revolution could influence the evolution of biohydrometallurgy.
This work was supported by the Complutense University of Madrid (project PR75/18-21576).
The authors declare no conflict of interest.
The role of the autonomic nervous system (ANS) and its organ-specific functions have, in large part, been elucidated. Analysis of heart rate variability (HRV) is a popular tool for the assessment of autonomic cardiac control. Small periodic fluctuations in heart rate are well known to physicians and scientific investigators. Because these fluctuations are caused by the varying activity of the ANS, an examination of HRV is needed to obtain information about the functional status of the ANS. Heart rate and changes in heart rate are sensitive indicators of ANS function; therefore, cardiovascular autonomic regulation is considered to be the most reliable indicator of ANS activity.
HRV describes the beat-to-beat variation in heart rate and is used to quantify the interplay between the sympathetic and parasympathetic divisions of the ANS. Although patterns of HRV demonstrate considerable promise for clarifying issues in clinical applications, the inappropriate quantification and interpretation of these patterns may obscure critical issues or relationships, and may impede—rather than foster—the development of clinical applications [1].
HRV analysis, which supports the evaluation of successive RR intervals using electrocardiographic (ECG) methods, has been a powerful tool in the assessment of autonomic cardiac control [2]. For example, in humans, reduced HRV is associated with an increased risk for ventricular arrhythmia and has been shown to be an independent prognostic factor for mortality in patients with cardiac disease(s) [3, 4]. On the other hand, some studies have demonstrated that analysis of HRV spectral performance in rats is an ineffective method for detecting heart-related autonomic control disorders in some experimental models of myocardial infarction or diabetic neuropathy [5, 6, 7].
The ANS is an important control system that affects the function of many organs, and its activity is affected by various factors, including age [8], sex, and internal processes, such as circadian rhythm and hormonal fluctuations that slowly rise and fall over the course of 24 h. Circadian fluctuations in HRV parameters in rats were confirmed in a study by Hashimoto et al. [9], who reported that sympathetic nerve activity predominates in the dark phase. The ratio of low frequency (LF) to high frequency (HF) demonstrated a nocturnal pattern, and the value in the dark phase was significantly higher than in the light phase. In 2001, Hashimoto et al. [10] extended the monitoring of circadian rhythmicity in HRV to diabetic rats. Although diabetic autonomic neuropathy modifies circadian rhythms in HRV in diabetic WBN/Kob rats, in healthy nondiabetic Wistar rats, significant light–dark (LD) differences were detected in some of the monitored HRV parameters. In both age-different and pre-diabetic Wistar and diabetic WBN/Kob rats, no LD differences were found in the LF parameter of HRV; however, significant LD differences in the HF parameter were detected, except in older diabetic rats. Significant LD differences were found in the LF/HF ratio, but only in prediabetic Wistar rats.
In a telemetry study, Mamalyga [11] described fluctuations in ANS activity during a 24 h period, in which the control groups of male rats exhibited the greatest predominance of sympathetic activity between 12:00 h and 24:00 h. Similarly, in this time range, the LF parameter and LF/HF ratio exhibited higher values, and the HF parameter of HRV exhibited lower values. Analysis of multiday ECG recordings demonstrated the predominance of different mechanisms of heart rhythm regulation in experimental and control rats over a 24 h period. More severe dysfunction of neuroautonomical mechanisms of regulation in experimental rats was reflected in circadian dynamics. Further evidence supporting the existence of circadian rhythms in ANS activity was obtained in a study by Hsieh et al. [12], who monitored various physiological signals after implantation of sensors into the abdomen of rats and were recorded without interruption for >10 days. There was no difference in sleep/wakefulness patterns, physical activity, body weight, and autonomic functioning assessed according to HRV among control, sham, and experimental rats. Continuous recording further revealed circadian rhythms in HRV parameters, namely a 24 h cycle in RR intervals, the total power of HRV, and HF and LF powers of the RR spectrum. As such, we believe that this information may be useful in future biobehavioral studies.
In common practice, experiments are performed during “regular” working hours, even after the synchronization of rats to the LD cycle (12 h:12 h). Although this synchronization is often described in the methods section of these studies, the time of day when the experiments are performed is not reported. Therefore, it is assumed that the experiments are performed during the day (i.e., during the light) and, thus, on “sleeping” rats in their inactive period of the regimen day. However, the question is, what are the reactions of animals in their active period if there are fluctuations in the functions of individual systems in both sexes? Is there alternative reactivity of these systems, or is there a uniform reaction in both sexes? Therefore, if sex differences in the results of various experimental studies are documented, it is necessary to respect this fact. As such, future studies should decode these questions and try to include females in experiments whenever possible.
In the planning stages and design of
However, approaches based on ECG recordings of animals in an anesthetic state are not ideal nor valid for HRV analysis due to significant heart rate fluctuations associated with impaired autonomic modulation of the heart [13, 14]. In addition, anesthesia may contribute an important additional risk for animal mortality under some pathological conditions such as myocardial infarction and diabetes mellitus [15, 16, 17]. General anesthesia weakens autonomic function and baroreflex control. This side effect should be avoided as much as possible because it limits the ability of the subject to respond to physiological challenges during surgery [18]. Therefore, any research intervention that could affect aspects of the ANS and its impact(s) on internal organs should take into account the anesthetic used. Intravenous anesthetics may have different qualitative and quantitative effects on the peripheral ANS and, thus, may alter the activity of the sympathetic or parasympathetic divisions of the ANS.
In the vast majority of experimental studies, only male rats are used; however, there is also the other sex (i.e., female), in which differences may already exist in the very essence of the monitored functional system and exhibit a different response to interventions. At the same time, the study of sex differences is a driving force for development and, in many cases, the basis of health and medicine. However, there are opinions that the investigation of sex differences is ineffectual and does not merit extensive research [19].
Although there are several reasons why female animals are omitted, the primary rationale is simple—males and females are biologically different. Among other reasons, some scientists consider males to be representative of humans and differences from male norms are considered to be atypical or abnormal. Others attempt to “protect” females from the adverse effects of various interventions [20]. Still, others generalize findings from males and females, regardless of differences and, generally speaking, most scientists use male rats because they want to avoid accounting for hormonal cycles in females, which may reduce the homogeneity of the study population and affect the impact of experimental interventions [21]. When females are included in experiments, two problems arise—the sample size is effectively halved—the economic aspect; and the dispersion of results increases. One explanation for the increased variance is the simple fact that males and females are different and these differences increase the range of variability. However, if males and females are mixed, scientists may find a beneficial effect of a tested drug, for example, that lowers blood pressure, in both sexes [19]. On the other hand, on obtaining results from
As such, whether to acknowledge sex differences in
These data support the concept that sex-based variations should also be taken into account, given that females in human and animal studies exhibit different mechanisms of cardiovascular regulation [29]. Although these data suggest that if there are sex differences in individual cardiovascular parameters, they are predominantly regulated by the ANS. Logically, therefore, if sex differences exist in cardiovascular activities, sex differences in the circadian oscillations of individual divisions of the ANS must also exist in parallel.
The aim of the present study was not to downplay or critique the excellent and valid results of experimental
The present study conformed to the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (publication number 85–23, revised 1996). The study protocol was approved by the Ethics Committee of the Medical Faculty of Safarik University (Kosice, Slovak Republic; permission number 2/05 and permission number ŠVPS SR: Ro4234/15–221).
The experiments were performed using Wistar albino rats (weight, 340 ± 40 g, 3–4 months of age) acquired from a breeding and vendor company (VELAZ, Koleč, Czech Republic, certificate number 70029/2013-MZE-17214), with veterinary registration number CZ 21760118.
The animals were quarantined for 2 weeks in the Laboratory of Research Biomodels of the Medical Faculty of Safarik’s University in Košice (official number SK UCH 08018) and adapted to an LD cycle (12 h light:12 h dark [intensity of constant artificial illumination during the light period, 80 Lux]); 40–60% humidity; cage temperature 24°C; two animals/plastic cage for 4 weeks. The rats were fed a standard pellet diet, with
Anesthesia (zoletil, 30 mg/kg, Virbac, France) was administered in prescribed doses in the adaptation room by intraperitoneal injection based on the weight of the animal. After testing the effect of anesthesia (loss of uprighting reflexes, reaction to painful stimulus), the animals were transferred to the operating room, where they were fixed to an experimental table on which subcutaneous electrodes were used to record ECG and HRV. Again, the depth of anesthesia was assessed depending on whether the painful stimulus caused noticeable motor movements (minimal limb movement and muscle tension change) or cardiovascular responses such as changes in heart rate or onset of heart rhythm disorders.
The effect of the light period on the monitored parameters was examined after adaptation to an LD cycle, with the light period from 06:00 h to 18:00 h. The effect of the dark period was monitored after adaptation to the inverse setting of the LD cycle (i.e., with the light period from 18:00 h to 06:00 h). The animals were randomly divided into four experimental groups (n = 20 each) according to sex and light conditions—group 1, female (light period); group 2, female (dark period); group 3, male (light period); and group 4, male (dark period). In
HRV was analyzed using the ID Instruments computer system for biopotential recording from an average of 220 heart cycles, 20 minutes after administration of anesthesia at 09:00 h—12:00 h using separate animals. In analyzing HRV parameters, the focus was on the evaluation of RR interval duration spectral power at very-low-frequency (VLF, 0.003–0.04 Hz), low-frequency (LF, 0.04–0.15 Hz), and high-frequency (HF, 0.15–0.4 Hz), total spectral power of HRV, and the LF/HF ratio. The experiments were performed throughout the year and the results were averaged independently of the season and, in females, independently of the estral cycle. All animals (i.e., 20/20) were included in the statistical analysis. Before and after administration of the anesthetic, as well as during measurement, there were no adverse events or unexpected changes in HRV or ECG parameters, although considerable variability was observed. On completion of the measurement, the animals were transferred to the animal facility.
Data are expressed as mean ± standard deviation (SD). Data were analyzed using InStat (GraphPad, San Diego, CA, USA). The Tukey–Kramer test was used to compare data from the groups, and differences with p < 0.05 were considered to be statistically significant.
Evaluation of the RR interval can sometimes be problematic because different effect(s) of the anesthetic on this parameter has been described. The data reported in Table 1 indicate values of the duration of the RR interval from telemetry studies and under different types of general anesthesia according to sex and dependence on the LD cycle (Figure 1).
Light period | Dark period | |||
---|---|---|---|---|
Anesthesia | Female | Male | Female | Male |
Telemetry studies | 168.7 (167.3–170.1) (n = 1) | 163.2 (157–168.5) (n = 2) | 140.2 (139.5–141) (n = 1) | 145.9 (142.6–149.2) (n = 2) |
Pentobarbital | 177 (174–180) (n = 1) | — | 165 (163–167) (n = 1) | — |
Ketamine | 271.1 (231.5–310.7) (n = 2) | — | 213.1 (194.1–232.1) (n = 2) | — |
Tribromoethanol | — | — | — | — |
Thiopental | — | — | — | — |
Urethane | — | — | — | — |
Zoletil (Present study) | 142.30 (117.1–167.5) | 145.05 (136.5–153.6) | 134.97 (125.9–144.1) | 124.68 (119.5–129.8) |
Duration of RR interval from telemetry studies and for different types of general anesthesia according to sex and dependence on the light–dark cycle.
Data presented as the average RR interval duration (ms) (range); (n, number of experiments from which RR interval was evaluated).
Distribution of average values and ranges of RR intervals from telemetry studies and under different types of general anesthesia in male rats, without specification of synchronization to the light–dark cycle or the time of day when the experiments were performed. Tel – Telemetry studies (168.5(165.6–171.5), n = 3) [
Baseline RR interval analysis from telemetry studies [9, 7, 27, 30, 31] involving male Wistar rats, in which a chronobiological approach was applied, indicates that there is a circadian rhythm in the duration of RR intervals in rats, with a lower RR interval duration during the active (i.e., dark) period of the regimen day. Although adaptation of animals to the LD cycle was described in these articles, exactly what time of day the measurements were performed was not reported, nor whether they were average values from the entire 24 h period or only from certain time intervals the measurements were performed and recorded. The averaged results of baseline RR interval duration indicate that sex differences are exhibited in both the light and dark period of the rat regimen day; however, more experimental studies are needed to confirm this conclusion.
When comparing the duration of the RR interval in male rats from telemetry studies, it is clear that the shorter duration occurred during the dark period, which corresponds to a higher heart rate. Under zoletil anesthesia, a shorter RR interval was found in both light phases of the rat regimen day compared with values from telemetry studies, indicating a tachycardic effect of this anesthetic. The shortened duration of the RR interval corresponded to increased heart rate in both sexes in both lighted periods of the regimen day. Among females, LD differences were not observed in the duration of the RR interval (light, 142.30 ± 25.19 ms vs. dark, 134.97 ± 9.09 ms), in contrast to males, in which a significantly (p < 0.001) longer RR interval was recorded during the light part of the day (light, 145.05 ± 8.51 ms vs. dark, 124.68 ± 5.14 ms). Sex differences were found only in the dark (i.e., active) part of the day, with significantly shorter RR intervals in males. On the other hand, significant LD differences were maintained in males but eliminated in females. Addtitionally, compared to values reported in telemetry studies (Table 1), the RR interval was shorter, indicating a higher heart rate.
Our results, therefore, indicate that in zoletil-anesthetized rats, LD differences were maintained only in males but not in females. Considering the results of telemetry studies by Molcan et al. [50, 51], heart rate exhibits a significant circadian rhythm in non-anesthetized rats, in which the heart rate in the dark period fluctuated from 347 beats/min to 363 beats/min, and from 309 beats/min to 321 beats/min in the light period. Thus, it appears that although zoletil exerts a tachycardic effect, it can eliminate―or, at least modify―the circadian rhythm of heart rate, but only in females.
Such elimination or modification of LD differences in heart rate among females may also be partly explained by the greater sensitivity of females to acidosis, hypoxia, and hypercapnia under general anesthesia [52]. Previous studies have described the effect of hypoxia on the modulation of daily rhythmicity [53, 54, 55, 56, 57]. The fact that hypoxia modifies circadian oscillations of important variables, such as body temperature and metabolism, can lead to the expectation that the rhythms of many functions are interrupted by hypoxia on the basis of their relationship with the primary variables. Such a relationship likely contributes to a greater parasympathetic effect(s) on the heart [58]. Additionally, the effect of anesthetics can contribute to the loss or modification of rhythmicity. For example, in female rats under pentobarbital anesthesia, parasympathetic activity increases and sympathetic and baroreflex activity decreases; however, LD differences in heart rate are eliminated. Under ketamine/xylazine anesthesia, a preference toward parasympathetic activity was increased and sympathetic and baroreflex activity was depressed, resulting in significant bradycardia but with the maintenance of LD differences [59].
The paradox, under ketamine/xylazine anesthesia, therefore, remains—on the one hand, there is clearly evident increased parasympathetic activity and, on the other hand, increased heart rate. This paradox has been described by several authors [60, 61, 62, 63, 64, 65], who assumed that stimulation of the vagal nerve releases catecholamines, which in turn can affect heart activity. This is also probably the case with zoletil anesthesia, which may have a similar effect on the release of catecholamines through higher parasympathetic activity, and is particularly evident in males in both light periods of the regimen day. Because sympathetic tone is significantly reduced and parasympathetic tone dominates, it is assumed that the duration of RR intervals is predominantly determined by the parasympathetic system.
Despite the large variation in HRV spectral powers under zoletil anesthesia, in terms of sex differences, parasympathetic activity dominated in both sexes and in both light periods. In terms of sex differences, female HRV was significantly lower compared to males in the light period, while in the dark part of the regimen day, it was, in contrast, significantly higher in females compared to males (Figure 2).
Representation of heart rate variability (HRV) spectral powers in a rat model under zoletil anesthesia in both sexes. VLF – Spectral power of the very low frequency of HRV; LF - spectral power of the low frequency of HRV; HF - spectral power of high frequency of HRV; TSP – Total spectral power of HRV. Yellow columns – Light period of the rat regimen day; blue columns – Dark period of the rat regimen day.
Sympathetic activity dominates the normal life cycle of rats [7, 65] and zoletil anesthesia increases parasympathetic activity in both sexes. Similar results have been reported in previous studies. Administration of the anesthetic agent tribromoethanol in male Wistar rats [66], ketamine hydrochloride and diazepam in albino Wistar rats [67], and ketamine/xylazine and pentobarbital in females [59] resulted in predominant parasympathetic activity. However, our results indicate that precisely defining changes in HRV are difficult due to significant variability, which in turn makes it difficult to attribute sex differences. Thus, we agree with the opinion described in the introduction that approaches based on ECG recording under general anesthesia are not fully valid for HRV analysis.
In males under zoletil anesthesia—spectral power of HF (parasympathetic activity, r = 0.96) during the light and dark periods of the regimen day, spectral power of LF (baroreflex activity, r = 0.95), but also spectral power of HF (parasympathetic activity, r = 0.81) significantly contributed to changes in the total spectral power of HRV. Sympathetic activity is practically not involved in the formation of the total spectral power of HRV. The participation of individual spectral powers, as well as the total spectral power of HRV in the duration of RR intervals, is minimal in both lighted periods of the rat regimen day (Table 2). After analysis of the dependence of the duration of RR intervals on the total spectral power of HRV, we came to the conclusion that the duration of RR intervals (i.e., heart rate) is not regulated by the ANS in both light periods of the rat regimen day. We assume that other mechanisms are likely involved in the regulation of heart rate and are activated by zoletil.
Variable | Sex, light cycle | |||
---|---|---|---|---|
Female, light | Female, dark | Male, light | Male, dark | |
RR-VLF | r = 0.34 | r = −0.13 | ||
RR-LF | r = 0.26 | r = −0.12 | ||
RR-HF | r = 0.37 | r = 0.20 | r = 0.06 | |
RR-TSP | r = 0.28 | r = 0.06 | ||
TSP-VLF | r = 0.05 | |||
TSP-LF | ||||
TSP-HF |
Correlation coefficients of RR interval duration between spectral powers of heart rate variability (HRV) and the share of individual spectral powers in changes in the total spectral power of HRV.
Bolded values indicate statistically significant dependence between single parameters. VLF – spectral power of the very low frequency of HRV; LF - spectral power of the low frequency of HRV; HF - spectral power of the high frequency of HRV; TSP – total spectral power of HRV.
In female rats under zoletil anesthesia, the spectral power of LF (baroreflex activity, r = 0.99) and spectral power of HF (parasympathetic activity, r = 0.92) contributed significantly to changes in the total spectral power of HRV during the light period of the day and during the dark period proportionally in all three spectral powers of HRV. Sympathetic activity in both lighted periods was involved in the formation of the total spectral power of HRV in females (Table 2). After analysis of the dependence of the duration of RR intervals on the total spectral power of HRV, we found that the duration of RR intervals (i.e., heart rate) was under the regulatory influence of the ANS in both lighted periods of the rat regimen day (light, r = 0.51; dark, r = 0.61) with proportional representation of all three spectral powers of HRV.
We conclude that there are sex differences in the total spectral power of HRV in zoletil-anesthetized Wistar rats. In the light period in females, HRV was significantly lower than in males, and vice versa in males in the dark period of the regimen day. This means that, in females, the myocardium may be more sensitive to ANS regulatory interventions in the dark versus the light period. It is generally accepted that decreased HRV is a predictor of myocardial infarction mortality and increased HRV is associated with decreased morbidity and mortality. From this point of view, in zoletil-anesthetized female Wistar rats, during the active (dark) period, there is greater electrical stability in the myocardium than during the inactive (light) period. On the contrary, in males, the heart more sensitive reacts to changes in ANS activity in the light versus the dark period of the regimen day.
In females, changes in HRV were the result of sympathetic (i.e., VLF) and baroreflex (i.e., LF) activities and, in males, parasympathetic (i.e., HF) activity dominated. Among females, changes in RR were primarily due to changes in HRV, whereas in males, changes in HRV had no effect on RR in both lighted parts of rat regimen day. The results of these studies show that not only sex—but also the time of day experiments are performed—also plays an important role [68]. However, supportive evidence of HRV changes in rats during a 24 h period is lacking.
The LF/HF ratio can be used to quantify the changing relationship between sympathetic and parasympathetic nerve activity (i.e., sympathetic-vagal balance) [69, 70, 71]. The exact interpretation of the LF/HF ratio also depends on the assumption that physiological interventions always cause mutual changes in parasympathetic and sympathetic activity.
Our results demonstrate that the LF/HF ratio depends on the light periods of the regimen day. In females in the light period, the LF/HF ratio was significantly higher and in the dark period, significantly lower than in males. These conclusions, however, should be interpreted with caution. In a study addressing the meaning of HRV examination, Billman [72] questioned the evaluation of the LF/HF ratio. The LF component of HRV does not provide a cardiac sympathetic response index, but rather reflects a complex and not a readily recognizable mixture of sympathetic, parasympathetic, and other unidentified factors with parasympathetic factors, which account for the largest part of the variability in this frequency range. As a result, it is difficult to recognize the physiological basis for LF/HF. In addition, a relatively large amount of data suggests that the spectral power of the HF component cannot be attributed solely to changes in cardiac vagal efferentation, further compromising the accurate interpretation of the LF/HF ratio [72].
In
Based on our results, we conclude that under zoletil anesthesia, sympathetic (VLF) and baroreceptor (LF) activity were decreased, and parasympathetic (HF) activity was increased in both sexes and in both light periods. LD differences were preserved mainly in the HF component; thus, the circadian rhythm in parasympathetic activity likely also exists in both sexes. In terms of sex differences based on the total spectral power of HRV, our results suggest that HRV, in the light period of the rat regimen day, was significantly lower in females versus males. In the dark period, females exhibited higher HRV than males. In terms of LD differences, in females, HRV was lower in the light versus the dark period, unlike males, in which HRV was higher in the dark versus the light period of the rat regimen day.
The authors declare no conflict of interest.
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\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\n\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
\n\n1. CONFERENCE PAPERS & PRESENTATIONS
\n\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\n\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\n\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\n\n2. NEWSPAPER & MAGAZINE ARTICLES
\n\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\n\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\n\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\n\n3. GREY LITERATURE
\n\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\n\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\n\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\n\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\n\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\n\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\n\nFor more information on this policy please contact permissions@intechopen.com.
\n\nPolicy last updated: 2017-03-20
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