Frequency of iron deficiency (IDA) anemia in pregnant women.
\r\n\tThis book aims to offer readers a comprehensive understanding of ceramic materials. The detailed guidance provided in this book will help not only the students, researchers and professionals in the field of materials science and allied disciplines but the researchers and professionals in other fields.
\r\n\r\n\tThe book aims to provide the latest developments on the advanced ceramics and their latest applications in a wide variety of fields. The key features of this book intend to provide the reader with an understanding of how ceramics are applied, explores recent characteristics and properties of these materials, taking into account their structures and compositions, and discusses the various processing of ceramics.
\r\n\r\n\tThis book will rapidly become the reference work on the subject of ceramic materials.
",isbn:"978-1-83881-212-6",printIsbn:"978-1-83881-204-1",pdfIsbn:"978-1-83881-213-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"9adbe58d10d5ca2b61e9ff2b6b138f40",bookSignature:"Dr. Mohsen Mhadhbi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9894.jpg",keywords:"New Ceramics, Traditional Ceramics, Crystallography, Composition and Structure, Processing of Ceramics, Grain Size, Dislocations, Nanoindentation, Corrosion Cracking, YoungÃÂs Modulus, Mechanical Testing, Applications of Ceramics",numberOfDownloads:1106,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 29th 2020",dateEndSecondStepPublish:"August 5th 2020",dateEndThirdStepPublish:"October 4th 2020",dateEndFourthStepPublish:"December 23rd 2020",dateEndFifthStepPublish:"February 21st 2021",remainingDaysToSecondStep:"8 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Mohsen Mhadhbi is a reviewer and editorial board member of different scientific publishers and congresses, as well as a member of a number of international associations, to name a few: American Association for Science and Technology, International Association of Advanced Materials (IAAM).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"228366",title:"Dr.",name:"Mohsen",middleName:null,surname:"Mhadhbi",slug:"mohsen-mhadhbi",fullName:"Mohsen Mhadhbi",profilePictureURL:"https://mts.intechopen.com/storage/users/228366/images/system/228366.jpeg",biography:"Dr. Mohsen Mhadhbi obtained his Ph.D. degree from the Faculty\nof Sciences of Sfax, Tunisia. He is currently Assistant Professor\nof Chemistry in the National Institute of Research and Physical-chemical Analysis, Tunisia. His research interests include\ninorganic chemistry, material engineering, intermetallics, and\npowder technology. He has published works in national and\ninternational impacted journals and books. He is a teacher in\ninorganic chemistry. He has supervised several researchers in materials science. 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Iron deficiency is associated with serious health problems such as impaired working capacity, weakness, malaise, headaches, cognitive impairment, decreased concentration or attention, etc. [1]. The lack of iron in the body can be due to inadequate intake, impaired absorption, increased needs and excessive losses. Inadequate intake of iron is often associated with a vegetarian (or vegan) diet, malnutrition or lack of iron in the diet. Same food with a predominant fat and sugar content, fast food, various diets used to maintain low body weight eventually lead to iron deficiency and/or anemia. In India, for example, about 30% of people are vegan; in Russia, this indicator is more modest—about 3–4%, as in most countries of Europe (Switzerland, Spain, Portugal, Poland, etc.). Impaired absorption of iron in the gastrointestinal tract (GIT) plays an important role in the development of iron deficiency and/or anemia. Diseases of the GIT are found in 20–24% of women of reproductive age [2]. Increased iron needs arise in children which is associated with their active growth. In adolescents, this is associated with an increase in the total mass of red blood cells and muscle mass. In young men, however, iron deficiency is less common than in girls, although their growth and growth rate are higher. In girls the high incidence of iron deficiency anemia is associated with the additional factor of blood losing during menstruation. Chronic blood loss and iron deficiency initiate in puberty if there is a disturbance of the development of menstrual function and they occur in a quarter of girls and adolescents [3]. Chronic repeated blood loss is the most common cause of iron deficiency anemia. The highest rates of iron deficiency are characteristic for women of childbirth age which is associated with monthly blood loss, pregnancy, parturition and lactation. A study conducted in 1998, by S. Kagamimori et al. has shown that 78% of Japanese schoolgirls have iron deficiency anemia (IDA) of varying severity 3 years after the onset of menstruation [4]. Women of childbearing age are at risk of developing IDA.
Many of them have chronic latent iron deficiency which remains undiagnosed for a long time as there are no expressed clinical symptoms and the body is well adapted to it. The content of iron and ferritin in the serum during pregnancy decreases as a result of an increase in the volume of plasma and an increase in total iron-binding capacity (TIBC), the percentage of transferrin is also reduced. Increased needs are only partially counter balanced by increased absorption in the intestine and mobilization of iron stores. If iron stores are partially or completely depleted at the beginning of pregnancy; which is observed with frequent and/or profuse menstruation, iron deficiency can be relative or absolute by the time of delivery. Up to 50–60% of women do not have enough iron reserves during pregnancy [5, 6] which is associated with adverse perinatal outcomes.
The data of Rosstat (2014) indicate that the number of women with abundant menstrual bleeding increased by 1.5 to 2 times in 10–15 years [26]. Women often do not consult a specialist for example, 59% of patients with heavy menstruation consider them normal and 41% are sure that they are not amenable to treatment [7]. Regular excessive loss of blood (more than 60–80 ml per cycle) disrupts the whole complex of physiological parameters, hemoglobin levels fall in erythrocytes and iron in plasma [8].
With physiological blood loss these changes are not observed. Adequate nutrition and a healthy lifestyle allow the body to independently restore the volume of blood and iron stores.
The consequence of monthly excessive menstrual blood loss with insufficient intake of iron is iron deficiency anemia which is confirmed by the following inferences [9]:
Patients with iron deficiency anemia lose a higher amount of menstrual blood in comparison with healthy women.
The users of hormonal contraceptives (even in the presence of a menstrual-like reaction), the iron content in the body is higher than in women who do not take estrogen-progestational agents and who have spontaneous menstruation.
With the purpose of revealing abundant menstrual flow (which causes IDA) the FIGO experts advice the gynecologist to ask their patients the following questions [10]:
How much bleeding is profuse?
Do you have to change the pads at night?
Do the protection pads completely soak in after 2 hours during the days of the most profuse bleeding?
Does menstrual blood loss affect the physical condition?
Do you observe the release of large clots of blood during menstruation?
Have you ever experienced any weakness or lack of air (symptoms of iron deficiency) during menstruation?
Does menstruation reduce the quality of life?
Does social life require correction in these days?
Are you worried about the unpleasant moments associated with bleeding?
The duration of more than 7 days and the volume of blood loss over 80 ml as well as the presence of related physical, emotional and other problems are the characteristics of profuse menstruation. Normal menstruation is inherent in the duration of 2–7 days, the amount of blood lost is 50–80 ml and absence of pain that would disrupt the habitual life or require the intake of medication.
Detection of frequent and/or abundant uterine bleeding for more than 6 months should initiate a patient’s examination for hemoglobin and other indicators of red blood cells. The greatest need for iron occurs during pregnancy and lactation. Iron deficiency or IDA leads to many numerical obstetrical complications primarily associated with metabolic disorders in the placental tissue.
In cases of iron deficiency during the first trimester of pregnancy, development of “defective” endometrium is observed which is facilitated by the initiation of intensive peroxidation of lipids in its cells followed by a change in the excitability of cell membranes and a decrease in the functional activity of the tissue. This leads to an inadequate implantation of the fetal egg. There is lack of proper rearrangement of the spiral arteries. This process is high energy-intensive and in IDA the cells lack oxygen sufficient for energy metabolism. Without reorganization of the uterine arteries, adequate fetal blood supply is impossible and primary placental insufficiency develops.
In the 2nd trimester, IDA in pregnant women leads to hypoxic disorders [11]. Circulatory disorders in the placenta and a lack of oxygen cause a failure of the second wave of trophoblast invasion. Hypoxia provokes the release of stress hormone cortisol which negatively affects the growth of the fetus. With further progression of pregnancy in iron deficiency, oxygenation of the blood worsens and total pathological disturbances occur in the tissues which affects the fetoplacental complex, fetal growth, pregnancy and parturition. A systematic review of “Maternal anemia and pregnancy outcomes in low- and middle-income countries” according to the scientific data of world-wide publications in 2016 found that anemia during pregnancy is associated with significantly higher risks [12]:
low birth weight (RR = 1.3);
premature birth (RR = 1.6);
perinatal mortality (RR = 1.5);
neonatal mortality (RR = 2.7).
The course of pregnancy in women with IDA inevitably affects the physical and psychomotor development of her child. Iron deficiency has a significant limiting effect on the brain’s potential due to the negative impact on morphological structures.
The nervous system will reach its morphological maturity only then the brain will be ready for full work [13, 14].
All the basic structures of the nervous system are built up in the first trimester [11]. At the 3rd-4th weeks after fertilization a neural plate is formed. During 4–7 weeks neural tube is developed from which the brain and spinal cord are subsequently formed. By the end of the 8th week from the anterior part of the neural tube are formed five brain vesicles that give rise to all the parts of the brain such as the cerebral hemispheres, pons and cerebellum, middle and intermediate brain and medulla. In 5–10 weeks differentiation of some parts of the brain develops the cortex and subcortical structures.
In the second and third trimesters of pregnancy the structures of fetal nervous system are more complex. The neuronal precursor cells and the neuroglia begin to differentiate. From the 20th week nerve centers are formed which ensure the functioning of the main vital organs and begin the myelination processes. Disturbances of neurogenesis due to iron deficiency significantly limit the potential of the brain in the future.
In the third trimester cells differentiate into neurons and glial cells (astrocytes, oligodendrocytes, ependymocytes) grow axons and dendrites of neurons, synaptic contacts are formed and neural processes intensively myelinate. Obviously there should not be any iron deficiency for the prevention of defective morphological and functional development of the brain [11]. The slowdown of energy metabolism in the brain in iron deficiency occurs for two reasons; the activity of iron-requiring enzymes decreases and the amount of oxygen supplied to the cells decreases the expenditure during the intensive development processes increases by a factor of 2.
The results of numerous studies indicate the following facts:
Mental and psychological development is particularly affected by iron deficiency during intrauterine growth and/or in the early years of postnatal life.
The consequences of iron deficiency are expressed in adulthood, preventing the full realization of the inherent genetic potential [14, 15, 16, 17, 18].
Children who lacked iron in utero or infancy compared with peers who did not lack iron in the subsequent years of life especially during the age 19–28:
lag behind in mental development;
suffer from mental disorders;
have delayed neuromotor development, difficult temperament (mettle);
are depressed and apathetic, more anxious;
suffer from attention deficit disorder combined with hyperactivity.
Analyzing the long-term studies (2012–2017) regarding the course of pregnancy in 321 women aged 19–45 years (continuous random sample) conducted at the Department of obstetrics and gynecology with the perinatology course of the Peoples Friendship University of Russia (Head of the Department, RAS Corresponding Member V.E. Radzinskiy) (Table 1) we found that there was no difference in the incidence of iron deficiency anemia among different age groups of women.
Age of women (years) | 19–24 | 25–29 | 30–34 | 35–39 | 40–45 |
Number of women (n) | 65 | 67 | 64 | 63 | 62 |
Frequency of IDA n (%) | 14 (21.5%) | 15 (22.4%) | 14 (21.9%) | 14 (22.2%) | 14 (22.6%) |
Frequency of iron deficiency (IDA) anemia in pregnant women.
р > 0.05 - the reliability of the differences is not revealed.
We also studied the frequency of iron deficiency anemia in women with preterm labor (PL). The subject of the study were 132 pregnant women who entered the maternity hospitals in Moscow to acquire medical assistance. Patients were divided into three groups: Group I - women with preterm labor at term of gestation from 22 to 27 weeks ± 6 days (n = 34); Group II - patients who gave birth prematurely at the gestation period of 28–37 weeks ± 6 days (n = 56) and Group III - women with term labor which constituted the control group (n = 42).
The greatest number of complications in all trimesters of pregnancy was observed in patients with PL including iron deficiency anemia (Figure 1). In the first trimester IDA was detected in 6 (17.6%) women with early PL and in 6 (10.7%) with PL at a period of 28–36/7 weeks in women who gave birth in time this complication was not observed. In the second trimester mild-to-moderate IDA was diagnosed in 9 (26.5%) of women who gave birth at the gestation age of 22–27/6 weeks, 15 (26.8%) gave birth within 28–36/7 weeks and 3 (7.1%) of women in the control group (p < 0.05). In the third trimester mild anemia was observed in group II in 15 (26.8%) women and in 4 (9.5%) between those who gave birth in time. Anemia or iron deficiency is one of the factors of unfavorable perinatal outcomes.
Frequency of iron deficiency anemia in the observed groups. *Reliability of differences was revealed when comparing women with premature and term labor (p < 0.05).
After giving birth the frequency of IDA increased most significantly in women with PL and in women with early PR it was found in 11 (32.4%) of them in patients with preterm labor at a term of 28–36/7 with a frequency of 18 (32.1%). Anemia was found less often in women with term delivery - 5 (14.3%). One third of the women who had premature delivery suffered from IDA and this is not only because anemia developed during pregnancy but also because in women with PL significantly more often the delivery was an operative route (cesarean section). In the group with early PL in 5 (14.7%) in the group with PL in the period of 28–36/7 in 17 (30.3%) and the smallest number 3 (7.1%) of CS was performed in women with term delivery.
The results of the study confirmed the opinion of Professor Serov V.N. (2009) that premature birth is the delivery of a sick child from a sick woman. Anemia was more often diagnosed in women with premature labor.
All women with anemia with both preterm and term (n = 34) delivery were examined by the end of lactation (the average duration was 1.8 ± 0.4 years). In the postpartum period they received both bivalent and ferric iron. The number of erythrocytes, hemoglobin level and serum ferritin were measured. In 14 women there were no clinical and laboratory signs of anemia and iron suppression was based on the results of normalization of serum ferritin. Twenty patients were stopped taking iron supplements in the postpartum period on the basis of normalization of hemoglobin and revealed iron deficiency anemia of mild degree after lactation (Table 2). When determining the level of hemoglobin in the blood (Hb) it was found that the average level varied from 92 to 109 g/l (101.2 ± 1.3 g/l). Women were examined by a gastroenterologist and physician and treatment was prescribed by a physician. In the observed group there were no patients with blood diseases, inflammatory diseases and autoimmune diseases. Ten (50%) women were diagnosed with diseases of the gastrointestinal tract which was a risk factor for iron absorption and 3 (15%) patients were diagnosed with excessive menstrual bleeding (hormone therapy was prescribed). After 30 days the number of erythrocytes and hemoglobin reached to normal level. Serum ferritin reached normal values by day 90 (Table 2).
Indicators | Initial indicators | In 30 days | In 60 days | In 90 days |
---|---|---|---|---|
Number of erythrocyte ×1012/l | 3.2 ± 0.3 | 3.9 ± 0.1* | 4.1 ± 0.2* | 4.2 ± 0.3* |
Hemoglobin content (g/l) | 101.2 ± 1.3 | 109.7 ± 1.1* | 113.5 ± 1.2* | 114 ± 0.9* |
Serum ferritin (fl) | 23.2 ± 1.1 | 27.3 ± 1.3* | 39.7 ± 1.2* | 52.1 ± 0.2* |
Indicators of “red” blood smear in women with mild anemia (n = 20) treated with Iron III hydroxide polymaltozate.
р < 0.05 in comparison with initial indicators.
In the reproductive age anemia is the most common extragenital condition leading to health problems, adverse perinatal outcomes and often associated with organic diseases of the uterus. The International Federation of Gynecology and Obstetrics (FIGO) classification [19] identified the structural and non-structural causes of abnormal uterine bleeding. The results of the work of world-class experts [20] stated that in Russia about 50% of uterine bleeding is due to organic diseases of the uterus. In comparison, in the USA, Canada, Brazil, Korea and China this reason was found in 34–44% of women. Identification and recovery of women with uterine leiomyoma in the pre pregnancy period as in 20–50% of women leiomyoma is the cause of severe, irregular and prolonged uterine bleeding, iron deficiency anemia is a reserve for reducing complications of pregnancy and adverse perinatal outcomes.
A prospective study conducted from 2010 to 2015 included 292 women with uterine leiomyoma in female residents of the Krasnodar Territory. Inclusion criteria to the study were: reproductive age, uterine fibroids, pregnancy planning. Exclusion criteria: extragenital diseases leading to anemia; lack of reproductive plans; pregnancy.
The average age of women was 31.2 ± 1.5 years. Clinical characteristics and anamnesis (the medical history of a patient) of women are presented in Table 3. The inhabitants of the city were more than 160 (54.8%) compared to the residents of the village 132 (45.2%). More often women with fibroids had secondary specialized education - 161 (55.1%). Equally women were registered - 144 (49.3%) and unregistered - 135 (46.2%) marriages. 13 (4.5%) patients were unmarried but they planned a pregnancy.
Parameter | Amount of women (n = 292) | |
---|---|---|
Absolute number | Relative number, % | |
Inhabitants of the city | 160 | 54.8 |
Inhabitants of the village | 132 | 45.2 |
Education | 125 | 42.8 |
Secondary specialized education | 161 | 55.1 |
Registered marriage | 144 | 49.3 |
Unregistered marriage | 135 | 46.2 |
Unmarried | 13 | 4.5 |
Clinical characteristics and anamnesis of women.
The study of the reproductive anamnesis (Table 2) revealed that 179 (61.3%) of women had a history of delivery, i.e. they planned a second or third child. Practically all women 275 (94.2%) had an anamnesis for an official abortion. At the time of the examination none of the participants used any reliable means of contraception (COCs, IUDs). 183 (62.7%) of women reported using interrupted sexual intercourse and condoms the remaining 109 (37.3%) planned a pregnancy so they did not use contraception.
The duration of uterine leiomyomas was 4.3 ± 0.2 (2–10 years). The main complaints of women planning pregnancy were bleeding in 201 (68.8%), pain syndrome in 161 (55.1%), disturbance of the function of neighboring organs in 135 (46.2%) and asthenic syndrome in 192 (45.5%).
The number of uterine fibroids per woman varied from 2 to 12 on average 5.4 ± 0.3 and the number differed depending on the localization of the node. Multiple uterine fibroids were found in 266 (91%) women. Subserous localization of leiomyomas was detected in 181 (62%) women, subserous-interstitial and interstitial - in 260 (89%) women. Submucous site localization was determined in 32 (11%) patients. The diameter of the largest fibroid node did not exceed 110 mm an average of 49.8 ± 18.4 mm (15–110 mm).
The average level of hemoglobin in the blood (Hb) varied from 82 to 145 g/l (116.2 ± 2.3 g/l). The lowest level of Hb was observed in women with a predominance of submucous localization of the nodes - 90.8 ± 1.6 g/l (82–99 g/l). Anemia was diagnosed in 158 (54.1%) women. Anemia of mild degree was detected in 79 (27.1%) women. Hemoglobin level in these women was in the range of 109–94 g/l (100.1 ± 0.7 g/l). Anemia of moderate severity was detected in 79 (27.1%) women, the hemoglobin level varied from 91 to 72 g/l (84.4 ± 1.1 g/l). All women experienced profuse menstrual and intermenstrual bleeding.
In 134 (45.9%) women anemia was not detected and the hemoglobin level was determined in the range of 120–145 g/l and averaged 127.5 ± 1.2 g/l. Outpatients with anemia were administrated with divalent (84 - 28.8% women) and ferric iron (50 - 17.1% women). The comparative characteristics of the drugs revealed the following: in the treatment of IDA saline iron causes severity and pain in the stomach in 10 (11.9%), nausea in 11 (13.1%), constipation in 18 (21.4%) and diarrhea in 6 (7.1%) of women.
The average period of preparation for surgery after the administration of iron supplementation was 82.3 ± 0.1 days. In all women with mild anemia (79 - 27.1%) regardless of whether they received two or three-valent iron, normal level of red blood cell values were found. Normalization of the indices was achieved in 8 (2.7%) women with concomitant anemia of medium degree. In 71 (24.3%) compensation indices were impossible due to excessive amount of bleeding. They had to undergo surgery with uncompensated indicators of red blood cells.
Uterine fibroids and polyps are an indication for surgical treatment and hysteroscopy. However, most abnormal and/or excessive amount of bleeding from the uterus requires medical therapy. The classification of FIGO [19] allows not only to determine the cause of abnormal and/or excessive amount of bleeding from the uterus but also to prescribe a therapy that helps to reduce blood loss:
Chronic abnormal uterine bleeding (AUB) is abnormal in terms of volume, regularity, and/or frequency of uterine bleeding during most cycles in the last 6 months. As a rule, this condition does not require immediate medical intervention.
Acute AUB is an episode of profuse bleeding in which the specialist has sufficient reason for urgent intervention in order to prevent further blood loss. It can occur against a background of chronic AUB or for the first time in life.
Intermenstrual AUB occurs between predictable periods of cyclic menstruation. FIGO experts recommend replacing the term intermenstrual abnormal uterine bleeding on the concept of metrorrhagia.
Classification of causes of AUB called PALM-COEIN relates the causes of uterine bleeding in women of reproductive age to one of the nine categories (Table 4). The first four, grouped in the PALM group can be identified visually (structural). The rest are not related to structural anomalies and objectification is not amenable (non-structural).
PALM (structural) | COEIN (non-structural) |
---|---|
Polyp Adenomyosis Leiomyoma Malignancy and hyperplasia | Coagulopathy Ovulatory dysfunction Endometrial Iatrogenic Not yet classified |
Classification of causes of abnormal uterine bleeding (FIGO, 2011).
Diagnostic measures for abnormal uterine bleeding include not only establishing the cause of bleeding and examination but also for the presence of anemia (hemoglobin level, hematocrit, general blood test).
Treatment of IDA in abnormal uterine bleeding cannot include only iron drugs as repeated blood loss will not lead to normalization of blood parameters. In cases of structural changes (polyps, fibroids) surgery is required. Non-steroid anti-inflammatory drugs (NSAIDs) have a high efficiency (blood loss on the background of NSAID intake decreases by an average of 58%), but it is not safe for the patient especially with prolonged use [8, 21]. The ability of NSAIDs to compensate uterine bleeding is due to inhibition of cyclooxygenase enzyme activity that leads to a decrease in the synthesis of prostacyclin that inhibits platelet aggregation. Tranexamic acid (synthetic lysine derivative) is an effective and a fairly safe drug which reduces blood loss by an average of 58%. The positive effect of tranexamic acid on the quality of life and sexual relations is reported [22, 23]. Contraindication to the administration of tranexamic acid is the presence of an episode of thrombosis. The mechanism of action of tranexamic acid is associated with reversible blocking of plasminogen and prevention of degradation of fibrin. Levonorgestrel-releasing intrauterine system (IUD-LNG) reduces menstrual blood loss by 74–97% [24]. During the first month with the use of IUD-LNG the duration of bleeding may increase. In adolescence IUD-LNG are not used since their mechanism of action is associated with endometrial atrophy.
Combined oral contraceptives (COCs) have a wide spread in reducing blood loss from the uterus. The effectiveness of COC is 43 - 88% [12]. Bleeding when using COC usually stops within 24 hours (the so-called hormonal hemostasis). The effect of COC is associated with the suppression of endometrial proliferation and the indirect reduction in the amount of blood loss.
The use of cyclic gestagens in the luteal phase are ineffective for the treatment of profuse menstruation, however they regulate the menstrual cycle [8]. Admission of medroxyprogesterone acetate (10 mg/day) or norethisterone acetate (2.5–5 mg/day) in a cyclic mode from the 16th to the 25th day provides a predictable bleeding profile.
Gonadotropin-releasing hormone agonists (GnRH agonists) are ineffective in the treatment of profuse menstruation. They are used only for certain indications as second line therapy [8]. These drugs completely block the function of the hypothalamic-pituitary-ovarian axis and cause amenorrhea in 89% of patients which is accompanied by severe side effects such as vaginal dryness, hot flashes, sweating, and with prolonged use (6 months or more) - osteopenia. The mechanism of action of GnRH agonists is associated with a decrease in the number of gonadotropin receptors in the pituitary gland with suppression of gonadotropin release and subsequent decrease in the level of estradiol to the state of hypogonadism.
For having a pregnancy with adequate iron reserves in the body it is extremely important that menstruating women of childbirth age do not experience a deficit in it. For the prevention of iron deficiency in this population in 2016 WHO (World Health Organization) updated the recommendations according to which iron drugs at a dosage of 60 mg/day should be taken to all menstruating women and adolescent girls for 3 months in the year and 3 months before conception. WHO experts recommend to use such preventive measures at the national level in countries where the incidence of anemia reaches 40%.
The optimal choice for women with iron deficiency (latent or already formed anemia), are oral drugs.
Bivalent iron drugs are ferrous sulfate, as well as fumarate, gluconate and glyceryl sulfate of iron.
Trivalent iron drugs are polymaltose complex of iron hydroxide, iron succinylate protein.
Preparations of two- and trivalent iron are comparatively effective but they have differences in tolerability and compliance.
In order to overcome the negative effects of salt iron and improve the tolerance an iron drug based on hydroxide of the polymaltose complex (HPC) was created which has advantages over iron salt drugs with high efficiency, safety, no risk of overdose, intoxication and poisonings and less dyspeptic complications. This allows us to recommend iron preparations based on the hydroxide of the polymaltose complex to women with IDA in their reproductive age [25]. Discontinuation of the treatment with iron drugs is indicated after the normalization of serum ferritin and replenishment of the iron storage.
Anemia in women of reproductive age is the most frequent extragenital disease. It impairs the quality of women life and in pregnancy, leads to complications of gestation (miscarriage, placental insufficiency, etc.) and adversely affects the growth and development of the fetus. Iron deficiency before conception will disrupt the formation of the nervous tissue (the brain), which is manifested by a decrease in intelligence, disturbances of psychomotor development and other abnormalities in the future. Often the cause of IDA or iron deficiency in women are the organic diseases of the uterus (polyps, fibroids) and functional disorders - abnormal and/or profuse uterine bleeding. Chronic iron deficiency as a rule remains undiagnosed for a long time as there are no expressed clinical symptoms and the body is well adapted to it. Therefore, role of the gynecologist in diagnosing anemia as well as revealing and treatment of gynecological diseases that led to IDA is important. All the iron drugs have the same efficacy but the fewest side effects (in gastrointestinal tract) have been in trivalent drugs which allows them to be recommended for the treatment of anemia in the reproductive age.
Chromium is a unique transition metal with relatively high abundance on earth crust (1.4 × 10−2%). Chromium can form several species with different oxidation states from −4 to +6. Chromium with 0, +3, and +6 oxidation states are most commonly found and utilized in ambient conditions [1]. In industrial sectors, chromium-based materials have been used as coating material for corrosion resistant, pigments and dyes, wood preservatives, tanning agent, catalyst, and medical apparatus [1]. Chromium, especially for chromium(III), also showed certain biological activity especially in regulating carbohydrates and lipid metabolism [2, 3]. As an essential micronutrient, a low dietary of chromium will exhibit several adverse effects such as glucose intolerance, growth disorders, diminished longevity, etc. [3, 4].
Chromium toxicity has been a controversial problem due to its status as an essential micronutrient [5]. Various studies have shown that numerous acute and chronic adverse effects can be caused by any dermal or systemic exposure of chromium species in human organ systems [6]. The toxicity and biological activity of chromium seem to be correlated directly with the concentration of corresponding chromium species [7]. In this case, chromium species have its optimum concentration to produce beneficial effects. Meanwhile, accumulation of less toxic chromium species in relatively high concentration will still produce a negative effect in the accumulation site [8, 9]. Chromium picolinate, for instance, has been mainly used as food supplement. Chromium(III) in this compound tend to accumulate in male Sprague-Dawley rats’ cells over the period of investigation [10] and may be oxidized to more carcinogenic chromium(V) and chromium(VI) within the cells [11].
As the outermost organ that protects the human body from various pollutants, the skin is usually exposed to various sources of chromium, and it causes many dermatological acute and chronic negative effects such as contact dermatitis [12], systemic contact dermatitis [13], and possibly skin cancer [14]. In the same way, any topical or systemic administration of chromium compounds also can exhibit a beneficial effect for the skin such as antiacne [15], rapid wound healing [16], and anti-aging [17]. In this chapter, both toxicity and biological activity of chromium species in the skin are described starting from the source and route of exposure, toxicity and its possible treatment, and biological activity.
In modern life, chromium has been used in many forms and applications with Cr(0), Cr(III), and Cr(VI) as the main oxidation states. Various sources of chromium that affect or may affect the skin have been identified and tabulated in several review [12, 18, 19]. In general, exposure route of chromium that comes from these sources can be classified into two pathways including dermal and systemic pathways. In these cases, direct dermal exposure would cause contact dermatitis, irritation, and skin cancer, while systemic administration would elicit systemic contact dermatitis and skin tumor.
Dermal exposure (Figure 1) is initiated from direct contact of chromium sources on the skin. Chromium species are then accumulated on the skin surface or penetrated into the skin layers mediated by sweat or other biological fluids. The penetration of chromium species either as particulate or soluble forms occurred via three possible routes including transcellular by crossing the cell, intercellular by partitioning into the lipid matrix, and transappendageal by entering hair follicle and sebaceous glands [20, 21]. There are many factors involved in the penetration process including concentration of chromium species, medium (solvent and pH), intrinsic properties of chromium species (molecular volume of chromium species, counter ion, nature of chemical bond and polarity, solubility, and valence), reactivity towards protein, previous penetration or accumulation, skin characteristics (gender and race, age skin, density of sebaceous gland, thickness of skin, and anatomy of skin), and environmental factors (temperature, humidity, and UV radiation) [21, 22]. In a normal skin condition, Cr(VI) ions tend to have higher solubility [23] and percutaneous permeability than Cr(III) ions [24, 25]. However, Cr(III) have higher protein affinity to form metal-protein complex which tends to make it retain in the skin epidermis [26]. After penetrating the skin, Cr(VI) species are reduced by proteins or endogenous antioxidants to form Cr(III) [27] which then react further with any DNA or protein to form Cr(III)-protein complex as the actual allergen (haptens) [28].
Several pathways of dermal exposure: (A) deposition of Cr(VI) in the skin surface causes irritation or chemical burn; (B) penetration of Cr(VI) through transcellular and intercellular pathways induces cell apoptosis and contact dermatitis, while Cr(III) tend to suspended in the skin surface due to strong affinity to skin protein; (C) deeper penetration to blood stream causes organ disruptions, (D) Cr species from systemic administration trigger systemic contact dermatitis, (E) deposition of Cr species on hair causes hair discoloration; (F) penetration of Cr species into hair follicle induces rapid hair fall. Figure is drawn using ChemBioDraw Ultra version 14.0 software.
In systematic exposure, chromium mostly enter the human body via oral consumption of certain chromium sources such as food or food supplement [29], foodstuff [30], and drinking water [31] or from applications of chromium-based implants [32]. In the digestive system, most of Cr(III) consumed are excreted to feces and some of it (~2%) is absorbed by epithelial cells covering the stomach and enterocytes covering the intestines through passive absorption (diffusion) [33]. This absorption was affected (increased or decreased) by the presence of various ligand such as amino acids, vitamins, carbohydrates, plasma proteins, certain metals, and other chelating agents [34]. After the absorption, Cr(III) complex would be accumulated inside the cells or actively transported to the blood stream by still an unknown transporter. Cr(III) ions then bound to transferrin (siderophilin) or other plasma proteins in the blood stream and travel to the whole body [33, 34].
Contact dermatitis is a common skin disease caused by repeated dermal contact with certain allergens (haptens) leading to delayed-type hypersensitivity effect [35]. Many haptens have been identified to cause contact dermatitis such as metals, fragrances, and flavors, preservatives, plastics, rubber, pharmaceutical, cosmetics, woods and plants, textile, etc. [35]. Chromium-induced contact dermatitis is characterized by the presence of certain clinical manifestations in feet and hands. Acute dermatitis is usually indicated by the formation of erythema, oedema, papules, vesicles, and weeping, while chronic dermatitis tends to form scaly, dry, and fissured skin [36]. Various chromium-induced contact dermatitis cases have been reported involving different chromium sources such as cement [37, 38], leather [38, 39, 40, 41, 42, 43], tattoo ink [44], cellular phone [45, 46], etc. Concentration threshold for soluble chromium in each chromium-containing product should not exceed 1 ppm to minimize elicitation of contact dermatitis [47].
In general, chromium-induced contact dermatitis is formed through several steps which can be described as the following (Figure 2) [48, 49]: initially, after penetrating the skin, Cr(VI) ions are reduced by endogenous antioxidant to form Cr(III) and oxygen reactive species (ROS). Cr(III) as the real allergen is bound to certain proteins to form the hapten, while ROS induces the releasing of interleukin-1β (IL-1β) which then activates antigen-presenting cells (Langerhans cells (LC)). Activated antigen-presenting cells bind with the hapten, mature, travel to the regional lymph nodes, and stay in paracortical T-cell areas. After that, activated antigen presenting cells-hapten complex activates naïve T cells by helping in vigorous blast formation and proliferation to become chromium-specific T cells. Activated chromium-specific T cells then travel through blood stream and recirculate to give hypersensitivity effect detecting a lower concentration of hapten in different parts of the skin.
Simplified elicitation mechanism of chromium-induced contact dermatitis adapted from several references [
Treatment of chromium-induced contact dermatitis could be conducted in several approaches including avoiding direct contact to chromium source and topical application of chelating agent and barrier creams to prevent any cutaneous permeation, corticosteroid to relieve inflammation, and antioxidant to reduce oxidative stress [36, 50]. Various antioxidants have been tested in treating chromium-induced contact dermatitis such as
Systemic contact dermatitis is a kind of dermatitis elicited by systemic administration of certain allergen that previously sensitizes the skin through direct dermal contact [57]. Several groups of allergens have been identified to cause this inflammatory disease such as metals, medications, food, plants and herbals, and certain chemicals [57, 58]. Systemic administration of these allergens is also described in various routes including oral, subconjunctival, intramuscular, pulmonary inhalation, intranasal, intrauterine, endocardial, arthroplastic, intravenous, intraarticular, subcutaneous, intradermal, dental, intratubal, and endovascular [59]. The pathophysiology of this disease still remains unclear, but several mechanisms have been proposed [60, 61, 62, 63, 64, 65]. Moreover, the theory suggesting type 3 immune response (antigen-antibody complexes) involved in systemic contact dermatitis (SCD) has not fully been proven [58].
Chromium as a metal allergen has been found to cause systemic contact dermatitis either through oral, dental, or arthroplastic routes [13, 66, 67]. Consumption of Cr(III)-based supplements in the form of chromium picolinate [68] and chromium chloride [69] has been shown to cause SCD. Oral ingestion of potassium dichromate previously used as a homeopathic drug also induces dermatitis as clinical manifestation of SCD [70, 71]. In certain case, SCD is also induced by various metal alloys applied in orthopaedical, cardiac, neurological, and abdominal associated devices [72]. In these cases, chromium-containing alloys such as stainless steel SAE 316 L, cobalt-chromium-molybdenum steel, and Vitalium™ release metal ion [73] are reported to cause SCD [74, 75, 76, 77, 78, 79]. These reported SCD cases are identified with the presence of several manifestations including erythroderma [74], and localized/generalized eczema or urticarial [76, 77, 78]. These findings suggested that any chromium sources applied in systemic routes could elicit SCD with certain clinical manifestations and degrees of severity.
Treatment of chromium-induced systemic contact dermatitis may be conducted in several approaches including managing diets and lifestyles by gut remediation and avoiding the food and sources that contain chromium; systemic or topical treatment using immune-suppressants such as corticosteroid; phototherapy; and hyposensitization therapy [80, 81]. Sharma developed a guideline for the preparation of low chromate diet that could help in controlling daily chromium consumption from food and ameliorating skin condition [82]. In case of SCD from arthroplastic routes, revision or removal of implant needs to be conducted by considering the time of hypersensitivity incidence after surgery and degree of severity [74]. Revision of implant could be conducted by using less allergenic implant such as titanium-based implant or chromium-based implant coated with certain biocompatible materials such as polytetrafluoroethylene, ZrN multilayers, diamond-like carbon, titanium nitride, graphite-like carbon, and tantalum [74, 79, 83]. Revision or removal of implants may not produce rapid disappearance [76] probably due to the presence of soluble or particulate debris of implant that produce inflammations [84, 85].
Chromium, especially Cr(VI), is a potent human carcinogen. In a human cell, carcinogenesis of chromium(VI) (Figure 3) occurs through the penetration of chromium(VI) species into the cell via sulphate/phosphate anion transport system, reduction of chromium(VI) by endogenous antioxidant to produce ROS and chromium(III), and alteration of DNA directly by chromium(VI) or indirectly by ROS [86]. The alteration of DNA then produces different types of products including Cr-DNA adducts, DNA–protein and DNA interstrand cross-links, DNA breaks, and DNA base damage [87]. Carcinogenicity of chromium(VI) has induced lung cancer in workers from various chromium-based industries [88, 89, 90] and has been associated to incidence of other cancers [91]. However, the meta-analysis study showed that the correlation between exposure of chromium(VI) and the high mortality in skin cancer is not significant [91]. This study indicated that there is no supporting data confirming the chromium species as carcinogen in inducing skin cancer in human.
Simplified mechanism of chromium carcinogenesis adapted from several references [
Several studies, however, showed that chromium species could induce skin cancer in rats and mice either as single carcinogen or cocarcinogen. Oral administrations of drinking water containing sodium dichromate dehydrate to male F344/N rats for 2 years showed that the sample developed various types of skin cancer [92]. Two other studies using hairless SK1-hrBR mice also exhibited that chromium(VI) could act as cocarcinogen in promoting UV-induced skin tumor [93, 94]. Davidson and co-workers [93] showed that oral administration of chromium(VI)-containing drinking water and UV irradiation to hairless mice have synergistic effect in promoting skin tumor. Exposure of chromium(VI) or UV radiation alone did not induce skin tumors [93]. Uddin and co-worker also conducted the same experiment and found that systemic administration of exogenous antioxidant (vitamin E and selenomethionine) did not improve skin condition [94]. It indicated that chromium(VI) cocarcinogenicity may be occurred in different mechanisms without involving ROS [94]. These three studies indicate that acute or chronic oral administration of chromium(VI) species has a great potency in promoting skin cancer in mammals including humans.
Irritation and chemical burn are caused by dermal exposure of chromium(VI) particle, solution, or mist in large quantities. Solid deposition of chromium(VI) would develop to “chromium ulcers” or “chrome holes” [67], while high concentration of chromium(VI) solution would lead to chromium burn. A mechanism for this ulcer formation is still unclear, but it may be related to the disruption of actin cytoskeleton by chromium(VI) leading to mitochondria-dependent apoptosis in skin fibroblasts cells [96]. Several reports exhibited these irritation and burning effects from different chromium species such as solid CrO3 [97], chromic acid solution [98, 99, 100], hot chromium(III) sulphate solution [101, 102], and chromium acid mist [103].
Management of irritation is conducted by considering preventive and treatment approaches. Prevention of irritation is conducted by using barrier creams, moisturizers, etc., while treatment could be done by using moisturizers and corticosteroids [50]. For chromium burn, treatment is conducted by combining mechanical excision, hemofiltration, and systemic administration of chelating agent and antioxidant [100].
Human hair is naturally exposed to a certain amount of chromium [104] that come from various sources [105, 106, 107]. Excessive and repeated exposures of chromium in certain environmental condition cause discoloration of blond, dyed-blond, and white hair (to become green) [108, 109, 110] and cause rapid hair fall [111, 112]. The mechanisms of these two effects are still unclear. Hair discoloration is probably the result of interaction between chromium ions (and also copper and nickel) and protein in hair (keratin) [113], while rapid hair fall may be related to several mechanisms such as promoting premature end of hair cycle [114] or disruption of hair shaft formation [115].
Acne vulgaris is a common dermatological condition that affects physical and psychological aspects of patients [116]. Several diseases that show the presence of a certain degree of acne also relate with depression and emotional stress such as type-2 diabetes, rheumatoid arthritis, and polycystic ovarian syndrome (PCOS) [117, 118, 119]. Pathophysiology of this disease involves several key mechanisms including excessive sebum production due to hormonal and environmental conditions, alteration of fatty acids composition due to sebum metabolism by
Several reports exhibited that certain chromium(III) compounds have high activity in improving acne vulgaris. Initially, chromium has been used in the form of high-chromium yeast or chromium GTF (glucose tolerance factor) by consuming 400 μg chromium daily which exhibited comparable improvement in acne conditions [15]. This form of treatment, recently, is considered as a complementary and alternative medicine (CAM) for the treatment of acne vulgaris [125]. Further improvements used different chromium compounds including chromium picolinate [126, 127] and chromium salt such as chromium (III) chloride [128].
In most cases, the usage of chromium compound as antiacne is usually combined with other active compounds such as vitamins, certain minerals, and herbal medicine sources in the form of oral [129, 130, 131] or topical [128] formulation to get more effective treatment results. Application of topical formulation containing chromium (III) chloride and magnesium sulphate showed total improvement in acne vulgaris with temporal mild to moderate irritation as a side effect [128]. Oral capsule containing methionine-bound zinc complex, chromium, and vitamins also exhibited 80–100% improvements for mild to moderate acne vulgaris [131]. In another study, a combination of several nutrients with potential antiacne and anti-depressant properties (eicosapentaenoic acid, epigallocatechin-3-gallate, zinc gluconate from green tea extract, selenium, and chromium) may also improve inflammatory acne lesions and mood aspect of patients [132].
Treatment of acne vulgaris in polycystic ovary syndrome (PCOS) showed mix results. A study by Amr and Abdel-Rahim showed that using 200 μg/day oral consumption for 8 weeks has no significant improvement in acne and hirsutism [126]. In a different study, chromium supplementation by women with polycystic ovary syndrome (PCOS) in a randomized, double-blind, placebo-controlled trial exhibited that the treatment gives beneficial effects on acne and hirsutism using 1000 μg/day oral consumption for 6 months [127]. These two studies indicated that the treatment of acne vulgaris in PCOS patients needs greater dose and longer duration.
Action mode of chromium in ameliorating acne vulgaris has not been fully elucidated yet, but there are two mechanisms proposed including (1) by decreasing serum testosterone concentration and (2) lowering the depression of patients. In the first mechanism, chromium can decrease serum testosterone level possibly due to the reduction of testicular steroidogenic enzymes activities [133]. In this case, a lower level of serum testosterone reduces sebum production in sebaceous glands [134]. The second mechanism explains that chromium as an anti-depressant [135, 136, 137] may reduce sebum production [138] and affect
Aging is a complex multifactorial process of damage accumulation that causes the deterioration of fitness [140, 141]. Aging has been the main risk factor for several deadly diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration [141]. In the skin, aging is identified by the presence of folds and wrinkles due to the declining and degradation of collagen [142], loss of elasticity [143], and decreasing of various skin functions [144]. At least, there are seven factors that may produce these clinical manifestations including passage of time, genetics, radiation such as ultraviolet and infrared radiations, lifestyle, chronic debilitating diseases, dysfunction of hormonal system, and gravitational force [145]. Several mechanisms have been proposed to explain the effect of these factors on aging including oxidative stress, telomere shortening, epigenetic dysregulation, DNA damage, genetic mutation, inflammation, mitochondrial dysfunction, and accumulation of glycation end product [146, 147].
Treatment for skin aging can be conducted through three approaches including adjusting lifestyle by routine exercise, calorie restriction, and maintaining mental health; gene therapies; and medications. Among other approaches, medication could be the simplest approach in fighting skin aging such as by using topical or systemic agents [148]. Chromium as dietary supplement (50–200 μg) has been used in preventing skin aging by controlling and regulating blood sugar and lipid levels [17]. Either in topical or systemic applications, chromium is usually combined with different vitamins and minerals to obtain optimum results based on certain parameters such as improving insulin function using chromium picolinate [149], promoting mitochondrial biogenesis and lipid metabolism using oligomannuronate-chromium(III) complexes [150], replacing or removing excess iron production using chromium(III) chloride or chromium picolinate [151, 152], and activating telomerase [153].
Antioxidant activity of chromium may also contribute to its anti-aging properties since oxidative stress has a certain role in the damaging process. Supplementation of chromium(III) in adult male and female with type-2 diabetes mellitus minimized the increase of oxidative stress (thiobarbituric acid reactive substances—TBARS) and increased total antioxidant status [154, 155]. Several combinations have been made by formulating chromium(III) with zinc [156], niacin [157], and vitamin C/E [154] and showed a protective effect against skin damage against oxidative stress.
Antioxidant activity of chromium(III) is correlated to the dose applied as shown in several experiments. Incubation of BALB/3 T3 clone A31 cells and HepG2 cells with chromium(III) chloride concentration higher than 400 μM would induce the formation of oxidative stress, while lower optimized concentration (M = 100–200 μM) would increase superoxide dismutase and catalase antioxidant activities [7]. In vitro study on the effect of chromium(III) and chromium(VI) on catalase activity also showed this dose-dependent activity in which treatment of cell-free catalase using chromium(III) (dose range 1–5 × 10−5 mol/L) and chromium(VI) (dose range 1–4 × 10−5 mol/L) separately increased the catalase activity [158]. These two studies clearly describe that either chromium(III) or chromium(VI) has a certain optimum concentration to exhibit their beneficial effects.
Cutaneous wound is the skin defect or skin opening that is caused by external forces [159]. Formation of this wound triggers a set of complex biochemical processes to repair the damage that are called as wound healing or wound repair. In normal condition, there are five consecutive phases occurred in wound healing process including (1) homeostasis phase (immediately) through the migration of thrombocytes and formation of fibrin clot to stop the bleeding; (2) first inflammatory phase (day 1–day 6) by sensing the injury, sending the danger signal, and initializing the inflammation; (3) second inflammatory phase (day 1–day 6) through elimination the pathogens and cleaning the wound; (4) proliferation phase (day 4–day 14) through epithelialization, angiogenesis, granulation tissue formation, and collagen deposition to repair the damage and initialize the tissue remodeling process; and (5) remodeling phase (day 8–year 1) through the deposition of collagen to reach maturation of tissue structure [160, 161, 162]. Several internal and external factors have been identified to affect the wound healing process including oxygenation, infection and foreign body, lifestyle, hormonal effect, age, and gender [163].
Several studies have shown that chromium(III), in a certain condition, could improve cutaneous wound either in normal or diabetic Wistar rats using a single dose of a combination of zinc(II) (1.5 mg/kg weight) and chromium(III) (0.02 mg/kg weight) [164] and C57BL6/J mice using chromium(III) chloride (80 μg/kg weight/day) for 21 days [16]. The mechanism of this effect has not been fully elucidated yet, but it may be related to chromium(III) activity in increasing insulin sensitivity, insulin-like growth factor 1 (IGF-1) serum concentration, and protein deposition [16, 165]. In this case, high glucose concentration could inhibit proliferation and differentiation of skin keratinocytes [166] and increase the stiffness of collagen [167] which further inhibits wound healing. In healing acetic acid-induced colitis wound, chromium(III) also acted as an anti-inflammatory agent by inhibiting several inflammatory markers and downregulating pro-inflammatory cytokine genes and antioxidant by suppressing oxidative stress without any significant side effect [168].
In different situations, the use of chromium-based skin clips [169] and orthopedic implant [74] gave an adverse effect by delaying surgery wound healing process. These cases represented a hypersensitivity effect as a manifestation of systemic contact dermatitis. In vitro study using human skin keratinocyte cell line (HaCaT cells) in a medium containing chromium(III) solution (10−6 M) showed that chromium(III) ions can decrease wound closure rate and be further decreased when the medium was replaced with another chromium(III) ion-containing medium [170]. Chromium(III) ions also caused downregulation of toll-like receptor-2, -4, and -9 messenger ribonucleic acids (TLR-2, -4, and -9 mRNA), upregulation of matrix metalloproteinase 2 and 13, and upregulation of intercellular adhesion molecule 1 messenger ribonucleic acid (ICAM-1 mRNA) [170].
There’s no exact explanation for these opposite effects. However, it may be related to the local concentration of chromium species in wound location. An enhancing effect of wound healing was obtained by applying a relatively small concentration of chromium species via oral administration. In human, for instance, there is only 2% of oral chromium(III) that will be absorbed through stomach and intestine and distributed throughout the body. In the same time, an adverse effect was obtained when local chromium concentration was high due to a particulate and soluble chromium released from the implants.
Chromium as versatile heavy metals showed contradictive properties dealing with its dermatologic toxicity and biological activity properties. The main factors that probably correlate to these properties are concentrations and species of chromium. Significant increment of local chromium concentration (more than 1 ppm for chromium[VI] species) either from dermal or systemic administration would increase the risk of dermatologic toxicities, while topical or oral administration of small recommended dietary concentration of chromium (50–200 μg for chromium picolinate) would give several beneficial effects. More studies need to be conducted to know the exact effect of the local concentration of corresponding chromium species in many systems.
The financial support from Ministry of Research, Technology and Higher Education of the Republic of Indonesia who has funded the research in calixarene- and resorcinarene-based heavy metal adsorbents is acknowledged.
The authors state that there is no conflict of interest.
As this section deals with legal issues pertaining to the rights of individual Authors and IntechOpen, for the avoidance of doubt, each category of publication is dealt with separately. Consequently, much of the information, for example definition of terms used, is repeated to ensure that there can be no misunderstanding of the policies that apply to each category.
",metaTitle:"Copyright Policy",metaDescription:"Copyright is the term used to describe the rights related to the publication and distribution of original works. Most importantly from a publisher's perspective, copyright governs how authors, publishers and the general public can use, publish and distribute publications.",metaKeywords:null,canonicalURL:"/page/copyright-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\\n\\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\\n\\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\\n\\nAgreement samples are listed here for the convenience of prospective Authors:
\\n\\n\\n\\nDEFINITIONS
\\n\\nThe following definitions apply in this Copyright Policy:
\\n\\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
\\n\\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
\\n\\nMonograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
\\n\\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
\\n\\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\\n\\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings and Videos.
\\n\\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\\n\\nTERMS
\\n\\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\\n\\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
\\n\\nAnd for any purpose, provided the following conditions are met:
\\n\\nAll Works are published under the CC BY 3.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
\\n\\n\\n\\n
LICENSE | \\n\\t\\t\\tUSED FROM - | \\n\\t\\t\\tUP TO - | \\n\\t\\t
\\n\\t\\t\\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \\n\\t\\t\\t | \\n\\t\\t\\t\\n\\t\\t\\t 1 July 2005 (2005-07-01) \\n\\t\\t\\t | \\n\\t\\t\\t\\n\\t\\t\\t 3 October 2011 (2011-10-03) \\n\\t\\t\\t | \\n\\t\\t
Creative Commons Attribution 3.0 Unported (CC BY 3.0) | \\n\\t\\t\\t\\n\\t\\t\\t 5 October 2011 (2011-10-05) \\n\\t\\t\\t | \\n\\t\\t\\tCurrently | \\n\\t\\t
The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\\n\\nContent reuse:
\\n\\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\\n\\nContent adaptation & reuse:
\\n\\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\\n\\nReposting & sharing:
\\n\\nOriginally published in {full citation}. Available from: {DOI}
\\n\\nRepublishing – More about Attribution Policy can be found here.
\\n\\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\\n\\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\\n\\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\\n\\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\\n\\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\\n\\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
\\n\\nUnder the following terms:
\\n\\nThere must be an Attribution, giving appropriate credit, provision of a link to the license, and indication if any changes were made.
\\n\\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\\n\\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\\n\\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
\\n\\nContent reuse:
\\n\\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\\n\\nContent adaptation & reuse:
\\n\\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\\n\\nReposting & sharing:
\\n\\nOriginally published in {full citation}. Available from: {DOI}
\\n\\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\\n\\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\\n\\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\\n\\nShare — copy and redistribute the material in any medium or format
\\n\\nUnder the following terms:
\\n\\nUsers wishing to repost and share the Video Lectures are welcome to do so as long as they acknowledge the source in the following manner:
\\n\\n© {year} IntechOpen. Published under CC BY-NC-ND 4.0 license. Available from: {DOI}
\\n\\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\\n\\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\\n\\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\\n\\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\\n\\nPolicy last updated: 2016-06-08
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\n\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\nAgreement samples are listed here for the convenience of prospective Authors:
\n\n\n\nDEFINITIONS
\n\nThe following definitions apply in this Copyright Policy:
\n\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
\n\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
\n\nMonograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
\n\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
\n\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\n\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings and Videos.
\n\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\n\nTERMS
\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\n\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
\n\nAnd for any purpose, provided the following conditions are met:
\n\nAll Works are published under the CC BY 3.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
\n\n\n\n
LICENSE | \n\t\t\tUSED FROM - | \n\t\t\tUP TO - | \n\t\t
\n\t\t\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \n\t\t\t | \n\t\t\t\n\t\t\t 1 July 2005 (2005-07-01) \n\t\t\t | \n\t\t\t\n\t\t\t 3 October 2011 (2011-10-03) \n\t\t\t | \n\t\t
Creative Commons Attribution 3.0 Unported (CC BY 3.0) | \n\t\t\t\n\t\t\t 5 October 2011 (2011-10-05) \n\t\t\t | \n\t\t\tCurrently | \n\t\t
The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nRepublishing – More about Attribution Policy can be found here.
\n\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\n\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\n\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\n\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
\n\nUnder the following terms:
\n\nThere must be an Attribution, giving appropriate credit, provision of a link to the license, and indication if any changes were made.
\n\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\n\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\n\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\n\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\n\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\n\nShare — copy and redistribute the material in any medium or format
\n\nUnder the following terms:
\n\nUsers wishing to repost and share the Video Lectures are welcome to do so as long as they acknowledge the source in the following manner:
\n\n© {year} IntechOpen. Published under CC BY-NC-ND 4.0 license. Available from: {DOI}
\n\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\n\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\n\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\n\nPolicy last updated: 2016-06-08
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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