Target recommendations for CML [4].
\r\n\tThere will be a chapter on secondary causes of sexual dysfunction disorders related to diabetes, cardiovascular disease, and obesity. A chapter on remedial measures to enhance sexual activity and maintain human relationships will be discussed. As there is a growing number of cancer survivors a chapter on cancer-related sexual dysfunction will be welcomed for including it.
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Typical symptoms of CML include fatigue, anorexia, and weight loss. However, about 40% of patients are asymptomatic, and in these patients the diagnosis is based on an abnormal blood count [1].
CML is categorized into three phases: chronic, accelerated, and blast crisis. At the beginning of the chronic phase (CP), some patients are asymptomatic, but others have fatigue, weakness, headaches, irritability, fever, night sweats, and weight loss. The accelerated phase (AP) comes after a variable period of diagnosis from a few months to several years, and it is characterized by increased bone marrow and peripheral blood blasts, peripheral blood leukocytosis and basophilia, anemia and thrombocytopenia unrelated to treatment, or the development of cytogenetic evolution. Subsequently, the disease progresses to the blast phase (BP), defined hematologically by the increase of leukemic blasts in the peripheral blood and/or bone marrow (more than 20%). At this stage of the disease, many patients die within 3–6 months. The progression to AP and BP seems to be associated mainly with genomic instability, which predisposes to the appearance of other molecular abnormalities [3].
The average diagnosis of CML is 64 years. However, all age groups, including children, are affected. About 15% of all leukemias are CML. It is estimated for the USA that 1 out of 526 people will have CML in their lifetime. The American Cancer Society estimates for CML in the USA by 2019: about 8990 new cases will be diagnosed with CML (5250 in men and 3740 in women) and about 1140 CML deaths (660 men and 480 women) [4].
The first case of leukemia was described in 1827 by Alfred Velpeau. Velpeau observed in a 63-year-old patient an enlarged spleen and liver associated with fever, weakness, and the presence of blood pus [5]. Later, Alfred Donné described the autopsy of a patient who had an enlarged spleen and semi-purulent blood under a microscope [6].
However, the first description of leukemia was credited to John Hughes Bennett in 1845. Bennett gave a more complete and scientific description of a 28-year-old patient who had postmortem examination with massive enlargement of the liver, spleen, and lymph nodes, in addition to the presence of purulent blood [7]. In the same year, Rudolf Virchow described the autopsy of a 50-year-old female patient with splenomegaly and pus in her blood vessels [8].
In 1852, Bennett described 37 cases of leucocythemia [9]. Later, in 1856, Virchow noted that cases of splenomegaly leukemia had some granular blood cells with irregular or divided nuclei, while patients with lymphadenopathy already had smooth nucleus cells [10]. Virchow proposed two main varieties of chronic leukemia, splenic and lymphatic, which today are identified as leukemia and lymphoma, respectively [11].
The introduction of blood cell staining techniques in 1878 by Paul Ehrlich revolutionized hematology, allowing a differentiation of different types of leukocytes [12]. With this, Ehrlich distinguished lymphoid and myeloid leukemias [13].
The improvement of cytogenetic techniques allowed the study of chromosomal arrangements in various pathological conditions. Thus, specific human disorders were found to be associated with specific chromosomal abnormalities (e.g., Down syndrome, associated with an extra copy of chromosome 21) [14].
In 1960, Peter Nowell and David Hungerford identified a small chromosome in two CML patients. This chromosome was called the Philadelphia (Ph) chromosome, according to the chromosome standardization committee, which suggested that abnormal chromosomes be designated by the name of the city in which they were discovered [11, 14, 15]. The discovery of this chromosome was a very important step in understanding the pathophysiology of CML.
Chromosome banding techniques revolutionized the cytogenetic approach. Thanks to this advance in 1973, Janet Rowley demonstrated that the Ph chromosome was not a simple deletion but a reciprocal and balanced translocation between the long arms of chromosomes 9 and 22 [16]. Still in the 1970s, Herbert Abelson and Louise Rabstein identified the
In 1984, Groffen et al., through the cloning of genomic DNA from CML patients, identified chromosome breaks within a limited region on chromosome 22, which they called the breakpoint cluster region (BCR) [18, 19]. Thus, the highly specific presence of the BCR chromosome breakpoint in patients with Ph-positive CML strongly suggested the involvement of this gene in leukemia.
In the formation of the Ph chromosome, the
The Ph is detected by G-band karyotyping in around 90% of CML patients among whom 5–10% may have variant chromosome types [23, 24, 25]. Variants of Ph chromosome are characterized by the involvement of another chromosome in addition to chromosomes 9 and 22. Variant rearrangements can be simple or complex. Simple-type variants involve another chromosome, for example, t (9; 22; 6). Complex variants participate in the translocation of two or more chromosomes, besides chromosomes 9 and 22 [26, 27].
Variant Ph breakpoints occur in hotspots across the genome, usually in the G-light bands, within the cytosine and guanine (CG) richest parts of the genome [28]. CG content correlates with chromatin condensation and transcription activity; that is, open chromatin is transcriptionally active and relatively likely to undergo breakage and repair with a consequent tendency to illegitimate recombination and translocation [24].
Variant Ph chromosomes are distinguished from additional chromosomal abnormalities or clonal evolution that drives disease progression. The clonal evolution is a reflection of a genetic instability that characterizes the transition to advanced phase [29]. However, the mechanism of variant Ph generation and the molecular bases of biological differences between classic Ph and variant Ph chromosomes are not fully understood [30].
In atypical CML (aCML), patients are Ph-negative. This leukemia presents initial characteristics and clinical course similar to those of Ph-positive patients. However, Ph-negative patients have more heterogeneous characteristics, often more aggressive disease progresses with worse prognosis [31].
The
The normal
Despite the many junctions that exist, in Ph-positive hematological neoplasms, the junctions e14a2 and e13a2 are the most frequent. These two junctions generate the same transcript encoding the p210 BCR-ABL protein. The junction e19a2 produces a transcript encoding the p230 BCR-ABL protein. And junction e1a2 creates a transcript that encodes p190 BCR-ABL [21, 29].
All domains of c-ABL protein—SRC-homology-2 (SH2) domain, SH3 domain, tyrosine kinase domain, nuclear localization signal (NLS), nuclear export signal (NES), DNA-binding domain (DBD), and actin-binding domain (ABD)—are present in the three BCR-ABL proteins. However, the three BCR-ABL proteins have different BCR domains [33].
The SH2 and SH3 regulatory domains mediate protein-protein interactions and control activation of transduction signals. The SH3 domain is known as a negative regulator of kinase activity, acting as a counterpoint to the SH2 domain, inactivating its tyrosine kinase-activating and receptor potential [34]. In BCR-ABL products, a partial or complete deletion of the SH3 domain occurs, losing negative control. In contrast, the SH2 domain is eventually activated by the presence of a tyrosine kinase-activating component [35].
The BCR-ABL fusion protein acts as an oncoprotein by activating several signaling pathways that lead to transformation. Myc, Ras, c-Rafn MAP/ERK, SAPK/JNK, STAT, NFKB, PI-3kinase, and c-Jun are included as signal cascade molecules. Many signaling proteins have been shown to interact with BCR-ABL through various functional domains and/or to become phosphorylated in BCR-ABL-expressing cells. In brief, BCR-ABL activates the main signal pathways, such as RAS/MAPK, PI-3kinase, c-ABL pathways and CRKL pathways, and JAK-STAT, and the Src pathway to play a major role in transformation and proliferation. Inhibition of apoptosis is thought to result from activation of the PI-3 kinase and RAS pathways with induction through AKT of Myc and BCL-2 [36].
Activation of these signaling pathways leads to deregulation of cellular processes such as proliferation, differentiation, DNA repair, decreased adhesion of leukemic cells to bone marrow stroma, and reduced apoptotic response to mutagenic stimulation, leading to uncontrolled clonal proliferation [37].
Approximately 40% of patients are asymptomatic, and the diagnosis is made with a blood count [1], performed by any clinical situation, preoperatively or even at a checkup. Several methodologies may be employed for the diagnosis of CML patients, including microscopic examination of peripheral blood and bone marrow, cytogenetics, and molecular biology.
In peripheral blood of patients with CML, there is a leukocytosis of approximately 225,000/mm3 ranging from 20,000 to 600,000/mm3 and an intense increase in circulation granulocytes. Granulocytosis is characterized by a small proportion of leukemic blasts and promyelocytes and predominance of intermediate forms (such as myelocytes and metamyelocytes), in addition to maturing and fully mature neutrophils (rods and segmented). Differential leukocyte count shows staggered left shift from mature neutrophils to myeloblasts. Fifteen to 20% proportions of basophils may be found [1, 37].
The presence of mild anemia and thrombocytosis are also common in CML. There is a small correlation between hemoglobin concentration and the total number of white blood cells (hemoglobin values range from 9.7 g/dL ranging from 5.4 to 14.4 g/dL). Depending on the stage of the disease, the number of platelets ranges from 485,000/mm3, ranging from 25,000 to 1,400,000/mm3. Basophilia and eosinophilia are common findings. Leukocyte alkaline phosphatase is generally low and can be used to distinguish CML from other myeloproliferative diseases [1, 37, 38].
Analysis of bone marrow (BM) through myelogram reveals granulocytic hyperplasia, leading to a leukoerythroblastic ratio of 20:1. The differentiation sequence is maintained, however with a predominance of younger cells such as promyelocytes and myelocytes. The number of megakaryocytes is increased. Other nonspecific biopsy findings include reticulin fibrosis and vascularization [1, 37].
The cytogenetic picture of CML provides unique and crucial information for diagnosis. Cytogenetic analysis of bone marrow or peripheral blood cells allows the identification of the Ph translocation and other chromosome changes that are associated with the leukemic process. Diagnostic assays at baseline for CML patients are based on the standard banding cytogenetics (chromosome banding analysis or CBA) and fluorescence in situ hybridization (FISH) [39].
Cytogenetic examination is preferably performed on bone marrow cells. The t (9; 22) (q34; q11) is easily recognized when the cell cycle of leukemic cells is disrupted in the metaphase. Identification of translocation 9; 22 requires analysis of at least 20 metaphases [40].
The FISH technique is used when the result is urgent. Fast and specific, this technique allows detection of
The most modern and effective methods for detecting BCR-ABL transcripts are based on molecular biology techniques. Polymerase chain reaction (PCR) testing of peripheral blood RNA is highly sensitive: it can detect 1 Ph-positive cell expressing the BCR-ABL fusion transcript in 105–106 normal cells [1].
Real-time PCR is a great ally of clinical oncologist seeking better therapeutic outcomes because it helps in defining treatment, which can be more or less aggressive according to each patient’s response [41]. Importantly, molecular methods, although extremely sensitive, do not allow observation of concomitant gene or chromosomal alterations.
Therapy for treatment of CML developed very slowly. Heinrich Lissauer, in 1865, described the use of arsenic in two leukemia patients [42], nothing new in view of the fact that the use of arsenic for cancer therapy had been described in the Indian Ramayana more than 2000 years earlier [43].
In the 1920s, radiotherapy entered clinical practice, and it was soon used for the treatment of CML, and for over 50 years, radiotherapy was considered the standard treatment. Radiation was usually directed to the spleen for symptomatic relief [43, 44, 45].
After the Second World War, there was the rapid development of alkylating agents. Thus, busulfan largely replaced radiotherapy in the 1960s. Later, hydroxyurea (hydroxycarbamide) was introduced in the USA (United States of America). Prospective studies showed that patients treated with hydroxyurea survived longer than those treated with busulfan. However, it was not clear whether this was due to the beneficial effect of hydroxyurea or a mitogenic effect of busulfan [44].
In the early 1980s, interferon-α (IFN-α) was introduced for the treatment of CP-CML. Few patients achieved any level of Ph-negative hematopoiesis, and others achieved a complete and lasting Ph-negative hematopoiesis. In rare cases, IFN-α may be discontinued without subsequent relapse. Thus, IFN-α replaced busulfan and hydroxyurea in the treatment of CP-CML if the patient was not eligible for allogeneic BM transplantation [46].
In 1979, Fefer and colleagues treated four CP-CML patients with high doses of chemoradiotherapy, followed by transfusion of stem cells from their genetically identical twins [47]. At follow-up intervals of 22–31 months, these patients remained well absent of Ph-positive metaphases in their marrow. The previously fatal leukemia brought the possibility of treatment and cure through BM transplantation [45].
Researchers began to treat CP-CML patients with allogeneic BM transplantation between identical HLA siblings. In the beginning, conditioning consisted of the use of cyclophosphamide and full body irradiation. However, years later, it was decided to use busulfan with cyclophosphamide [48]. According to the Center for International Blood & Marrow Transplant Research, allograft-associated transplant-related mortality for CP-CML patients is about 10–20% at 1 year, and the survival at 5 years is about 60% [49]. Most survivors have no evidence of leukemia, but occasional patients relapse early after transplantation [44].
Thus, from the 1990s, the treatment of choice for all relatively young CP-CML patients (under 50 years old) was an allogeneic stem cell transplant (SCT). In France, patients with CML who were not eligible for allograft were treated with IFN-α plus cytarabine [50], although more recent data from Italy cast doubt on this conclusion [51].
Accumulated knowledge of action mechanism of BCR-ABL was sufficient to initiate experiments with target molecule designs to be used in the treatment of CML. From the knowledge that tyrosine kinase is the effective portion of oncoprotein, it was evident that its inhibition would be the most attractive target as a therapeutic strategy. The goal was to design a small chemical compound that would compete with ATP binding at the kinase domain site. Thus, with this site occupied by an “ATP-like” molecule, it would not be possible to provide any phosphate group for substrate transfer. With this, the tyrosine residues would remain in the “non-phosphorylated” form, and the protein substrate would not be able to change its conformation so that it could be associated with the effectors described above, resulting in the interruption of oncogenetic signals to the nucleus of cell.
This “ATP-like” molecule, known as imatinib, revolutionized the treatment in oncology and specifically of CML, opening the “era of targeted specific therapy.” One of the first studies on the effectiveness of imabinib treatment (the International Randomized Study of Interferon and STI571 [IRIS] trial) estimated the rate of complete cytogenetic response (CCyR) at 12 months in the imatinib arm was 69%. Such responses are in relation to the standard treatment of the time (IFN-α and cytarabine) [52].
One of the last IRIS updates showed an estimated overall survival (OS) rate of 83% at 10 years (20.1% of patients had unknown survival status when data was analyzed). It should be mentioned that, despite these excellent results, 31 and 52% of patients assigned to imatinib discontinued treatment by 5 and 10 years of follow-up, respectively. The main cause of treatment discontinuation was the unsatisfactory therapeutic effect (11%), while only 4% of patients discontinued treatment due to side effects [53].
Treatment with imatinib induces a hematological response in 90% of patients diagnosed in the CP and a cytogenetic response in 80% of them, which made bone marrow transplantation, the only curative treatment for CML, to be indicated only in those patients who develop imatinib resistance, observed in 20–25% of cases [52].
Known mechanisms of imatinib resistance include the presence of mutation point in the BCR-ABL tyrosine kinase domain, amplification of the BCR-ABL gene, overexpression of the multidrug resistance gene known as P-glycoprotein, and low expression of pickup transporters such as SLC22A1 (hOCT1) [54].
The second generation TKIs (2GTKIs), dasatinib, nilotinib, and bosutinib, were initially approved in CML patients who were resistant or intolerant to imatinib. Due to a more potent in vitro inhibition of the unmutated BCR-ABL kinase with a good safety profile, these second generation TKIs were later evaluated and approved in the first-line setting [55].
Dasatinib is an oral, second generation TKI that is 350 times more potent than imatinib in vitro. It also inhibits the Src family of kinases, which may be important in blunting critical cell signaling pathways [56]. Compared to the structure analog of imatinib, nilotinib’s affinity for the ATP-binding site on BCR-ABL1 is 30–50 times more potent in vitro [57]. Like dasatinib, nilotinib initially demonstrated the ability to induce hematologic and cytogenetic responses in patients who had failed imatinib [56]. Bosutinib appeared to retain activity across most known mutations that confer imatinib resistance, except for T315I. Responses were independent of whether patients had resistance to or intolerance of imatinib [56].
A subset of patients with CML exhibited either primary or secondary resistance to imatinib. Primary resistance refers to patients never responding to imatinib, whereas secondary resistance occurs when a patient who had an initial response to imatinib eventually loses the response [36]. Although a significant proportion of patients respond to 2GTKI therapy after imatinib failure, most of them (70%, approximately) will eventually discontinue such treatment in the short term due to loss of response or toxicity [55].
There are many treatment mechanisms of resistance, and several of them, mostly in vitro or in selected patient samples, have been reported. However, their individual contribution to this phenomenon has not been completely defined. The most frequently identified mechanism of resistance is the development of mutations in the ABL tyrosine kinase domain [55].
A third generation TKI, ponatinib, is approved in CML patients with refractory CML or Ph-positive acute lymphoblastic leukemia (Ph + ALL) and those harboring the BCR-ABL1T315I mutant [58]. Clinical trials using the approved dose of 45 mg/day of ponatinib show the main concern with this drug is the increased incidence of cardiovascular complications [55]. Table 1 shows the target recommendations for CML, according to the American Cancer Society.
The quality of response to TKI treatment is categorized according to the laboratory method used. Patients are monitored by hematological, cytogenetic, and molecular response, and their terminology has been standardized by the European Leukemia Net [59].
Hematologic response is defined by the presence of platelets <450 × 109L, without differential immature granulocytes and <5% basophils, and a non-palpable spleen. Cytogenetic response (CyR) is defined according to the proportion of positive Philadelphia chromosome (Ph +) in bone marrow cells. The association between CyR and improved survival made the cytogenetic response the gold standard of CML therapy [36]. Table 2 shows the cytogenetic response definition.
First generation TKI | CML patients newly diagnosed |
Second generation TKI | CML patients resistant or intolerant to imatinib |
Third generation TKI | CML patients with refractory CML or Ph-positive acute lymphoblastic leukemia and those harboring the BCR-ABL1T315I mutant |
Interferon or chemotherapy | CML patients who cannot take TKI or those who are not responding to treatment |
Allogeneic stem cell transplantation | CML who have failed at least two TKIs and for all patients in advanced phase disease |
Target recommendations for CML [4].
Complete cytogenetic response (CCyR) | 0% Ph-positive metaphases |
Partial cytogenetic response (PCyR) | 1–35% Ph-positive metaphases |
Minor cytogenetic response (mCyR) | 36–65% Ph-positive metaphases |
Minimal cytogenetic response (min CyR) | 66–95% Ph-positive metaphases |
No response (NR) | >95% Ph-positive metaphases |
Cytogenetic response definition [59].
The IRIS study, conducted in 2003, defined two types of molecular response assessed by real-time PCR: major molecular remission (MMR) and complete molecular remission (CMR). Major molecular remission is defined as a three-log drop of the initial load of BCR-ABL at the time of diagnosis; this value is equal to or less than 0.1%. Complete molecular remission is defined when the BCR-ABL transcript is undetectable [60].
Response to treatment is monitored during the first 3 months through clinical evaluation, blood count, and biochemical exams every 2 weeks. After the third month, cytogenetics is recommended every 6 months until complete CCyR is achieved. From the moment the patient reaches CCyR (Ph + 0%), monitoring is performed through real-time PCR quarterly to detect minimal residual disease [61].
For patients who fail frontline therapy, the second-line options include second and third generation TKIs. Even though second and third generation TKIs are potent and selective TKIs, some patients still do not respond to treatment. Allogeneic stem cell transplantation (allo-SCT) remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs and for all patients in advanced phase disease [56].
Patients exposed primarily to TKI treatment do not respond negatively to allo-SCT. Conversely, if patients referred for transplant have the lower CML burden, they may respond better to allo-SCT [62].
Allo-SCT is the only treatment with healing potential. However, it remains associated with substantial risks of morbidity and mortality. For appropriate counselling of patients, a rapid and simple way to assess risk is needed [63]. Pre-allo-SCT risk factors for CML are donor type, disease stage, recipient age, recipient-donor gender combination, and, lastly, time between diagnosis and allo-SCT. Table 3 presents the risk factors for allo-STC [63, 64, 65, 66, 67].
Prognostic factors | Score |
---|---|
Donor type | 0—related identical human leukocyte antigen (HLA) |
1—unrelated identical HLA | |
Disease stage | 0—chronic phase (CP) |
1—accelerated phase (AP) | |
2—blast phase (BP) | |
Receiver age | 0—< 20 age |
1—20–40 age | |
2—> 40 age | |
Gender donor/receiver | 1—female/male |
0—male/female | |
Time from diagnosis to transplant | 0—< 12 months |
1—> 12 months |
In the era of TKIs, there is no doubt for the first-line treatment for CML patients. But when allo-SCT is indicated, this scoring system is still of great value in estimating overall disease-free survival and procedure-related mortality.
When considering allo-SCT for CML patients, it is important to know that a poor response to one or more TKIs does not predict a negative transplant response. TKIs pharmacologically block BCR-ABL activity, while allo-SCT depends on graft-versus-leukemia (GVL) effect [68].
The challenge of allo-SCT for treatment of leukemia and other malignancies of the hematopoietic system is the prevention of graft-versus-host disease (GVHD) without losing the GVL effect. Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T-cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD [69].
Allo-SCT should not be seen as a last resort but as a treatment strategy to be considered viable at the beginning of treatment for patients who have suboptimal responses to TKIs. The key issues for HSCT in CML are those of patient selection, risk stratification, and outcome optimization by means of regimen selection and improved supportive care [68].
CML is a myeloproliferative disease, resulting from clonal expansion of hematopoietic progenitor stem cells, characterized by
Allo-SCT is a possible cure for CML; however, it is associated with mortality and morbidity increased due to complications in the pre- and posttransplantation periods, such as GVHD, immunosuppression, and multiple organ toxicity.
Although great progress has been made for the improvement in clinical treatment during the past decades, it is common for patients to develop resistance to treatments. Therefore, further exploring the novel therapeutic strategies is still crucial for improving disease outcome.
Laryngomalacia is the most common cause of stridor in neonates and infants. In fact, laryngomalacia is the common cause of stridor in 60–70% of newborns and infants which makes laryngomalacia the most common congenital laryngeal anomaly [1]. Supraglottic collapse produced by certain anatomic variants causes airway obstruction in Laryngomalacia, which is most severe during inspiration. Flexible fiberoptic laryngoscopy is used to diagnose laryngomalacia. The general course is benign, with stridor progressing for 6 months until gradually disappearing by 12–24 months of age. The majority of cases resolve with minimal or no treatment. Of all the laryngomalacia patients, only ten to fifteen percent patients will have significant upper airway obstruction symptoms, including increased breathing effort, feeding difficulties, and failure to thrive. Supraglottoplasty is recommended in such severe situations.
The larynx is subdivided into three parts supraglottis, glottis, and subglottis. The supraglottis is the part between the inferior boundary of the hyoid bone and the vestibular folds. Therefore, the structures present in the supraglottis area are the epiglottis, arytenoid cartilages, and aryepiglottic folds. Laryngomalacia affects these supraglottic structures.
The pediatric airway is different from that of adults in many ways. The relatively large tongue in relation to the oropharynx, therefore pediatric patients are more likely to sustain airway obstruction under anesthesia due to relatively large tongue. The larynx is located more cephalic in the neck in neonates and infants. This high cephalic position helps to facilitate spontaneous breathing right after birth and prevents aspiration. The epiglottis is short, stubby and omega-shaped, angled over the vocal cords. Also, the infantile laryngeal cartilage is more flexible than older children and adults, which is a probable cause of collapsible characteristics of the neonatal and infantile larynx.
The most common symptom in infants with laryngomalacia is positional stridor. Stridor commonly appears in the first few days of life, although children may not seek medical help until they are many months old. Stridor is usually worse in the supine position, particularly during crying or eating, because such activities necessitate increased respiratory efforts. The severity of symptoms increases during several months of infancy but usually resolves by two years of age and often earlier [2].
Although stridor is a common symptom of laryngomalacia, it is not often the cause of presentation to the medical facility. Sometimes patients with severe disease present with other respiratory complaints such as respiratory distress, use of accessory respiratory muscles and hypoxemia. Laryngomalacia can also present with atypical symptoms like snoring, obstructive sleep apnea and difficulty in swallowing. Although incidence and distribution of these atypical presentations are yet to be established [3]. Difficulty in swallowing causes decreased intake and respiratory distress increases metabolic demand thus can lead to failure to thrive in infants with laryngomalacia.
The natural history of laryngomalacia and that it resolves during the second year of life is supported by the low level of evidence and lacks endoscopic evidence. The time range within which laryngomalacia resolves and the proportion of patients in which laryngomalacia do get spontaneously resolved is yet to be answered. Atypical presentations are to be further explored. Therefore, prospective longitudinal trials are required to better understand the natural history of laryngomalacia [4].
Laryngomalacia in older children presents with obstructive sleep apnea syndrome. Other reasons in older children for seeking medical attention are exercise-induced stridor and dysphagia [5].
The exact etiology and pathophysiology of laryngomalacia are still unknown. Multiple causal theories of laryngomalacia have been proposed. The neurological basis is one of the leading theories, which states that the abnormal integration of the laryngeal nerves leads to altered laryngeal tone. This theory has been supported by a pathologic study that has shown increased diameter of supraglottic nerve in patients with severe laryngomalacia. Another theory proposes an imbalance of demand and supply during inspiration as a cause of congenital laryngomalacia. This theory of imbalance needs further study. Acid reflux disease has not been established as a cause of laryngomalacia, although almost 60% of infants who present with laryngomalacia also have accompanying acid reflux disease. Acid reflux disease causes irritation and thus edema of the upper airway which further worsens laryngeal obstruction.
In the scenario of debated etiologies of laryngomalacia, a neurological basis is considered as the most probable etiology of laryngomalacia among all the theories mentioned before. Another case report supporting the neurological basis is a unique case report where a child who was diagnosed case of moyamoya disease suffered acquired laryngomalacia following a neurologic insult. The child suffered a cerebrovascular accident following which she developed laryngomalacia presenting with severe stridor and chest retractions and a nocturnal oxygen requirement, and severe laryngomalacia being noted on laryngoscopy. Prior to the cerebrovascular accident, she had no symptoms of laryngomalacia and had undergone several laryngoscopies, both awake and anesthetized, which showed no evidence of laryngomalacia [6].
Children with laryngomalacia showed vitamin D deficiency and increased proinflammatory cytokine IL-6, which may result from dysregulation of the immune responses. Laryngomalacia could be an inflammatory disease secondary to maternal deficiency of 25(OH)-vitamin D with subsequent Vitamin D deficiency in exclusively breast-fed infants during neonatal and infantile periods [7].
The patient factors that influence disease severity are Apgar score at birth and during the first several minutes after birth, resting oxyhemoglobin saturation level at the time of presentation, and the presence of a secondary airway anomaly. Additional co-morbidities in children with laryngomalacia increases disease severity and also affect the prognosis of surgical outcome. Such co-morbidities can be gastroesophageal reflux disease, laryngopharyngeal reflux, neurologic disease, congenital heart disease, genetic syndrome, or anomaly.
Patients with severe laryngomalacia will require surgery. Patients who have gastroesophageal reflux disease or laryngopharyngeal reflux and one additional co-morbidity are more likely to require revision supraglottoplasty. Those with three medical co-morbidities are more likely to require tracheostomy [8].
There are a number of classifications of laryngomalacia. A simple and well-detailed classification of laryngomalacia by Olney et al. describing type 1, type 2, and type 3 laryngomalacia as prolapsing arytenoids, shortened aryepiglottic folds, and prolapsing epiglottis [9]. The classification of Olney et al. is simple, but covers only about two-third of laryngomalacia cases and also mixes static and dynamic findings.
Van der Heijden et al. after studying various laryngomalacia classifications have proposed a Groningen Laryngomalacia Classification System (GLCS) which is based on the photo and video documentation of eighty five patients diagnosed in a tertiary referral centre combined with a review of the literature [10].
This simplified system is supposed to ease communication among professionals and provide a base for treatment algorithms. In laryngomalacia, there is a collapse of the supraglottic airway during inspiration causing obstruction. This is a dynamic change of the airway happening during inspiration. Some previous classifications were based on static findings. Anatomical findings such as omega-shaped epiglottis, short aryepiglottic folds and acutely angled epiglottis over laryngeal inlet are static findings. In laryngomalacia obstruction is due to dynamic change in the airway, and static findings do not completely explain these dynamic changes and therefore are not the excellent choice for the classification of laryngomalacia. McSwiney et al. were the first to introduce a system in order to classify laryngomalacia and it was based on static findings [11]. McSwiney et al. further combined omega-shaped epiglottis and posterior displacement in one single type of laryngomalacia, suggesting omega shaped epiglottis is exclusively associated with posterior displacement of the epiglottis. Although, omega-shaped epiglottis can also present in conjunction with medial displacement of aryepiglottic folds during inspiration. Holinger et al. divided laryngomalacia into six different types, with static and dynamic findings described as separate entities. Shah et al. exclusively described dynamic changes but the definitions of the different types of laryngomalacia were insufficiently described [12]. Kay et al. use a system in which Type 1 is defined as static finding and Type 2 as a dynamic finding and type 3 is a collection of “all other etiologies” including neuromuscular disease, which renders the classification less reliable [13]. None of these systems discussed here are widely accepted. Classifications require simplification in such a way that they not only provide a genuine classification based on dynamic findings but also allow making a righteous decision for the intervention required.
The Groningen laryngomalacia classification system is a newly proposed classification system exclusively based on dynamic laryngeal changes. In Groningen’s laryngomalacia classification, laryngomalacia is divided into three types; Type 1 is inward collapse of arytenoid cartilages, Type 2 is medial displacement of aryepiglottic folds, and Type 3 is posterocaudal displacement of epiglottis against the posterior pharyngeal wall.
The GLCS has also proposed the probable surgical intervention for each category required. They suggested that the decision between surgical management and conservative strategy should be based on the severity of laryngomalacia, and when surgical management is planned, the GLCS can suggest the surgical intervention required. The surgical intervention suggested for Type 1 laryngomalacia of GLCS is the removal of redundant mucosa over arytenoids with or without the removal of cuneiform or corniculate cartilage. In Type 2 laryngomalacia suggested intervention is incision or excision of a wedge of aryepiglottic folds. In Type 3, epiglottopexy would be the surgical intervention required. However, these treatment options should be clinically individualized for each patient.
Kay et al. also provided a classification-based treatment algorithm. They discerned three types in which type I is recommended to be treated by dissection of the aryepiglottic folds, type II by resection of redundant mucosa over arytenoid cartilage, but cases with “all other etiology” were supposed to receive tracheostomy.
A thorough physical examination of the infant should be performed, with special attention to the oral cavity, nose, and neck. A complete birth history is required, including any surgical history or intubations performed on the patient. Parents should inform about any breathing problems children may have at home, with a focus on noisy breathing or apnea episodes. Laryngomalacia is characterized by noisy breathing that worsens with meals or while lying supine. The clinician should investigate the patient’s eating habits and keep track of any weight loss or failure to thrive.
It’s important to ensure choanal patency and rule out piriform aperture stenosis. A complete oral cavity examination is required to rule out cleft lip or cleft palate, glossoptosis, Pierre-Robin sequence, or micrognathia, all of which can cause breathing and feeding difficulties. A thorough examination of the neck is also required to rule out any tumors or vascular abnormalities. Hemangiomas with a beard-like distribution should be given special attention, as these infants are more prone to have hemangiomas in the airway. In order to properly evaluate a patient with suspected laryngomalacia, a flexible laryngoscopy examination of the supraglottic airway in an awake newborn is required. The infant should be transferred to the operating room for a diagnostic bronchoscopy if the examiner notices serious symptoms.
Flexible fiberoptic laryngoscopy is the mainstay in the diagnosis of infant stridor. It permits the real-time visualization of the aerodigestive tract during spontaneous ventilation. It allows complete visualization of the oropharynx, hypopharynx, supraglottis, glottis and subglottis. Due to the simplicity and ability to thoroughly examine the dynamic collapse of the supraglottic airway during awake respiration, flexible fiberoptic laryngoscopy is presently the gold standard for the diagnosis of laryngomalacia.
Direct laryngoscopy and diagnostic bronchoscopy in the operation theater give the clinician a complete evaluation of the upper aerodigestive tract to the level of carina and the mainstem bronchi. It is a valuable procedure principally in patients with severe symptoms or in patients who have concomitant secondary airway anomalies. Surgical intervention is also possible with direct laryngoscopy when warranted.
Radiologic studies might be helpful in the diagnosis of swallowing difficulty. A modified barium swallow examination is preferred in infants with laryngomalacia since aspiration may be silent and not detectable clinically.
A polysomnogram is beneficial in determining the presence and severity of obstructive sleep apnea, particularly in older children. To improve the apnea-hypopnea index in such children surgical intervention like supraglottoplasty might be beneficial.
Airway fluoroscopy due to low sensitivity and exposure to ionizing radiation is not advocated in the assessment of infant stridor.
Most of the children of laryngomalacia can be managed conservatively as the symptoms usually disappear by the end of the second year of life. In the majority of cases, laryngomalacia is a self-limiting condition. Only 5–20% of children with severe laryngomalacia undergo surgical intervention. As mentioned before transoral supraglottoplasty has a low complication in otherwise healthy children [14]. To reduce inspiratory obstruction in laryngomalacia, redundant tissue in the upper airway is cut and/or the aryepiglottic folds are loosened in bilateral supraglottoplasty. While bilateral supraglottoplasty is generally well tolerated, about 10% of individuals experience side effects such as laryngeal edema, new-onset aspiration, or supraglottic stenosis. Supraglottic stenosis is a life-threatening condition that is difficult to treat surgically. A few clinicians have reported performing unilateral supraglottoplasty to lessen the risk of problems associated with bilateral surgery.
For the treatment of severe laryngomalacia, Walner et al. advocated a staged approach to bilateral supraglottoplasty [15]. Staged supraglottoplasty implies a unilateral supraglottoplasty on the most affected side, followed by, if necessary, an opposite-side operation week to months later. For the surgery, they used cold steel instruments, with or without the use of a microdebrider.
In the staged approach first stage of surgery involves the removal of the redundant tissue on the most affected side using either straight or curved microscissors. Then to release the ipsilateral aryepiglottic fold a small wedge of tissue was removed. Microdebrider can also be used to remove redundant tissue overlying the arytenoid cartilage on the most affected side, and then a small wedge of tissue from the aryepiglottic fold on the same side can be removed after using microscissors. Afrin-soaked pledgets were used on the cut surfaces to reduce bleeding. Walner et al. further describe that after surgery all patients were extubated and monitored for 24 hours prior [15]. Patients were reevaluated for symptoms after 4 to 6 weeks. If the problems of breathing or feeding continued, the second step of surgery was employed to provide further relief. An opposite-side supraglottoplasty was performed, with redundant arytenoid mucosa excised and the aryepiglottic fold released on the side opposite to the original surgery. If aryepiglottic fold on the side previously operated appears to be too tight it was re-released. According to Walner et al., 73% of individuals who underwent the first stage of surgery had considerable improvement or resolution of stridor, while 100% of those who underwent the second stage had significant improvement or resolution of stridor. There were no complications in any of the patients.
Low-temperature plasma radiofrequency ablation (LTP-RFA) is another surgical therapy option. According to the severity of laryngomalacia, Hongming Xu et al. presented the first prospective four-arm randomized trial to compare the efficacy and short outcomes of patients with moderate and severe laryngomalacia who were randomly treated with LTP-RFA, traditional surgical supraglottoplasty, or wait-and-see policy [16]. When compared to typical surgical supraglottoplasty, LTP-RFA treatment dramatically reduced operating time, length of hospital stay, and amount of intraoperative hemorrhage in children with severe laryngomalacia, but treatment efficacy was equivalent. In addition, when compared to the control group, LTP-RFA treatment dramatically alleviated laryngomalacia symptoms in children with moderate laryngomalacia. Post-operative pneumonia was the most common consequence, affecting 11% of patients.
Choice of ventilation strategy is the main concern for the anesthesia team in the case of laryngomalacia. The following are the ventilation strategy that can be utilized [17]:
Spontaneous breathing is the choice of ventilation with experienced anesthesia and surgeon teams.
Controlled mechanical ventilation using a small internal diameter endotracheal tube is nowadays used rarely, as the tube interferes in the vicinity of the surgical site.
Intermittent apnea technique is another choice for ventilation under anesthesia but surgery needs to be interrupted in between for manual ventilation when the patient desaturates and thus surgeon gets limited time duration in between two ventilations.
Jet ventilation can sometimes be used for this surgery.
Laryngomalacia despite the fact that it is a self limiting disease, caregivers must recognize severe cases. A child’s growth may be hindered in severe cases of laryngomalacia due to breathing and feeding difficulty. Laryngomalacia is resolved in more than 90% of cases after supraglottoplasty, which enhances the child’s quality of life. Only in a few cases a second surgery is required to resolve residual symptoms.
The authors declare there are no conflict of interest.
Groningen Laryngomalacia Classification System
Low-temperature plasma radiofrequency ablation
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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So, in this chapter, we aim to present a comprehensive review of surgical approaches to the temporomandibular joint.",book:{id:"6025",slug:"temporomandibular-joint-pathology-current-approaches-and-understanding",title:"Temporomandibular Joint Pathology",fullTitle:"Temporomandibular Joint Pathology - Current Approaches and Understanding"},signatures:"Mohammad Esmaeelinejad and Maryam Sohrabi",authors:[{id:"172188",title:"Dr.",name:"Mohammad",middleName:null,surname:"Esmaeelinejad",slug:"mohammad-esmaeelinejad",fullName:"Mohammad Esmaeelinejad"},{id:"240723",title:"Dr.",name:"Maryam",middleName:null,surname:"Sohrabi",slug:"maryam-sohrabi",fullName:"Maryam Sohrabi"}]},{id:"41355",title:"Ossifying Fibromas of the Craniofacial Skeleton",slug:"ossifying-fibromas-of-the-craniofacial-skeleton",totalDownloads:4819,totalCrossrefCites:5,totalDimensionsCites:6,abstract:null,book:{id:"2619",slug:"histopathology-reviews-and-recent-advances",title:"Histopathology",fullTitle:"Histopathology - Reviews and Recent Advances"},signatures:"Bruno Carvalho, Manuel Pontes, Helena Garcia, Paulo Linhares and Rui Vaz",authors:[{id:"140061",title:"Dr.",name:"Bruno",middleName:null,surname:"Carvalho",slug:"bruno-carvalho",fullName:"Bruno Carvalho"},{id:"142266",title:"Dr.",name:"Manuel",middleName:null,surname:"Pontes",slug:"manuel-pontes",fullName:"Manuel Pontes"},{id:"142267",title:"Dr.",name:"Paulo",middleName:null,surname:"Linhares",slug:"paulo-linhares",fullName:"Paulo Linhares"},{id:"142268",title:"Prof.",name:"Rui",middleName:null,surname:"Vaz",slug:"rui-vaz",fullName:"Rui Vaz"},{id:"142958",title:"Dr.",name:"Helena",middleName:null,surname:"Garcia",slug:"helena-garcia",fullName:"Helena Garcia"}]},{id:"58358",title:"Internal Derangements of the Temporomandibular Joint: Diagnosis and Management",slug:"internal-derangements-of-the-temporomandibular-joint-diagnosis-and-management",totalDownloads:3334,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Millions of individuals worldwide suffer from temporomandibular joint (TMJ) disorders and are characterized by pain and joint dysfunction. TMJ internal derangement (ID) is the most frequent type of temporomandibular disorders (TMDs). The ID of TMJ is defined as a joint dysfunction associated with an abnormal disc position. Identification and elimination of the causes of tissue breakdown of the TMJ that lead to ID are the key factors for successful treatment. The common causes for TMJ ID are trauma and parafunctional habits which lead to joint overload and degenerative changes in the articular structures, increased friction, and gradual disc displacement. Local and systemic inflammatory/degenerative arthropathies may also affect TMJ and cause ID. The aim of this chapter is to give comprehensive knowledge about the contemporary perspective of TMJ ID including diagnostic and therapeutic developments and innovations. Clinicians should establish the correct diagnosis and cause of the disease for appropriate management so that patients do not suffer from ineffective treatments. As an innovative development, TMJ replacements with alloplastic joint prosthesis and tissue-engineered structures hold promise for the future of management of TMJ ID.",book:{id:"6025",slug:"temporomandibular-joint-pathology-current-approaches-and-understanding",title:"Temporomandibular Joint Pathology",fullTitle:"Temporomandibular Joint Pathology - Current Approaches and Understanding"},signatures:"Ufuk Tatli and Vladimir Machon",authors:[{id:"203864",title:"Associate Prof.",name:"Ufuk",middleName:null,surname:"Tatli",slug:"ufuk-tatli",fullName:"Ufuk Tatli"},{id:"204401",title:"Dr.",name:"Vladimir",middleName:null,surname:"Machon",slug:"vladimir-machon",fullName:"Vladimir Machon"}]},{id:"61976",title:"Metabolic Alkalosis",slug:"metabolic-alkalosis",totalDownloads:1484,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Here we review the causes of metabolic alkalosis with an emphasis on the inherited causes, namely Gitelman syndrome and Bartter syndrome and syndromes which mimic them. We detail the importance of understanding the kidney pathophysiology and molecular genetics in order to distinguish these syndromes from acquired causes. In particular we discuss the tubular transport of salt in the thick ascending limb of the loop of Henle, the distal convoluted tubule and the collecting duct. The effects of salt wasting, namely an increase in the renin-angiotensin-aldosterone axis are discussed in order to explain the biochemical phenotypes and targeted treatment approaches to these conditions.",book:{id:"6790",slug:"fluid-and-electrolyte-disorders",title:"Fluid and Electrolyte Disorders",fullTitle:"Fluid and Electrolyte Disorders"},signatures:"Holly Mabillard and John A. Sayer",authors:null},{id:"41364",title:"Histological Change of Aquatic Animals by Parasitic Infection",slug:"histological-change-of-aquatic-animals-by-parasitic-infection",totalDownloads:8580,totalCrossrefCites:4,totalDimensionsCites:8,abstract:null,book:{id:"2619",slug:"histopathology-reviews-and-recent-advances",title:"Histopathology",fullTitle:"Histopathology - Reviews and Recent Advances"},signatures:"Watchariya Purivirojkul",authors:[{id:"149747",title:"Dr.",name:"Watchariya",middleName:null,surname:"Purivirojkul",slug:"watchariya-purivirojkul",fullName:"Watchariya Purivirojkul"}]}],onlineFirstChaptersFilter:{topicId:"193",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. Barderas",slug:"oxidative-stress-in-cardiovascular-diseases",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}}]},overviewPagePublishedBooks:{paginationCount:33,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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