\r\n\tFourth, the effects of digitalization on economic and sustainable development and the benefits of digitization for public services, including e-governance, e-payments, e-democracy, e-health, e-learning, e-payments, and so on, are also presented.
\r\n
\r\n\tAt the fifth stage, we will try to highlight the imperative role of blockchain technology, artificial intelligence, and machine learning in the digitization process.
\r\n
\r\n\tLast but not least, the main threats of a digital economy are presented under the form of cybercrime and “surveillance capitalism”, including the impact of financial crimes referring to card frauds, online frauds, digital frauds, digital shadow economy, black market, money laundering, etc.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"45ca4a969c50d02d2bab6894218c7ef8",bookSignature:"Prof. Monica Violeta Achim and Dr. Nawazish Mirza",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10918.jpg",keywords:"Definition, Digital Transactions, Innovative Financial Services, Cryptocurrency, E-governance, E-payments, Spiral Transformation of Knowledge, Financial Education, Artificial Intelligence, Machine Learning, Money Laundering Surveillance Capitalism Economy, the General Data Protection Regulation (GDPR)",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 25th 2021",dateEndSecondStepPublish:"September 17th 2021",dateEndThirdStepPublish:"November 16th 2021",dateEndFourthStepPublish:"February 4th 2022",dateEndFifthStepPublish:"April 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a year",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"In February 2020, Ph.D. Achim won the Prize for Excellence in Scientific Research, at Babeș-Bolyai University, Cluj-Napoca, Romania. 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1. Introduction
Langeback first described paranasal sinus mucoceles in 1820. It was only in the early 1900s that mucoceles were given their name by Rollet and popularized by Gerber, who published 178 cases. In 1995, Lambert attributed frontal or ethmoid mucoceles as the most common nasal condition to produce proptosis [1]
A mucocele is an epithelial-lined mucus containing sac that fills a paranasal sinus and is able to expand by alternative bone resorption and bone formation. A mucocele occurs when a sinus ostium or a compartment of a septated sinus becomes obstructed, thus causing the sinus cavity to become filled with mucus or to become airless. Paranasal sinus mucoceles may result from inflammation, tumor, trauma or surgical manipulation [2].Because of the anatomic proximity of the orbit, the pathologic process of paranasal sinus mucocele will easily affect the orbit [3,4]. Anatomically, the frontal, ethmoid, sphenoid and maxillary sinuses all interface with the orbit. The maxillary sinus shares the floor of the orbit, the frontal sinus is part of the orbital roof, the ethmoid extends along most of the medial wall of orbit and the sphenoid almost completely surrounds the orbital apex [3, 4]. Thus, mucoceles of the paranasal sinuses can easily affect the orbit and cause ophthalmic symptoms such as proptosis, blurred vision and displacement of globe [4,5]. Patients with paranasal mucoceles with orbital symptoms are often seen by the ophthalmologist first and then referred to otorhinolaryngologist [5].Occasionally they can present with intracranial complications.
It is essential to differentiate a mucocele from a mucus retention cyst. A mucus retention cyst is just a fluid filled sac along the sinus lining which does not expand and push into the eye socket, nose or brain and does not cause problems in the vast majority of cases. Notably, mucus retention cysts in the sinuses are more common than expected. Infact, about 30-40% of the population with absolutely no complaints of sinus problems will have cysts of the paranasal sinuses when they have CT scans performed. Most retention cysts of sinuses spontaneously shrink or do not change in size over the long term [6]. In the absence of associated complaints “wait and see” may be the appropriate management strategy for these retention cysts.
2. Material and methods
From 2005 to 2012, 13 patients with paranasal sinus mucoceles were treated with wide endoscopic endonasal marsupilization at the UKM Medical Center in Kuala Lumpur, Malaysia. Review of the patients’ complete medical records, including out-patient clinical records, operative notes and reports of imaging and histopathology were performed. The radiological imaging (CT/MRI) on preoperative coronal and axial views were reviewed.
3. Results
The demographic data on the 13 patients includes the age, sex, race, clinical presentation, type of radiological imaging performed, the surgical details and the post-operative follow-up are listed in Table 1. The most common sinus involved was the frontal, followed by the ethmoid, maxillary and sphenoid (Table 2). The most common clinical presentation was headache followed by eye and nasal symptoms (Table 3). Figure 1 shows a radiological image of a right ethmoidal mucocele in an adult patient with diplopia and headache. Figure 2 shows a radiological image of a gross right frontal mucocele in an adult patient with headache, reduced vision and proptosis. Figure 3 shows a radiological image of a sphenoid mucocele in a child with headache and vomiting. Figure 4 shows a radiological image of left maxillary mucocele in an adult patient with nasal blockage and foul smelling discharge.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tPatient / Age/sex/race \n\t\t\t
\n\t\t\t
\n\t\t\t\tPresentation\n\t\t\t
\n\t\t\t
\n\t\t\t\tSinus involvement on endoscopy\n\t\t\t
\n\t\t\t
\n\t\t\t\t Imaging\n\t\t\t
\n\t\t\t
\n\t\t\t\tSurgery\n\t\t\t
\n\t\t\t
\n\t\t\t\tFollow-up\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
1. 40/M/C
\n\t\t\t
supra orbital swelling, no diplopia or nasal symptoms
\n\t\t\t
Left frontal and ethmoid sinuses involvement
\n\t\t\t
CT: Expansile cystic mass Lt fronto ethmoid region \n\t\t\t
\n\t\t\t
Endoscopic marsupialization of fronto-ethmoidal mucocele
\n\t\t\t
Symptom free at 1 year follow up with no sign of recurrence
\n\t\t
\n\t\t
\n\t\t\t
2. 59/M/C
\n\t\t\t
Right frontal swelling with diplopia
\n\t\t\t
Right frontal sinus involvement
\n\t\t\t
CT: Expansile cystic lesion pushing interfrontal sinus septum with orbital roof involvement
\n\t\t\t
Bicoronal flap cranialization with endoscopic endonasal frontal sinusotomy and marsupilization
\n\t\t\t
Symptom free at 1 year follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
3. 40/M/M
\n\t\t\t
Nasal block, rhinorrhoea with anosmia
\n\t\t\t
Right frontal sinus involvement with bilateral nasal polyposis
\n\t\t\t
CR & MRI: Right frontal expansile cystic mass with intracranial extension, no evidence of mass effect or ring enhancement
\n\t\t\t
Endoscopic right frontal sinusotomy and bilateral ethmoidectomy with marsupilization
\n\t\t\t
Symptoms improvement with no evidence of recurrence of nasal polyps at 6 month follow-up
\n\t\t
\n\t\t
\n\t\t\t
4. 55/F/M
\n\t\t\t
Headaches with, right diplopia
\n\t\t\t
Right ethmoid sinuses involvement
\n\t\t\t
CT & MRI: Expansile right ethmoidal mass with thinning of lamina papyracea
\n\t\t\t
Endoscopic anterior and posterior ethmoidectomy with marsupilization
\n\t\t\t
Symptom free at 6 month follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
5. 59/M/Bengali
\n\t\t\t
Headaches, proptosis with reduced left eye movement
\n\t\t\t
Bilateral frontal sinus involvement
\n\t\t\t
CT: Expansile mass involving bilateral frontal sinuses
\n\t\t\t
Endoscopic drainage of bilateral frontal mucopyocele with marsupilization
\n\t\t\t
Symptom free at 6 month follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
6. 73/M/C
\n\t\t\t
Reduced vision, eye pain, headaches with nasal blockage
\n\t\t\t
Sphenoid sinus involvement
\n\t\t\t
CT: Expansile mass within sphenoid sinus compressing on optic nerves
\n\t\t\t
Endoscopic sphenoethmoidectomy and marsupialization
\n\t\t\t
Symptom free at 1 year follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
7. 75/F/C
\n\t\t\t
Left epiphora with swelling at medial cantus
\n\t\t\t
Left Fronto-Ethmoid sinuses involvement
\n\t\t\t
CT: Opacification of left frontal and ethmoidal sinuses
\n\t\t\t
Endoscopic left frontal sinustomy with anterior and posterior ethmoidectomy with marsupialization
\n\t\t\t
Symptom free at 1 year follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
8. 71/F/C
\n\t\t\t
Right nasal blockage, rhinorrhea, sneezing with epiphora
\n\t\t\t
Right maxillary sinus involvement
\n\t\t\t
CT: Hypodense mass in right maxillary sinus with remodeling of maxillary wall and hard plate
\n\t\t\t
Endoscopic right MMA with Marsupialization
\n\t\t\t
Symptom free at 6 months follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
9. 63/F/C
\n\t\t\t
Pain left eye with reduced vision and headaches
\n\t\t\t
Left spheno-Ethmmoid sinuses involvement
\n\t\t\t
CT & MRI: Bilateral opacity of ethmoid and sphenoid sinuses with evidence of compression of optic nerve and cavernous sinus
\n\t\t\t
Endoscopic ethmosphenoidectomy with marsupialization
\n\t\t\t
Symptom free at 1 year follow up with no evidence of recurrence
\n\t\t
\n\t\t
\n\t\t\t
10. 39/M/I
\n\t\t\t
Headaches with right protosis, and diplopia
\n\t\t\t
Right frontal sinus involvement
\n\t\t\t
MRI: Opacity within right frontal sinus with mass effect on right superior and medial wall
\n\t\t\t
Endoscopic right frontal sinusotomy with marsupialization
\n\t\t\t
Symptoms improvement with no evidence of recurrence at 1 year follow up
\n\t\t
\n\t\t
\n\t\t\t
11. 8/M/I
\n\t\t\t
Headaches with vomitting
\n\t\t\t
Sphenoid sinus involvement
\n\t\t\t
MRI: Expansile mass within sphenoid sinus involving the sphenoethmoidal recess
\n\t\t\t
Endoscopic sphenoethmoidectomy with marsupialization
\n\t\t\t
Symptoms improved with no recurrence at 3 months
\n\t\t
\n\t\t
\n\t\t\t
12. 62/M/C
\n\t\t\t
Lt nasal blockage with foul smelling nasal discharge
\n\t\t\t
Left maxillary sinus involvement
\n\t\t\t
CT: Expansile left maxillary mass
\n\t\t\t
Endoscopic wide left MMA with marsupilization
\n\t\t\t
Post DXT NPC with no recurrence at 3 months
\n\t\t
\n\t\t
\n\t\t\t
13. 58/M/M
\n\t\t\t
Rt nasal blockage with foul smelling nasal discharge
\n\t\t\t
Right maxillary sinus involvement
\n\t\t\t
CT: Expansile right maxillary mass
\n\t\t\t
Endoscopic wide right MMA with marsupilization
\n\t\t\t
Symptoms improved with no recurrence at 6 months
\n\t\t
\n\t
Table 1.
Dermographic presentation of 13 patients with paranasal sinus mucocele
M – Male
F – Female
Race-M (Malay), C (Chinese), I (Indian)
Rt– Right
Lt – Left
MMA – Middle meatal antrostomy
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
Frontal
\n\t\t\t
Ethmoid
\n\t\t\t
Maxillary
\n\t\t\t
Sphenoid
\n\t\t
\n\t\t
\n\t\t\t
Number of cases
\n\t\t\t
6
\n\t\t\t
4
\n\t\t\t
3
\n\t\t\t
3
\n\t\t
\n\t
Table 2.
Sites of involvement of paranasal sinuses
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
Headache
\n\t\t\t
Diplopia
\n\t\t\t
Proptosis
\n\t\t\t
Reduced vision
\n\t\t\t
Reduced eye movement
\n\t\t\t
Nasal symptoms
\n\t\t\t
Vomiting
\n\t\t
\n\t\t
\n\t\t\t
Number of cases
\n\t\t\t
7
\n\t\t\t
2
\n\t\t\t
5
\n\t\t\t
3
\n\t\t\t
2
\n\t\t\t
5
\n\t\t\t
1
\n\t\t
\n\t
Table 3.
Clinical presentation of head and eye symptoms
Figure 1.
Coronal CT imaging of patient number 4 showing a right iatrogenic frontoethmoid mucocele with intraoperative endoscopic drainage and follow up at 3 months post surgery showing a patent frontal sinustomy
Figure 2.
Picture of patient number 10 showing gross right protosis and the respective axial and coronal MRI sections revealing expansile frontal sinus lesion with loss of scalloping suggestive of a mucocele
Figure 3.
Axial views and coronal sections of T1 and T2 weighted MRI images of patient number 11 showing an expansile sphenoid lesion suggestive of mucocele in a 8-year Indian male.
Figure 4.
Axial views and coronal sections of CT images of patient number 12 showing a left expansile mass in the maxillary sinus suggestive of a mucocele in a 62 year male Chinese.
3.1. Surgical technique
All patients were operated under general aneasthesia. The patient is placed in supine position with head slightly elevated. Packing that has been soaked in a 4% cocaine solution is placed in the nasal cavity to initiate mucosal vasoconstriction. Both eyes are exposed in the surgical field. Under endoscopic visualization, submucosal injections of 1% lidocaine with epinephrine are administred along the lateral nasal wall and middle turbinate. Briefly the endoscopic endonasal marsupilization is as follows: wide middle meatal antrostomy and marsupilization for maxillary mucocele; initially complete ethmoidectomy followed by removal of antero-inferior wall of the sphenoid mucocele and marsupilizing the cavity for ethmoid and sphenoid mucocele;uncinectomy, anterior ethmoidectomy and widening of the frontal recess (Draf type 2 procedure) and marsupilization for fronto-ethmoid mucocele.Patients’ are observed at weekly follow-up with secretion aspirated and sinonasal washing with saline solution upto one month post-surgery. Patients are checked upon at follow-ups every three months for first year than once a year.
4. Discussion
Paranasal sinus mucoceles are rare in children but relatively common in adults. In the literature, the etiologies of pediatric mucoceles have focused on impaired secretion process such as cystic fibrosis, pathological pneumatization processus, atopy and trauma, [7,8].
Mucoceles are commonly caused by post-operative ostial obstruction or secondary to trauma but can also present as primary disease. Paranasal sinus mucoceles predorminently occur in the fronto-ethmoid region (64%), followed by the maxillary sinus (18.6%), the sphenoid sinus (8.4%) and the posterior ethmoid sinus (6.7%) [9] which was similar to that in our study. Another common site for occurrence of mucocele is within the supraorbital ethmoid region. Primary sphenoid mucoceles can be found in association with chronic ethmoid sinusitis and/or nasal polyposis and are uncommon in isolation [10].
In the literature review, proptosis, periorbital pain and impairment of ocular mobility were the most common manifestations of mucoceles in the anterior paranasal sinuses while blurred vision and impairment of ocular mobility [11] were frequently seen in mucoceles in the posterior sinuses. Mucoceles of the anterior paranasal sinuses may expand the anterior and medial sinus walls, pushing the globe outward and downward and restrict movement of the extraocular muscles, thus causing proptosis and impairment of ocular mobility [4, 12, 13].
The natural development of sinus mucoceles consists of gradual expansion. This slow growing expansion can result in bone remodeling, bulging and erosion and reaches adjacent structures such as other sinuses, orbit, clivus, skull base or brain. In case of an intracranial complication, infection may even lead to conditions such as meningitis, subdural or brain abcess [14]. By extension into adjacent structures, the mucocele gives rise to a variety of clinical manifestations. The most common symptoms reported are headaches, facial pain, anosmia, ocular displacement, ocular palsy and visual failure. Visual symptoms in patients with sphenoid mucocele include diplopia, ocular muscle paresis, exopthalmus and complete visual loss [15, 16, 17, 18]. One should also be aware of unusual presentation including hypopituitarism [19, 20, 21].
The anatomical proximity and fragility of the orbital structures explains the high occurrence of ocular complications in sinusopathy. As the optic nerve enters the orbital apex from the intracranial portion, the nerve is encompassed by the narrow bony canal and is in close proximity to the posterior ethmoid and/or sphenoid sinus. In majority of cases the bony wall between the nerve and the sinuses is as thin as 40-60um [22, 23]. Intracranially the optic nerve is covered by the pia mater, arachnoid and CSF. As the nerve enters the canal, it is surrounded by two layers of nerve sheath, the outer which is continuous with the periorbita and the inner which en sheaths the nerve to the eyeball. The optic nerve canal can be identified as a semicircular tube when viewed from the inside of the posterior ethmoid or sphenoid sinus. Since the optic nerve canal contains the nerve and two layers of nerve sheath without any soft tissues such as fat, pressure due to expansion of the mucocele may easily impact the nerve if the thin protecting bony wall is resorbed or if it is dehiscent congenitally.
Blurred vision is more often associated with mucoceles in the posterior than anterior paranasal sinuses and can affect the optic or other cranial nerves via two pathways. Firstly, expansion of the paranasal sinus wall may compress the optic nerve or compromise its blood supply with subsequent optic atrophy [12, 24, 25]. Secondly, optic neuritis may result from direct spread of suppuration from adjacent paranasal sinuses via bone loss or bone fissure [12, 26]. Both optic nerve compression and neuritis can cause deterioration of visual acuity [12, 26]. Besides the optic nerve, other cranial nerves (abducent or oculomotor) passing through the orbital apex or superior orbital fissure may be involved, thus resulting in impairment of ocular mobility [12, 25, 26, 27].
In a review of 47 patients suffering from ethmoid or sphenoid mucoceles, Moriyama et al [28] highlighted 70 per cent of patients first sought help from the ophthalmology department. The mucocele may compress the optic canal and cause visual disturbances, leading to loss of eye sight in severe cases. Further to direct pressure, ischemia or venous congestion around the optic nerve subsequently occurs [28]. Besides compression and its local effects, inflammation due to infection of the mucocele can spread to the nerve through zones of bony erosion. Therefore, the visual loss may be due to a local inflammatory response which responds to steroid therapy [29] but further diagnosis and immediate surgical drainage are imperative.
Preoperative diagnosis is usually based on CT and MRI. On CT scan, mucoceles usually fill a sinus structure and bulge against adjacent anatomical structures, but without infiltration and usually the bony margins of the lesion are well defined. MRI of mucoceles in both T1 and T2 weighted images show variable signal intensities as depicted in Fig 3. CT scans are preferable for definitive evaluation, assessment of bony involvement and presurgical planning. MRI scans are helpful in the evaluation of orbital or intracranial extension and in ruling out a neoplasm or fungus disease [30]. Therefore, CT and MRI imaging are complementary for the diagnostic evaluation of an expansile mass around the posterior ethmoid and sphenoid sinus. In the differential diagnosis, one should rule out a mucopyocele, sinus malignancy, hypophyseal tumor, craniopharyngioma, meningioma or optic nerve glioma, intracranial chordoma,cholesteatoma and neoplastic lesions of nasopharynx.
An urgent surgical intervention is advocated in a paranasal sinus mucocele with vision loss. The endoscopic endonasal approach is the most convenient for the treatment of mucocele in view of easy access, lower morbidity and a reduction in potential complications compared to intracranial route [31]. Several recent literatures have reported successful results in the management of mucoceles with endoscopic marsupilization as the main choice of treatment [32]. It has the advantage of magnification of the operative field, is minimally invasive, preserves the sinus architecture and produces good long-term results with adequate post-operative care. Some conditions are not suitable for endoscopic surgery alone including a far laterally placed frontal mucocele, hypertrophic bone occluding the area of the fronto-nasal recess and a mucocele arising secondarily from a malignancy [33]. With respect to patient number 2, the extensive mucocele with intraorbital extension was removed using both an endoscopic and an external approach through bicoronal flap and cranialization [34].
The paranasal sinus mucocele is widely opened and a sufficient part of the wall or outflow pathway is resected for adequate drainage and ventilation. With exposure of the dura or peri-orbital wall, the wall of the mucocele acts as a cover and no attempts are made to remove this mucosal lining to protect the orbit, optic nerve, dura and carotid artery. On adequate marsupilization of the mucocele, one should expect a rapid improvement of visual acuity but in cases with complete loss of vision prior to surgery, the prognosis may be much poorer. The microdebrider is used in endonasal surgery with great easiness and good surgical outcome. The degree of improvement of the visual acuity after mucocele marsupilization depends on the severity of the initial loss prior to surgery, the mode of development and the location of the mucocele and the time from onset of the opthalmological disorder until the surgical marsupilization [9]. Prompt surgical treatment is necessary in order to avoid permanent visual impairment and other sequel [3, 18]. If vision is seriously impaired, immediate surgery should be performed, preferably within 24 hours after the onset of visual disturbances [35].
5. Differential diagnosis
5.1. Paranasal sinus tumors
The differential diagnosis of mucocele includes paranasal sinus tumors as shown in Table 4.
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tNon-neoplastic\n\t\t\t
\n\t\t\t
\n\t\t\t\tNeoplastic\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Mucosal cyst
\n\t\t\t
Papillomas
\n\t\t
\n\t\t
\n\t\t\t
Antrochonal polyp
\n\t\t\t
Mesenchymal tumors (fibroma, lipoma, myxoma)
\n\t\t
\n\t\t
\n\t\t\t
Fungal disease
\n\t\t\t
Vasiform tumors (hemangioma, aneurysmal bone cyst, hemangiopericytoma)
Classification of benign lesions of the paranasal sinus tumors
6. Non-neoplastic
6.1. Mucosal cyst
Mucosal cyct of the paranasal sinuses are common with and incidence between 12 and 36% detected on radiography [36, 37, 38]. They are broadly classified into secretory and non-secretary cysts [39]. Obstruction of mucosal gland leads to formation of secretory cysts which are less common. The more common non secretory cysts are presumably caused by an accumulation of exudates in the sinus mucosa lifting the epithelial lining. The aetiologic factors behind cyst formation remain unknown. They are mostly unilateral but can be bilateral in 10 to 20% cases [40], [41]. They are usually seen as homogenous, dome-shaped opacities on CT scanning and are usually a chance diagnosis on sinus radiography.
6.2. Antrochoanalpolyp (ACP)
ACP is a benign lesion that originates from the mucosa of the maxillary sinus and grows into the nasal cavity to reach the choana (Fig 5). ACPs account for 4 to 6% of all nasal polyps with increased incidence of 33% in children [42], [43]. ACPs are usually unilateral with only a small number of reported cases with bilateral polyps [16]. It has been suggested that most ACPs originate from the posterior-medial wall [44]. Mean age of presentation is 17 years and it is reported to be twice as common in males than females [44].
Figure 5.
(A) A zero degree endoscope view of a left antrochoanal polyp in an adult male and (B) a coronal CT section of same patient showing a homogenous opaque mass in the maxillary sinus with opasification of the middle meatus and extension into choana.
Clinical manifestations usually start with unilateral nasal obstruction but other symptoms have been reported such as epistaxis, purulent rhinorrhea, post-nasal drip, snoring, obstructive sleep apnea, dysphonia and dysphagia [42, 44].
6.3. Fungal disease
Most sinus fungal infections are caused by Aspergillus species. Aspergilus flavus is the most common cause of sinus fungal ball. Infections by dematiaceous fungi such as Bipolaris, Curvularia or Alternaria are commonly seen in patients with allergic fungal sinusitis. Zygomycetes, such as Mucorales or Rhizopus are well-described aggressive organisms implicated in many cases of invasive fungal sinusitis [45, 46, 47].Fungal rhinosinusitis can be classified as invasive or non-invasive (Table 5). The prognosis of the fungal sinus infections is more dependent on the manifestation of the disease than on the specific causative species.
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tNoninvasive\n\t\t\t
\n\t\t\t
\n\t\t\t\tInvasive\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Saprophytic
\n\t\t\t
Acute invasive fungal sinusitis
\n\t\t
\n\t\t
\n\t\t\t
Allergic fungal sinusitis
\n\t\t\t
Chronic granulomatous invasive sinusitis
\n\t\t
\n\t\t
\n\t\t\t
Fungal ball
\n\t\t\t
Chronic invasive fungal sinusitis
\n\t\t
\n\t
Table 5.
Classification of fungal sinusitis
Figure 6.
A zero degree endoscopic view of right nasal cavity showing evidence of allergic mucin in an adult male presenting with chronic rhinosinusitis
Associated nasal polyposis is seen in up to 10% due to the chronic inflammatory response. Maxillary sinus fungal ball often presents with unilateral sinus disease and unrelenting symptoms of rhinosinusitis. Allergic fungal sinusitis is characterized by the presence of allergic mucin in patients with symptoms of chronic rhinosinusitis, polyposis and an IgE-mediated hypersensitivity reaction to fungal elements resulting in a self-perpetuating inflammatory cascade (Fig 6). A high index of suspicion for invasive fungal sinusitis is necessary in patients with immunodeficiency, fever and symptoms referable to the paranasal sinuses. CT of paranasal sinuses is often ordered to evaluate refractory symptoms. Complete or subtotal opacification of the involved sinus is not uncommon. Up to 41% demonstrated heterogenous opacification with calcifications (Fig 7). Bony erosion or sclerosis from mass effect can be identified in 17 to 36% [48, 49, 50].
Figure 7.
A CT scan coronal section showing heterogenous opacification of the left nasal cavity with calcification in an adult female with fungal sinusitis
6.4. Cholesterol granuloma (CG)
CG is a histologic term used to describe the coexistence of granulation tissue with cholesterol crystals and foreign body giant cells [51].The condition is well described in the temporal bone but is rarely encountered in the paranasal sinuses [52]. The maxillary sinus is most commonly involved [52, 53]. Only one case of bilateral maxillary sinus involvement has been reported [53]. CG has been observed more in men with 3:1 male to female ratio and an average age of 41 years.Only a small number of patients had a history of previous trauma or surgery [52, 53].
The factors contributing to the formation of CG includes disturbed ventilation in a bony cavity, impaired drainage and hemorrhage [52, 53, 54, 55]. Impaired drainage would result in obstruction to venous and lymphatic circulation thus predisposing to mucosal hemorrhage. The insufficient lymphatic drainage would fail to eliminate lipid components in red blood cells and contribute to accumulation of cholesterol crystals. These act as foreign material that stimulates the granulomatous reaction in the sinus cavity [52, 53, 56].
Patients with CG present with symptoms and signs resembling chronic sinusitis [52, 53]. Most of the patients present with nasal obstruction, post-nasal drip, rhinorrhea, facial pain or headaches (Fig 8 A). CT shows a cyst-like opacity which does not enhance with contrast (Fig 8B). Bony erosion or expansion has been reported in a small number of cases [53, 56].
Figure 8.
(A) Intraoperative view with 45 degree endoscope showing a polypoid left sphenoid sinus cholesterol granuloma in a young adult female presenting with persistent vertax headaches and (B) a CT scan coronal section showing a homogenous partial opacification of the affected sphenoid sinus
6.5. Hematoma
Hematoma of the maxillary sinus is also known as organized hematoma or hemorrhagic pseudotumor [57, 58, 59]. It is an uncommon cause of maxillary sinus mass with only a small number of reported cases from Korea and Japan [58]. Some of the hematoma have been reported in patients with bleeding diathesis such as Von Willebrand disease but there are several patients who present with what appears to be a spontaneous etiology [58, 59, 60]. Initially, a blood clot accumulates in the maxillary sinus secondary to facial trauma, operative bleeding, recurrent epistaxis or bleeding diathesis. Subsequently the hematoma develops and due to poor ventilation and obstruction of drainage it transforms into an organized hematoma by means of neovascularization and fibrosis [58, 59]. Encapsulation of the blood clot by fibrous tissue prevents reabsorption of the hematoma. Further bleeding causes increasing pressure and progressive expansion which leads to erosion of adjacent structures [59], [60].
The most common symptom at presentation is epistaxis followed by unilateral obstruction and facial swelling [57, 58]. Symptoms due to pressure on adjacent structures such as proptosis and infraorbital hypoaesthesia have been reported [61, 62]. CT scanning shows the hematoma as a nonenhancing soft tissue mass which can be heterogeneous or homogenous. Histologically the hematoma has a peripheral wall that consists of dense fibrous tissue with a spindle-shaped myofibroblast cells. The center of the hematoma consist of loose fibrous tissue which is relatively acellular and contains some intact erythrocytes [57, 58, 62].
6.6. Antrolithiasis
Antrolithiasis are calcified bodies that are formed from mineral salt deposition around a nucleus within the maxillary sinus cavity [63]. These are synonymous with rhinoliths which are reported within the nasal cavity. Anthroliths result from either endogenous (blood clot, mucus or pus) or exogenous factors (teeth and roots or other foreign material. The majority of cases reported had tooth extraction prior to presentation. The patients can be asymptomatic and may present with symptoms of unilateral chronic maxillary sinusitis. CT scan shows antroliths as radiopaque masses of varying sizes and shapes with irregular borders.
6.7. Eosinophilic Angiocentric Fibrosis (EAF)
EAF is an uncommon inflammatory fibrotic lesion that affects the submucosa of the nose, larynx and orbit [64, 65]. The pathologic process is manifested by predorminently eosinophilic perivascular inflammation and gradual replacement with progressive fibrosis [64, 67]. EAF is found with slightly higher incidence in young to middle-aged women than men [64]. The etiology of EAF is unknown but it has been closely linked to granuloma faciale [64, 68]. Majority of the lesions involve the nasal septum and lateral nasal wall with only few cases involving the maxillary sinus.
EAF is slow growing and can take many years to manifest [64, 65]. Symptoms are non specific and can initially include nasal obstruction, rhinorrhea,epistaxis and facial pain [64, 67, 68]. Due to mass expansion the patients will present later with facial swelling [64, 65]. Involvement of the orbit can lead to periorbital edema and proptosis [64]. Nasal endoscopy reveals thickening of the nasal septum with an intranasal mass [64, 65].
7. Neoplastic
7.1. Papillomas
Papillomas are the most common benign epithelial tumor found in the sinonasal area accounting for 10% of all neoplasms in this region [66].Histologically they are divided into inverted,cylindrical and everted [67]. Everted papilloma more often arises on the nasal septum whereas both inverted and cylindrical papillomas mostly arise on the lateral nasal wall within the middle meatus (Fig 9). The age of presentation is from 35 to 60 years with a male preponderance of 3.5: 1 [66, 68]. It is more common in Caucasions compared with other racial groups. A viral aetiology has been suggested with a link to papilloma viral subtypes 6, 11,16 and 18 [68].
Figure 9.
A zero degree endoscopic view of a left inverted papilloma arising from the lateral nasal wall in an elderly male
Patients generally present with obstructive nasal symptoms, rhinorrhea and chronic rhinosinusitis [66, 68]. CT scans shows a mass in lateral nasal wall with areas of apparent calcification and there may be sclerosis of the walls of the sinus [81] (Fig 10). Both a high recurrence rate and malignant transformation have been documented. A recent review of the literature of over 200 cases calculated 7.1% synchronous carcinoma and 3.6% metachronous carcinoma [70].
Figure 10.
A coronal CT scan section showing an aggressive inverted papilloma (hybrid tumor) arising from the left nasal cavity with evidence of anterior skull base erosion in an elderly Chinese male presenting with CSF rhinorrhea
7.2. Mesenchymal tumors: Fibroma, lipoma and myxoma
These rare tumors may be encountered in the nose and sinuses and generally present prior to adulthood. Isolated tumors within maxillary sinus are very rare.
7.2.1. Fibromas
Fibromas result from progressive inflammation or fibroblastic proliferation of the nasal mucosa [71]. They present as slow-growing, grey-white, smooth surfaced masses producing obstructive nasal symptoms.
7.2.2. Lipoma
Lipoma is the most common soft tissue tumor in adulthood in contrast to intraosseouslipoma which is a rare condition.The etiology of intraosseous lipoma is unknown but infaction, ischaemia, trauma and irradiation may be contributing factors [72]. Cases have been reported within the nasal cavity and very rarely in the maxillary sinus. The presentation is of nasal swelling and possible nasal obstruction.
7.2.3. Myxoma
Myxoma of the maxillary sinus is very rare but more frequent than fibromas and lipomas [73]. The age of presentation is between 2 and 15 years and may be related to dental malformations or missing teeth.
7.3. Vasiform Tumors: Hemangioma, Aneurysmal Bone Cyst and Hemangiopericytoma
These benign lesions arise from vascular tissue within the mucosa or bone of the nose and sinuses.
7.3.1. Hemangiomas
Hemangiomas represent about 20% of benign non-epithelial tumors of nasal cavity and paranasal sinuses [74]. Mean age of diagnosis is 40 years and the most frequent presenting symptoms are nasal obstruction and epistaxis. Invovement of maxillary sinus have been reported less frequently [91]. Both cavernous and capillary hemangiomas have been reported.
7.3.2. Aneurysmal bone cyst (ABCs)
ABCs are expansile lesions of unknown etiology that involves long bones and vertebrae of patients younger than 20 years. About 2% of ABCs are encountered in the head and neck region with jaw being the most frequently involved site. The present with facial swelling and obstructive nasal symptoms in the age group between 5 and 23 years. ABCs consist of multiple cavities filled with blood and serous fluids which are separated by septa and surrounded by rim of bone [75]. ABCs have a “honeycomb”appearance on gadolinium-enhanced MRI studies [75].
7.3.3. Hemangiopericytoma (HPC)
HPC is a rare benign vascular tumor derived from extracapillary cells (pericytes). Less than one-third of HPC occur in the head and neck and 5% are located in the nasal cavity and paranasal sinuses [76, 77]. Sphenoid and ethmoid sinuses are involved more frequently than the maxillary sinus. Both sexes are equally affected and can occur at any age but often develop after the second decade. The patients usually present with epistaxis and nasal obstruction with reddish submucosal nasal mass (Fig 11).
Figure 11.
(A) View with 30 degree endoscope in an adult Chinese female presenting with right nasal obstruction and maxillary sinus discomfort and (B) CT scan coronal section showing a polypoidal mass arising from the right maxillary sinus and histopathology report consistent with hemangiopericytoma
7.4. Tumors of muscle origin: Leiomyoma and rhabdomyoma
7.4.1. Leiomyoma
Leiomyoma is a smooth muscle tumor that originates in areas of abundance of muscle like the uterus.
It is extremely rare for these tumors to present in the sinonasal tract because of the paucity of smooth muscle. And only a handful of cases have been reported in the maxillary sinus [78]. The tumor seem to be slow-growing and non-aggressive and presenting with obstructive nasal symptoms.
7.4.2. Rhabdomyoma
Rhabdomyomais a skeletal muscle tumor and is extremely rare in the paranasal sinus.,which has a benign behavior and low recurrence rate [79, 80].
7.5. Odontogenic tumors
Odontogenic tumors originate either within the maxillofacial skeleton (intraosseous) or within the gingival or alveolar mucosa overlying the tooth bearing areas (extraosseous). They are usually slow growing and have been associated with non-eruption of the teeth. Patients usually present with swelling of alveolar process along with nasal obstruction and epistaxis. Superior displacement of globe has been reported with large odontogenic tumors.
7.5.1. Ameloblastoma
Ameloblastomais the most common odontogenic tumor. It is slow growing, locally invasive and has a high rate of recurrence if not treated effectively. Patients between the ages of 16 and 60 years are generally affected with the region of canine tooth and maxilla being the most common sites. They are often asymptomatic but can present with a painless swelling of the cheek, gingival and palate that may reach a large size. Ameloblastoma presents as a unilocular or multilocular radiolucency that may be associated with an impacted tooth.
7.6. Fibro-osseous lesions: Osteoma, ossifying fibroma, fibrous dysplasia and osteoblastoma
Fibro-osseous lesions represent a class of bony abnormalities: osteoma, ossifying fibroma, fibrous dysplasia and osteoblastoma. They are distinct but lie along a continuum from the most to the least content. They have some similarities in appearance but their clinical implications differ.
7.6.1. Osteomas
Osteomas are frequent incidental finding in up to 3% of CT scans of the paranasal sinuses [81] (Fig 12). Eighty percent occur in the frontal sinuses followed by the ethmoids and least in the maxillary sinuses. The etiology is either embryologic or secondary to trauma or an infective process. There is an association with Gardner syndrome which is an autosomal dominant condition characterized by intestinal polyposis and pigmented skin lesions in addition to osteomas [82]. Maxillary sinus osteomas are slow growing and usually asymptomatic but they may become symptomatic depending on the location and onset [83].
Figure 12.
(A) A CT scan coronal and (B) sagittal section showing osteoma arising from the anterior ethmoid sinuses in an adult female presenting with frequent headaches
7.6.2. Ossifying fibroma (OF)
OF is a well-circumscribed lesion that continues to grow after sexual maturity and can attain dramatic proportions [81, 84]. The vast majority is located in the posterior region of the mandible; those involving the maxillary sinus are uncommon [85]. Patient usually present between the third and forth decades and the lesion is more common in women [85]. The most common presentation is of painless cheek swelling but involvement of the orbit or nasal cavity may be signified by proptosis, loss of visual acuity, epiphora, nasal obstruction and epistaxis [81, 85]. Radiologically, the lesion is sharply circumscribed with an egg shell rim and central radiolucency which differentiates it from fibrous dysplasia with its indistinguishable borders.
7.6.3. Fibrous dysplasia (FD)
FD is a slow, progressive disorder where normal bone is replaced by fibrous tissue and immature woven bone [81, 84]. There are two main forms of FD: monostatic (70-85%) that involves only one bone and polystatic (15-30%) where multiple bones can be involved (Fig 13). The maxilla and mandible are the most commonly involved bones generally in the monostatic form. FD is a disease of the young where patients present in their first or second decade and is assumed to be “burnt out” as the patients reach skeletal maturity. The usual symptom is of painless facial deformity although other complaints such as loosening of teeth, nasal obstruction or epistaxis have been encountered [86]. CT scans shows lesions with indistinct borders and a homogenous “ground glass” appearance.
Figure 13.
An axial CT section showing a polystatic fibrous dysplasia in an adult female
7.6.4. Osteoblastoma
Osteoblastoma is an uncommon neoplasm characterized by proliferation of osteoblasts forming bone trabeculae set in a vascularized fibrous connective tissue stroma [87]. The tumor occur predorminantly in vertebrae and long bones and can affect craniofacial bones with the mandible being the most commonly involved. It is reported less in the maxillary bone and rarely in the maxillary sinus [88]. The majority of the patients are under 30 years and present with a facial swelling and is often painful [87]. CT scan features range from radiolucent to radiopaque lesions and are often mistaken for other fibro-osseous lesions.
7.7. Neuroectodermal tumors: Schwannoma and neurofibroma
7.7.1. Schwannomas
Schwannomas are benign nerve sheath tumors of which 50% occur in the head and neck region. They are very uncommon in the paranasal sinuses (only 4%) and a very small number involve the maxillary sinus [84]. The lesion slowly expands in the sinus cavity resulting in swelling, pressure symptoms and bony necrosis. The patients mostly present with nasal obstruction but other symptoms such as proptosis, epiphora, headaches, facial anesthesia and epistaxis have been reported [90]. CT scan shows a homogenous radio-opaque mass with evidence of bone remodeling (Fig 14).
Figure 14.
An axial CT section showing a left homogenous radio-opaque mass involving the maxillary sinus and infratemporal region in an adult female
7.7.2. Neurofibromas
Neurofibromas are heterogenous peripheral nerve tumors that arise from the connective tissue of the nerves especially the endoneurium [91]. They may occur as sporadic lesions but are much more common in association with neurofibromatosis type 1 (NF 1). Neurofibromas of the maxillary sinus are exceedingly rare.As with schwannomas, they slowly grow and expand within the sinus cavity causing swelling, pressure symptoms and bone necrosis. Presentation is similar to other expanding masses in the maxillary sinus. CT scan shows a well-circumscribed mass with some bony erosion.
8. Conclusion
Mucocele of the paranasal sinuses are well described complication of chronic sinusitis in adults but they rarely occur in the pediatric population. Mucocele can be associated with ophthalmic complications or intracranial complications. Radiological imaging includes CT-scan and sometimes MRI when intracranial complications are suspected. The differential diagnosis of mucocele includes paranasal sinus tumors. Usually a wide endoscopic endonasal marsupilization of paranasal sinus mucocele is a safe and less invasive than external approaches. Thus, a good understanding of paranasal sinus mucoceles by ophthalmologists and otorhinolaryngologists is essential for early diagnosis and rapid surgical intervention.
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Introduction",level:"1"},{id:"sec_2",title:"2. Material and methods",level:"1"},{id:"sec_3",title:"3. Results",level:"1"},{id:"sec_3_2",title:"3.1. Surgical technique",level:"2"},{id:"sec_5",title:"4. Discussion",level:"1"},{id:"sec_6",title:"5. Differential diagnosis",level:"1"},{id:"sec_6_2",title:"5.1. Paranasal sinus tumors",level:"2"},{id:"sec_8",title:"6. Non-neoplastic",level:"1"},{id:"sec_8_2",title:"6.1. Mucosal cyst",level:"2"},{id:"sec_9_2",title:"6.2. Antrochoanalpolyp (ACP) ",level:"2"},{id:"sec_10_2",title:"6.3. Fungal disease",level:"2"},{id:"sec_11_2",title:"6.4. Cholesterol granuloma (CG) ",level:"2"},{id:"sec_12_2",title:"6.5. Hematoma",level:"2"},{id:"sec_13_2",title:"6.6. Antrolithiasis",level:"2"},{id:"sec_14_2",title:"6.7. Eosinophilic Angiocentric Fibrosis (EAF) ",level:"2"},{id:"sec_16",title:"7. Neoplastic",level:"1"},{id:"sec_16_2",title:"7.1. Papillomas",level:"2"},{id:"sec_17_2",title:"7.2. Mesenchymal tumors: Fibroma, lipoma and myxoma",level:"2"},{id:"sec_17_3",title:"7.2.1. Fibromas ",level:"3"},{id:"sec_18_3",title:"7.2.2. Lipoma",level:"3"},{id:"sec_19_3",title:"7.2.3. Myxoma",level:"3"},{id:"sec_21_2",title:"7.3. Vasiform Tumors: Hemangioma, Aneurysmal Bone Cyst and Hemangiopericytoma",level:"2"},{id:"sec_21_3",title:"7.3.1. Hemangiomas",level:"3"},{id:"sec_22_3",title:"7.3.2. Aneurysmal bone cyst (ABCs) ",level:"3"},{id:"sec_23_3",title:"7.3.3. Hemangiopericytoma (HPC) ",level:"3"},{id:"sec_25_2",title:"7.4. Tumors of muscle origin: Leiomyoma and rhabdomyoma",level:"2"},{id:"sec_25_3",title:"7.4.1. Leiomyoma ",level:"3"},{id:"sec_26_3",title:"7.4.2. Rhabdomyoma",level:"3"},{id:"sec_28_2",title:"7.5. Odontogenic tumors",level:"2"},{id:"sec_28_3",title:"7.5.1. Ameloblastoma",level:"3"},{id:"sec_30_2",title:"7.6. Fibro-osseous lesions: Osteoma, ossifying fibroma, fibrous dysplasia and osteoblastoma",level:"2"},{id:"sec_30_3",title:"7.6.1. Osteomas",level:"3"},{id:"sec_31_3",title:"7.6.2. Ossifying fibroma (OF) ",level:"3"},{id:"sec_32_3",title:"7.6.3. Fibrous dysplasia (FD) ",level:"3"},{id:"sec_33_3",title:"7.6.4. Osteoblastoma",level:"3"},{id:"sec_35_2",title:"7.7. Neuroectodermal tumors: Schwannoma and neurofibroma",level:"2"},{id:"sec_35_3",title:"7.7.1. Schwannomas",level:"3"},{id:"sec_36_3",title:"7.7.2. Neurofibromas",level:"3"},{id:"sec_39",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Alberti PW, Marshall HF, Black JI. 1968. Fronto-ethmoidalmucocele as a cause of unilateral proptosis. Br J Ophthalmol52: 833-838'},{id:"B2",body:'Johnson JT, Ferguson BJ. 1998. Infection in: Cummings CW, Fredrickson JM, Harker LA, Krause CJ, Schuller DE, Rhicharson MA, eds Otolaryngology Head Neck Surgery, 3rd edition. St Louis: Mosby1115-1116'},{id:"B3",body:'Maniglia AJ, Kronberg FG, Culbertson W. 1984. Visual loss associated with orbital and sinus disease. 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Med Mycol 47(Suppl 1):S309-S314'},{id:"B46",body:'Michael RC, Michael JS, Ashbee RH, Matthews MS. 2008. Mucological profile of fungal sinusitis:an audit of specimens over a 7-year period in a tertiary care hospital in Tamil Nadu. Indian J PatholMicrobiol 51(4): 493-496 Abstract'},{id:"B47",body:'Plszewski J, Milonski J. 2008. The analysis of the bacterial and fungal flora in maxillary sinuses in patients operated due to FESS method. Otolaryngol Pol 62(4):458-461'},{id:"B48",body:'Ferguson BJ. 2000. Fungal balls of the paranasal sinuses. Otolaryngol Clin North Am 33(2):389-398'},{id:"B49",body:'Ferreiro JA, Carlson BA, Cody DT. 1997. Paranasal sinus fungal balls. Head Neck 19(6):481-486'},{id:"B50",body:'Klossek JM, Serrano E, Peloquin L, Percodi J, Fontanel JP, Pessey JJ. 1997. Functional endoscopic sinus surgery and 109 mycetomas of paranasal sinuses. Laryngoscope 107(1):112-117'},{id:"B51",body:'Friedmann I, Osborn DA. 1982. Pathology of granulomas and neoplasms of the nose and paranasal sinuses. In: WStCSymmers, ed. Systemic Pathology. Edinburgh/London/New York:Churchill Livingston:1920235'},{id:"B52",body:'Astarci HM, Sungu N, Samim EE, Ustun H. 2008. Presence of cholesterol granuloma in the maxillary and ethmoid sinuses. Oral Maxillofac Surg 12(2):101-103'},{id:"B53",body:'Chao TK. 2006. Cholesterol granuloma of the maxillary sinus. Eur Arch Otorhinolaryngol 263(6):592-597'},{id:"B54",body:'Graham J, Michaels L. 1978. Cholesterol, granuloma of the maxillary antrum. Clin Otolaryngol Allied Sci 3(@):155-160'},{id:"B55",body:'Niho M. 1986. Cholesterol crystals in the temporal bone and the paranasal sinuses. Int J Pediatr Otorhinolaryngol 11(1):79-95'},{id:"B56",body:'Kunt T, Ozturkan S, Egilmez R. 1998. Cholesterol granuloma of the maxillary sinus: six cases from the same region. J Laryngol Otol 112(1):65-68'},{id:"B57",body:'Lim M, Lew-Ghor S, Beale T, Ramsay A, Lund VJ. 2008. Maxillary sinus haematoma. J Laryngol Otol 122(2): 210-212'},{id:"B58",body:'Song HM, Jang YJ, Chung YS, Lee BJ. 2007. Organizing hematoma of the maxillary sinus. Otolaryngol Head Neck Surg 136(4):616-620'},{id:"B59",body:'LeePK, Wu JK, Ludemann JP. 2004. Hemorrhagic pseudotumor of the maxillary sinus. J Otolaryngol 33(3):206-208'},{id:"B60",body:'Ozhan S, Arac M, Isik S, Oznur 11, Atilla S, Kemaloglu Y. 1996. Pseudotumor of the maxillary sinus in a patient with von Willebrand’s disease. Am J Roentgenol 166(4):950-951'},{id:"B61",body:'Lee BJ, Park HJ, Hoe SC. 2003. Organized hematoma of the maxillary sinus, Acta Otolaryngol 123(7): 869-872'},{id:"B62",body:'Tabaee A, Kacker A. 2002. Hematoma of the maxillary sinus presenting as a mass- a case report and review of literature. Int J Pediatr Otorhinolaryngol 65(2):153-157'},{id:"B63",body:'Guneri P, Kaya A, Caliskan MK. 2005. Antroliths:survey of the literature and report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 99(4):517-521'},{id:"B64",body:'Kosarac O, Luna MA, RoJ Y, Ayala AG. 2008. Eosinophilic angiocentric fibrosis of the sinonasal tract. Ann Diagn Pathol 12(4):267-270'},{id:"B65",body:'Paun S, Lund VJ, Gallimore A. 2005. Nasal fibrosis:long-term follow-up of four cases of Eosinophilic angiocentric fibrosis. J Laryngol Otol 119(2):119-124'},{id:"B66",body:'Lund VJ. 2000. Optimum management of inverted papilloma. J Laryngol Otol 114(3): 194-197'},{id:"B67",body:'Michaels L. 1996. Benign mucosal tumors of the nose and paranasal sinuses. Semi-n Diagn Pathol 13(2):113-117'},{id:"B68",body:'Minovi A, Kollert M, Draf W, Bockmuhl U. 2006. Inverted papilloma: feasibility of endonasal surgery and long-term results of 87 cases. Rhinology 44(3):205-210'},{id:"B69",body:'Savy L, Lloyd G, Lund VJ, Howard D. Optimum imaging for inverted papilloma. J Laryngol Otol 114(11):891-893'},{id:"B70",body:'Mirza S, Bradley PJ, Acharya A, Stacey M, Jones NS. 2007. Sinonasal inverted papillomas:recurrence and synchoronous and metachronous malignancy. J Laryngol Otol 121(9):857-864'},{id:"B71",body:'Lin HL, Huang CC, Lee TJ. 2004. Endoscopic sinus surgery treatment for a huge sinonasal fibroma. Chang Gung Med J 27(3):233-237'},{id:"B72",body:'Uysal A, Kayiran O, Cuzdan SS, Bektas CI, Aslan G, Caydere M. 2007. Maxillary sinus lipoma:an unanticipated diagnosis. J Craniofac Surg 18(5):1153-1155'},{id:"B73",body:'Gregor RT, Loftus-Coll B. 1994. Myxoma of the paranasal sinuses. J Laryngol Otol 108(8):679-681'},{id:"B74",body:'Rabaso E, Rosell A, Plaza G, Martinez-Vidal A. Haemangioma of the maxillary sinus. J Laryngol Otol 111(7):638-640'},{id:"B75",body:'Fyrmpas G, Constantinidis J, Televantou D, Konstantinidis I, Daniilidis J. 2006. Primary aneurismal bone cyst of the maxillary sinus in a child: case report and review of the literature. Eur Arch Otorhinolaryngol 263(7):695-698'},{id:"B76",body:'Herve S, AbdAlsamad I, Beautru R, et al. 1993. Management of sinonasal hemangiopericytomas. Rhinology 37(4):153-158'},{id:"B77",body:'Stomeo F, Fois V, Cossu A, Meloni F, Pastore A, Bozzo C. 2004. Sinonasal hemangiopericytoma: a case report. Eur Arch Otorhinolaryngol 261(10): 555-557'},{id:"B78",body:'LaBruna A, Reagan B, Papageorge A, 1995. Leiomyoma of the maxillary sinus; a diagnostic dilemma. Otolaryngol Head Neck Surg 112(4): 595-598'},{id:"B79",body:'Fu YS, Perkin KH. 1976. Nonepithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: a clinicopathologic study of skeletal muscle tumors(rhabdomyoma and rhabdosarcoma). Cancer 37(1):364-376'},{id:"B80",body:'Reitter GS. 1921. Rhabdomyosarcoma of the nose: report of case. JAMA 76:22-23'},{id:"B81",body:'Eller R, Sillers M. 2006. Common fibro-osseous lesions of the paranasal sinuses. Otolaryngol Clin North Am 39(3): 585-600'},{id:"B82",body:'Alexander AA, Patel AA, Odland R. 2007. Paranasal sinus osteomas and Gardner’s syndrome. Ann OtolRhinolLaryngol 116(6):658-662'},{id:"B83",body:'Park W, Kim HS. 2006. Osteoma of maxillary sinus: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102(6):e26-e27'},{id:"B84",body:'Harrison DF. 1984. Osseous and fibro-osseous conditions affecting the craniofacial bones. Ann OtolRhinolLaryngol 93(3 Pt 1):199-203'},{id:"B85",body:'Chong VF, Tan LH. 1997. Maxillary sinus ossifying fibroma. Am J Otolaryngol 18(6): 419-424'},{id:"B86",body:'Muraoka H, Ishihara A, Kumagai J. 2001. Fibrous dysplasia with cystic appearance in maxillary sinus. Auris Nasus Larynx 28(1):103-105'},{id:"B87",body:'Jones AC, Prihoda TJ, Kacher JE, Odingo NA, Freedman PD. 2006. Osteoblastoma of the maxilla and mandible: A report of 24 cases and review of literature and discussion of its relationship to osteodosteoma of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102(5):639-650'},{id:"B88",body:'Osguthorpe JD, Hungerford GD. 1983. Benign osteoblastoma of the maxillary sinus. Head Neck Surg 6(1): 605-609'},{id:"B89",body:'Sarioglu S, Ozkal S, Guneri A, et al 2002. Cystic schwannoma of the maxillary sinus. Auris Nasus Larynx 29(3):297-300'},{id:"B90",body:'Sheikh HY, Chakravathy RP, Slevin NJ, Sykes AJ, Banerjee SS. 208. Benign schwannoma in paranasl sinuses: a clinic-patological study of five cases emphasizing diagnostic difficulties. J Laryngol Otol 122(6):598-602'},{id:"B91",body:'Boedeker CC, Ridder GJ, Kayser G, Schipper J, Maier W. 2005. Solitary neurofibroma of the maxillary sinus and pterygopalatine fossa. Otolaryngol Head Neck Surg 133(3): 458-459'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Balwant Singh Gendeh",address:"bsgendeh@gmail.com",affiliation:'
Department of Otorhinolaryngology-Head Neck Surgery, UKM Medical Center, Jalan Yaacob Latif, Bandar Tun Razak, Kuala Lumpur, Malaysia
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1. Introduction
Metabolomics is the study of metabolites within biofluids, cells, tissues, or organisms [1]. Whereas collectively, metabolites and their interactions are known as metabolome [2].
Metabolites are small molecules produced by metabolic reactions; these molecules are intermediate or end products of metabolic reactions. The metabolic reactions are catalyzed by naturally occurring enzymes within the organisms’ cells [3]. Compounds derived from primary and secondary metabolism are known as primary and secondary metabolites, respectively.
Primary metabolites are indispensable compounds used by organisms for their growth, development, and reproduction; these compounds are synthesized by the cells as a result of metabolism during the growth phase. Primary metabolites are referred to as central metabolites due to their key role in maintaining normal physiological processes. Primary metabolites include vitamins (B2 and B12), lactic acid, amino acids, polyols, alcohols such as ethanol, nucleotides, organic acids, etc. [3, 4].
The current chapter discusses the meaning and origin or sources of some important classes of secondary metabolites such as alkaloids, terpenoids, tannins, flavonoids, saponins, cardiac glycosides, phenolic compounds, etc., the economic impacts of secondary metabolite compounds including their role in improving human and animal health and well-being (as antibiotics, anticancer, anti-inflammatory, antifertility, antidiabetics, pain relievers, growth promoters, etc.). The chapter addresses the role of secondary metabolites in enhancing agricultural productivity (as pesticides, insecticides, preservatives, etc.); it also discusses the important present-day drugs derived from secondary metabolites, as well as some important biological/pharmacological effects or activities of different classes of the secondary metabolites and their folkloric usage based on reliable sources of information and genuine scientific investigations.
1.1 The meaning and origin of important classes of secondary metabolites
Secondary metabolites also known as phytochemical constituents, bioactive compounds, specialized metabolites, secondary products, or toxins are organic compounds produced by organisms such as plants, fungi, or bacteria as a result of secondary metabolic processes that lead to production and accumulation of diverse chemical compounds known as secondary metabolites. These compounds are not required for primary metabolic processes by the organisms [3, 4, 5]. Secondary metabolites are formed toward the end of the growth phase; thus, they are not directly involved in the normal physiologic processes of the organism such growth and development as well as reproductive processes. Instead, they increase the organism’s survivability through mediation of ecological interaction, to the organism, this serves as a selective advantage [4, 5]. Interspecies defenses such as defense against herbivory by plants are part of the important roles of secondary metabolites. However, humans use secondary metabolites as medicines, recreational drugs, flavorings, pigments, etc. [6].
Secondary metabolites are classified commonly based on their vast structural diversity, biosynthesis, and function. According to the literature, over 2140, 000 secondary metabolites are known; however, the main classes of secondary metabolites are five, which include alkaloids, terpenoids and steroids, nonribosomal polypeptides, polyketides and fatty-acid-derived substances, and enzyme cofactors [7].
1.2 The origin and sources of some important classes of secondary metabolites
Secondary metabolite is a term coined in 1910 by a Medicine and Physiology Nobel Prize laureate, Albert Kossel [8]. Friedrich Czapek, a Polish botanist, 30 years later described them as metabolic nitrogenous end products [9].
Secondary metabolites are produced by plants, fungi, or bacteria as well as many marine organisms such as snails, corals, tunicates, and sponges [10]. There are 150, 000–200, 000 bioactive compounds derived from the plant kingdom, 50, 000–100, 000 from animal kingdom, and 22,000–23, 000 from microbes [11].
1.3 Plant secondary metabolites
Plants are the major sources of secondary metabolites; they produced 80% of the known secondary metabolites occurring in nature [10]. Secondary metabolites are used by carnivorous plants to attract, capture, digest, and assimilate the prey [12]. One of the early known plant secondary metabolites is morphine, isolated in 1804 [11].
1.4 Fungal secondary metabolites
In 1928, Alexander Fleming while working at St Mary’s Hospital in London discovered the most known secondary metabolite, the penicillin. Penicillin was discovered experimentally from a mold, the Penicillium notatum [13, 14].
1.5 Bacterial secondary metabolites
Oligosaccharide, b-lactam, polyketide, non-ribosomal pathways, and shikimate are the main secondary metabolite production pathways in bacteria [15]. Although bacterial secondary metabolites have some beneficial effects, many are toxic to mammals through secretion of exotoxin, botulinum toxin secreted by Clostridium botulinum bacteria is a very good example [15].
1.6 The alkaloids
The name alkaloid was introduced by Carl Friedrich Wilhelm Meißner, in the year 1819. The name was derived from Latin root alkali, rooted from Arabic word al-qalwi meaning plants ashes. The wide usage of the word alkaloid came after J. Oscar’s publication in the year 1880 in Albert Ladenburg, the chemical dictionary [16].
A large variety of organisms produced alkaloids; these chemical compounds are derived from plants, bacteria, fungi, and animals [17]. Morphine was the first individual alkaloid isolated in 1804 from the opium poppy plant (Papaver somniferum) [18].
1.7 The cardiac glycosides
The ancient Romans, Syrians, and Egyptians used cardiac glycosides contained in plant extracts for medicinal purposes, the plant extracts from Urginea maritima (Scilla), squill, or sea onion were used as emetics and heart tonics. African warriors in the medieval age used Strophanthus species as arrows head poison against their targets. Cardiac glycosides were established in the twentieth century as agent for the treatment of heart failure [19].
Early writings of 1250 BC mentioned Digitalis purpurea; digitalis was included in herbal collections used in prescription by the Welsh family physicians. The origin of digitalis was from the foxglove plant. A botanist and physician of English origin, William withering in the eighteenth century described the foxglove plant’s clinical effects in a published monograph. He was the first investigator of the systemic bioactivity of digitalis. “An account of the Foxglove and some of its medical uses with practical remarks on dropsy, and other diseases” is a book authored by William Withering in 1785 reporting the toxicity and indications of digitalis [19].
Plant is main source of cardiac glycosides; however, bufadienolide was isolated from frogs and mammalian tissues that are rich sources of endogenous digitalis; this show that animal species are also good sources of cardiac glycosides [20].
1.8 The flavonoids
Flavonoids or bioflavonoids are yellow compounds derived from the Latin word Flavus, meaning yellow, their natural coloration [21]. Albert Szent-Györgyi and some group of scientists in the 1930s discovered that crude yellow extracts from lemons, oranges, etc., were more effective at preventing scurvy than vitamin C. They referred to these compounds as citrin or vitamin P, which were later discovered to be hesperidin, neohesperidin, etc., belonging to flavonoids rather than the vitamins [22].
Flavonoids are compounds belonging to polyphenolic structural class of secondary metabolites. They are widely found in vegetables, fruits, flowers, wine, tea, grains, roots, bark, and stem [23, 24]. Flavonoid compounds are found in several parts of plants, they are products extracted from plants using various extraction techniques such as chromatography [25].
1.9 The phenolic compounds
Phenolic compounds are secondary metabolites produced by the secondary metabolic pathways of plants [26]. They are derived from pentose phosphate and shikimic acid of plants through metabolization of phenylpropanoid [27, 28]. The composition of phenolic substances or polyphenols includes tannins, flavonoids, lignans, coumarins, and phenolic acids [26], colored anthocyanins [29]; these compounds are naturally found in vegetables, fruits, leaves, and roots among other products of plant origin [26, 27].
1.10 The tannins
Tannins are group of astringent and complex polyphenolic compounds found in plants, which can bind and precipitate proteins; the word tannin was derived from the usage of this compound in tanning animal hides and skins to make leather [30]; the term was first introduced in 1796 [31]. Commonly, tannins are found in wood, buds, fruits, leaves, stems, roots, seeds, and in the bark of trees [32]. Condensed tannins are the most abundant polyphenols, which are virtually found in plant families [33].
1.11 The terpenoids
Terpenoids or isoprenoids are modified terpenes [34, 35]; terpenoids usually contain additional functional group and oxygen [35]. These chemical compounds are the largest class of secondary metabolites representing 60% of the natural products known [36].
2. The biological activities of secondary metabolites
Unique structural diversity is provided by natural products when compared with standard combinatorial chemistry; these give opportunities for discovering novel lead compounds with low molecular weight. The world’s biodiversity evaluation of natural products for potential biological activity is less than 10%; thus, a lot of useful novel natural lead compounds await discovery [37].
Terrestrial plants are the major source of secondary metabolites; other sources include fungi, bacteria, as well as several marine organisms [10].
2.1 The pharmacological activity of plant-derived secondary metabolites
2.1.1 Antibacterial activity
Natural antibiotics are secondary metabolites produced by microbes that inhibit bacterial growth by targeting essential cellular processes such as the synthesis of the bacterial cell wall, DNA/RNA, and proteins. They are not essential for the growth of the organism (and usually produce at the end of the exponential phase of their growth). They have diverse roles, such as in cellular differentiation, nutrient sequestration, metal transport, ecological interactions, and defense [38, 39].
Between 1935 and 1968, 12 classes of antibiotics were launched and approved for use as drugs. However, between 1969 and 2000, the number dropped markedly, with only two classes introduced. Out of the 30 antibiotics launched between the year 2003 and 2015, 16 belong to natural products and their derivatives. They include three new classes of natural antibiotics—two actinomycete: the lipopeptide daptomycin in 2003 and fidaxomicin (of the tiacumicin family) in 2010. The third is a fungal product: retapamulin derived from pleuromutilin and approved in 2007 for topical use [38, 40].
Newman and Cragg reported the introduction of several natural secondary metabolites that have been reported to possess potent antibacterial activity including: anthrasil, omadacycline, dalbavacin, plazomicin, ceftaroline fasamil acetate, lefamulin, sarecycline, eravacycline imi-cilast-relebactam, etc. [41].
2.1.2 Anti-inflammatory activity
Inflammation is a normal biological process that occurs as a response to microbial infection, chemical irritation, or tissue injury. It is usually initiated by moving the immune cells from blood vessels and release of mediators to the damage site. It is then followed by reinforcement with inflammatory cells, release of reactive oxygen species (ROS), reactive nitrogen species (RNS), and proinflammatory cytokines to fight the foreign pathogens and repairing the injured tissues. In general, normal inflammation is rapid and self-limiting, but unresolved and prolonged inflammation causes various chronic disorders. As a pathologic condition, inflammation can include a wide range of diseases such as rheumatic and immune-mediated conditions, diabetes, cardiovascular accident, etc. [38, 42]. Aswad and coworkers reported the use of moupinamide, capsaicin, and hypaphorine—natural products—with high scores in their indexing of potential anti-inflammatory drug candidates [43]. Mona et al. also reported more than 15 herbs, where their anti-inflammatory effects have been evaluated in clinical and experimental studies including Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis [42].
2.1.3 Anticancer activity
Cancer is one of the leading causes of death (second to cardiovascular diseases) in the world, despite the availability of wide range of anticancer drugs. The estimated cancer burden in the world as reported by the World Health Organization (WHO) is 18.1 million new cases and 9.6 million deaths as at 2018 [38, 44]. Presently, research efforts are directed toward the discovery of natural products with anticancer potential [45]. Several secondary metabolites have been reported to possess anticancer potential; some of these compounds have the capacity to prevent oxidative stress and inflammation that causes damage to DNA, which in turn leads to carcinogenesis [45]. Natural products such as irinotecan, vincristine, vinblastine, etoposide, and paclitaxel from plants, actinomycin D and mitomycin C from bacteria as well as marine-derived bleomycin are widely used in the treatment of various cancers [44].
Also, fruits and vegetables are plant sources that are known to contain vitamins, minerals, folate, plant sterols, carotenoids, and various phytochemicals such as flavonoid and polyphenols—natural product compounds that are associated with reduced cancer mortality and risk [46]. The critical relationship of fruit and vegetable intake and cancer prevention has been thoroughly documented. It has been suggested that major public health benefits could be achieved by substantially increasing consumption of these foods [38].
Herbs and spices such as ginger, capsicum, curcumin, clove, rosemary, sage, oregano, and cinnamon are very rich in antioxidants due to the high content of phenolic compounds and have been shown to counteract reactive oxygen species (ROS)-mediated damage in different human cancers [47]. Many cyclic peptides and their derivatives obtained from marine organisms have been shown to possess anticancer, antimicrobial, anti-inflammatory, antiproliferative, and antihypertensive properties [46]. Furthermore, lactoferrin, a multifunctional protein found in bovine and camel milk, has also been reported to possess anticancer effect [48].
2.1.4 Antiviral activity
Natural compounds are an important source for the discovery and the development of novel antiviral drugs because of their availability and expected low side effects. Naturally occurring compounds with antiviral activity have been recognized as early as 1940s. The search for effective drugs against human immunodeficiency virus (HIV) is the need of hour. Most of the work related with antiviral compounds revolves around inhibition of various enzymes associated with the life cycle of viruses. Structure-function relationship between secondary metabolites and the HIV enzyme inhibitory activity has been observed [38].
2.1.5 Hepatoprotective activity
Diseases of the liver have been classified as high priority areas of health care, as an estimate by the World Health Organization shows approximately 500 million people of the world are suffering from a severe form of liver disorders that may lead to chronic hepatitis. Hepatic disorders can be caused by exposure to agents such as drugs, viruses, parasites, and toxins. Such an exposure usually may result in degeneration and inflammation of the liver; furthermore, it results in fibrosis and cirrhosis [49]. In addition, different chronic diseases such as diabetes may lead to development of hepatic clinical manifestations.
Several flavonoids such as catechin, apigenin, quercetin, naringenin, rutin, and venoruton are reported for their hapatoprotective activities [38]. Muhammad and coworkers review studies conducted on the composition, pharmacology, and nature of some selected plants in the light of possible mechanism deduced from experimental trials [49]. Also, a comprehensive review by Meng et al. [50], listed several plants and products that have been used in the prevention and treatment of chemically induced liver damages [50].
2.1.6 Important present-day drugs derived from plants secondary metabolites
Many drugs with wide range of pharmacological activities were derived from alkaloids [51]. Some of the important drugs derived from alkaloids include:
2.1.7 The pharmacological activities of cardiac glycosides
The effects of cardiac glycosides mainly for increasing heart muscle force of contraction and reducing heart rate are beneficial for treating cardiac arrhythmias and congestive heart failure; cardiac glycosides have long been used to manage these ailments. The commonest cardiac glycosides used clinically include digoxin, digitoxin, ouabain, and bufalin [61]. Other forms of cardiac glycosides are antiarin, thevetin A and B, peruvoside, neriifolin, thevetoxin, ruvoside, theveridoside, cerberin, convallarin, convallamarin, convallatoxin, glucoscillarene A, proscillaridine A, scillarene A, scilliglaucoside and scilliphaeoside, marinobufagenin, oleandrin, folineriin, adynerin, digitoxigenin, marinobufagenin, telocinobufagin [62]. Among these substances, literature has also reported the therapeutic uses of acetyldigoxin, digitoxin, digoxin, gitoformate, gitoxin, lanatoside C, metildigoxin (β-methyldigoxin), ouabain (strophanthin-g), peruvoside, proscillaridin, strophanthin-k [63], apart from digoxin, digitoxin, ouabain, and bufalin earlier mentioned [61].
2.1.8 The pharmacological activities of flavonoids and phenolic compounds
From plants, over 8000 phenolic compounds have been reported [64]. Interestingly, flavonoids make up half of these phenolic compounds [64]. Effectively, flavonoids and several other phenolic compounds have been reported to possess antibacterial, anti-inflammatory, antioxidants, anticancer, cardioprotective, immunomodulatory, and skin radioprotective effects from UV light. More so, these compounds are good pharmaceutical candidates for medical application [65]. Several flavonoids including apigenin, galangin, flavone and flavonol glycosides, isoflavones, flavanones, and chalcones have been shown to possess potent antibacterial activity [38].
2.1.9 The pharmacological activities of tannins
Certain carcinogenic incidences, such as esophageal cancer, have been related to tannins-rich foods consumption, especially the herbal tea and betel nuts. However, several reports showed that tannins’ carcinogenic effects are not due to tannins themselves but likely due to components associated with the tannins [66]. Many literatures revealed negative association between cancer incidences and consumption of tannins components and tea polyphenols, suggesting their anticarcinogenic effects [66].
The antimutagenic and antimicrobial activities of tannins have been documented. Tannins inhibit the growth of viruses, bacteria, yeast, and many fungi. It has also been reported that propyl gallate and tannic acid inhibit aquatic bacteria and foodborne bacteria; this action is not reported for gallic acid. In food processing industry, catfish fillets’ shelf-life can be enhanced using the tannic acid antimicrobial property. The antihypertensive, hypolipidemic, coagulative, and immunomodulatory effects of tannins have been reported [66].
2.1.10 The pharmacological properties of terpenoids
Terpenoids being the most abundant compounds in natural products have been reported to possess antibacterial, antimalarial, antiviral, hypoglycemic, neuroprotective, and anti-inflammatory activities. Furthermore, literatures have also documented the effects of terpenoids in treating and preventing cardiovascular diseases, antioxidation, immunoregulation, and promotion of transdermal absorption of substances [67].
2.2 The pharmacological activities of fungal-derived secondary metabolites
2.2.1 Some important drugs of fungal origin
2.2.1.1 Antibiotics
The beginning was the discovery of penicillin by Alexander Fleming from penicillium mold; penicillin is one of the most known antibiotics in use, and the beta lactam antibiotics penicillin and cephalosporin were all derived from fungus [68]. Other antibiotics derived from fungus include alamethicin, brefeldin A, aphidicolin, citromycin, fumagillin, cerulenin, eupenifeldin, fusidic acid, fusafungine, itaconic acid, usnic acid, helvolic acid, nigrosporin B, verrucarin A, vermiculine, etc. [68]. Tiamulin, retaparmulin, and valnemulin are antibiotics derived from pleuromutilin [68].
2.2.1.2 Antifungal agents
Antifungal griseofulvin is a derivative of penicillium species [69], azoxystrobin, echinocandins, strobilurin, micafungin, anidulafungin, and caspofungin are all antifungal agents originally derived from fungus [70].
2.2.1.3 Immunosuppressive agents
Bredinin, cyclosporin, mycophenolic acid, myriocin, endocrocin, and gliotoxin are all immunosuppressants isolated from fungus [71].
2.2.1.4 Potential antiviral agents
Compounds from several mushrooms such as Ganoderma lucidum, Grifola frondose, Garnoderma colossus, Lentinus edodes, Hypsizygus marmoreus, Scleroderma citrinum, Cordyceps militaris, Trametes versicolor, Flammulina velutipes, Fomitopsis officinalis are under research for potential antiviral activities validations [72, 73].
2.2.1.5 Potential antidiabetic and antimalarial agents
Ternatin and many other fungal isolates have potential hypoglycaemic effects [74]. Potential antimalarial agents of fungal origin under scientific elucidations include antiamoebin, codinaeopsin, zervamicins, and efrapeptins [75].
2.3 The pharmacological activities of bacterial-derived secondary metabolites
Pharmaceutical agents of bacterial origin include antibiotics, immunomodulators, nematicides, antitumor agents, coccidiostatic agents, enzyme inhibitors, and insecticides. Interestingly, Escherichia coli is used as a host in molecular biology for synthesis of recombinant proteins [76]. Selman Abraham Waksman, the father of antibiotics, discovered actinomycin; this effort was followed by the discovery of streptomycin in 1944 [77]. Other clinically important antibiotics derived from bacteria include bacitracin [78], polymyxin B [79], gentamicin [80], amphotericin b [81], tetracycline [82], erythromycin [83], rifamycin [84], vancomycin [82], neomycin [85], streptomycin [86], and chloramphenicol [87]. Etc.
3. The role of secondary metabolites in enhancing agricultural productivity
The resistance against herbivores and pathogens is a role played decisively by the chemical protection nature of plants, the secondary metabolites; they are plant features important especially for protection against a wide range of microorganisms such as bacteria, viruses, fungi, arthropods, herbivores, and vertebrates [88]. Soil decomposition is influenced by plant secondary metabolites by increasing nitrogen immobilization in the soil; cycling of carbon (C) and nitrogen (N) is affected by terpenes and tannins [89].
Exudates from plants roots contain secondary metabolites that can attract, kill, or deter underground microbes, herbivorous insects, and nematodes, competing plants and underground injuries are also inhibited [90]. Plants secondary metabolites contain potential toxic substances used for defense against insects; these chemical compounds can be utilized for design of future insecticides with multiple or specific targets [91]. A good example of an insecticidal compound of such nature is pyrethrin derived from the flowers of Pyrethrum cinerariaefolium plant; pyrethroids are the synthetic analogs of pyrethrin [92].
In terms of animals’ productivity, animals that ingest forages containing different plants secondary metabolites get their meat and dairy products enhanced in terms of biochemical richness making them good for human consumption [93].
In today’s food industries, plants secondary metabolites are used extensively as flavoring, coloring, and texturizing agents. Preservation and anti-browning are done with metabolites possessing antioxidative properties [94].
4. Folkloric usage of secondary metabolites based on reliable sources of information and genuine scientific investigations
The fact that animals and humans have been in existence before the advent of orthodox medicine is a proof that plants have been quite effective in treating diseases. The folkloric use of plant medicine has a long history [95]. From the earliest times, man acquired knowledge of the adverse and beneficial effects of plants from observations on animals. To distinguish edible from poisonous plants, grazing animals were observed and the plants not eaten were considered poisonous [96]. About 80% of the rural population today depends largely on medicinal plants for primary health care [97]. About 25% of all prescription drugs in developed countries are obtained directly or indirectly from plants [98].
Plants produce valuable organic compounds, some of which have potentials in treating ailments in both animals and humans [99]. Of the 252 drugs considered as basic and essential by the WHO, 11% are exclusively of plant origin and a significant number are synthetic drugs obtained from natural precursors [100]. In 1997, the world market for phytomedicinal products was estimated at US$10 billion [101]. This prompted the WHO to consider phytotherapy in its alternative or complementary health program. Locally produced plant medicines can be cheaper than imported synthetic drugs. One striking example is an herbal wound powder (Himax®) in Sri Lanka that was found to be as effective as an imported powder (Neomex®) and comparatively 80–90% cheaper [102].
The most easily accessible, affordable, and inexpensive sources of treatment in the primary healthcare system throughout the world are medicinal plants; there is a long history for the therapy of various disease conditions traditionally in various regions of the world [103].
Natural products’ earliest records were depicted on clay tablets from Mesopotamia (2600 BC) in cuneiform; there are documented evidences of the folkloric of the use of oils derived from Commiphora species and Cupressus sempervirens that are still in use today to treat inflammation, coughs, and colds [104]. The Egyptian pharmaceutical record “the Ebers Papyrus” (2900 BC) documented over 700 drugs of plant origins; these agents include infusions, gargles, ointments, and pills. The Chinese folkloric record books such as the Materia Medica (1100 BC) with 52 prescriptions, the Tang Herbal (659 AD) with 850 drugs, and the Shennong Herbal (100 BC) with 365 drugs provide records of natural products’ uses [104]. Theophrastus (300 BC), the Greek natural scientist and philosopher, is an expert in dealing with medicinal herbs, while Dioscorides (100 AD), the Greek physician, documented the uses and storage of medicinal herbs [104]. The monasteries in Germany, England, France, and Ireland preserved this knowledge during the Dark and Middle Western Ages. Preservation of the Greek and Roman knowledge was done by the Arabs. They also expanded of their own resources; this is done with the Indian and Chinese unfamiliar herbs to the Greek and Roman world [104]. In the eighth century, it was the Arabs who privately own pharmacies. Avicenna, a Persian physician, pharmacist, poet, and philosopher, contributed a lot to the science of medicine and pharmacy through his notable work such as the “Canon Medicine” [104].
4.1 Some reported medicinal uses of secondary metabolites
4.1.1 Alkaloids
Alkaloids have a wide range of pharmacological effects including antimalarial (quinine), antiasthma (ephedrine), anticancer (homoharringtonine), vasodilatory (vincamine), antiarrhythmic (quinidine), analgesic (morphine), antibacterial (chelerythrine), and antihyperglycemic activities (e.g., piperine) [37].
4.1.2 Anthraquinones
Huang et al. [105] and other teams clearly demonstrated that anthraquinones, such as emodin, aloe-emodin, and rhein, inhibit the growth and proliferation of various cancer cells, such as lung adenocarcinoma, myelogenous leukemia, neuroblastoma, hepatocellular carcinoma, bladder cancer, and others through cell death and survival’s modulation. Several anthraquinones are able to inhibit the replication of viruses or even directly kill enveloped or unenveloped strains [106]. Senna, cascara, frangula, rhubarb, and aloe are commonly used for their laxative effects [107].
4.1.3 Flavonoids
Flavonoids have various health-promoting effects such as antioxidative, anti-inflammatory, anticarcinogenic, and antimutagenic. Flavonoids have antioxidant effects associated with various diseases such as Alzheimer’s disease, cancer, atherosclerosis [108].
4.1.4 Cardiac glycosides
The most important use of the cardiac glycosides is its effects in treatment of cardiac failure. In cardiac failure, or congestive heart failure, heart cannot pump sufficient blood to maintain body needs. During each heart contraction, there is an influx of Na+ and an outflow of K+. Before the next contraction, Na+, K+-ATPase must reestablish the concentration gradient pumping Na+ into the cell against a concentration gradient. This process requires energy, which is obtained from hydrolysis of ATP to ADP by Na+, K+-ATPase. Cardiac glycosides inhibit Na+, K+-ATPase, and consequently increase the force of myocardial contraction [109].
4.1.5 Saponins
Saponins exhibit a biological role and medicinal properties such as anti-inflammatory [110], antibacterial, antifungal, antiviral, insecticidal, anticancer, cytotoxic, and molluscicidal action [111].
4.1.6 Terpenes and steroids
Terpenes include substances such as floral fragrances, which serve as insect attractants, pine oil, growth inhibitors, plant hormones (gibberellic acid and abscisic acid), and some of which are insecticidal. About 30,000 terpenes have been identified; they all possess repeating five-carbon isoprene units (a five-carbon ring) [112].
Artemesinin is a sequiterpene, which originated from the Chinese medicinal plant Quinhao (Artemisia annua). It was used to treat fever medicine for over two millennia. It was mentioned in the 52 Remedies recovered from the Mawangdui Tomb dating from the Han Dynasty 206 BC – 221 BC located in Henan Province [113]. Placitaxol (a diterpene) is quite effective in treating against ovarian, breast, colon, non-small-cell lung cancer, and malignant melanoma [114]. Terpenoids (diterpenoids, sesquiterpenoids, triterpenoids) and lignoids also have antiviral activities. A number of them inhibit replication of inhibit coronaviruses, including SARS-Corona Virus. Betulinic acid and savinin are competitive inhibitors of a protease (an enzyme that breaks down proteins) produced by the SARS-CoV 3CL virus [114]. It will be worthwhile testing the effect of these terpenoids on SARs-CoV 2, the cause of recent Covid-19 pandemic.
4.1.7 Alkylresorcinols
Secondary metabolites are known for their angiogenic or wound healing activity, new compounds such as the new alkylresorcinols isolated from the lipophilic extract of Urginea indica L. bulbs have been reported to possess wound healing activity following experimental trauma [115].
Conflict of interest
Authors declare no conflict of interest.
\n',keywords:"secondary metabolites, natural remedies, phytochemical constituents, bioactive compounds",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/79930.pdf",chapterXML:"https://mts.intechopen.com/source/xml/79930.xml",downloadPdfUrl:"/chapter/pdf-download/79930",previewPdfUrl:"/chapter/pdf-preview/79930",totalDownloads:93,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 21st 2021",dateReviewed:"November 26th 2021",datePrePublished:"January 28th 2022",datePublished:null,dateFinished:"January 6th 2022",readingETA:"0",abstract:"The chapter discusses the meaning and origin of some important classes of secondary metabolites such as alkaloids, terpenoids, tannins, flavonoids, saponins, glycosides, and phenolic compounds, etc., produced by some bacteria, fungi, or plants. Very important drugs that are used clinically are derived from these secondary metabolites. Several reports obtained in scientific journals and books written by different scientists working or who have worked in the fields of natural products medicine were reviewed. These different classes of secondary metabolites have shown activity against varied diseases, and compounds that are of novel structure and activity have been isolated and characterized from them. The chapter highlights the economic impacts of these chemical compounds including their role in improving human and animal health and well-being by serving as sources of some antibiotics, anticancer, anti-inflammatory, antifertility, antidiabetics, analgesics, growth promoters, etc. Secondary metabolites are also used to enhance agricultural productivity, they find uses as pesticides, insecticides, and preservatives. Some folkloric uses of secondary metabolites chemical compounds based on reliable sources of information and genuine scientific investigations are highlighted.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/79930",risUrl:"/chapter/ris/79930",signatures:"Hudu Garba Mikail, Mamman Mohammed, Habib Danmalam Umar and Mohammed Musa Suleiman",book:{id:"11331",type:"book",title:"Secondary Metabolites - Trends and Reviews",subtitle:null,fullTitle:"Secondary Metabolites - Trends and Reviews",slug:null,publishedDate:null,bookSignature:"Dr. Ramasamy Vijayakumar and Dr. Suresh Selvapuram Sudalaimuthu Raja",coverURL:"https://cdn.intechopen.com/books/images_new/11331.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-208-8",printIsbn:"978-1-80355-207-1",pdfIsbn:"978-1-80355-209-5",isAvailableForWebshopOrdering:!0,editors:[{id:"176044",title:"Dr.",name:"Ramasamy",middleName:null,surname:"Vijayakumar",slug:"ramasamy-vijayakumar",fullName:"Ramasamy Vijayakumar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 The meaning and origin of important classes of secondary metabolites",level:"2"},{id:"sec_2_2",title:"1.2 The origin and sources of some important classes of secondary metabolites",level:"2"},{id:"sec_3_2",title:"1.3 Plant secondary metabolites",level:"2"},{id:"sec_4_2",title:"1.4 Fungal secondary metabolites",level:"2"},{id:"sec_5_2",title:"1.5 Bacterial secondary metabolites",level:"2"},{id:"sec_6_2",title:"1.6 The alkaloids",level:"2"},{id:"sec_7_2",title:"1.7 The cardiac glycosides",level:"2"},{id:"sec_8_2",title:"1.8 The flavonoids",level:"2"},{id:"sec_9_2",title:"1.9 The phenolic compounds",level:"2"},{id:"sec_10_2",title:"1.10 The tannins",level:"2"},{id:"sec_11_2",title:"1.11 The terpenoids",level:"2"},{id:"sec_13",title:"2. The biological activities of secondary metabolites",level:"1"},{id:"sec_13_2",title:"2.1 The pharmacological activity of plant-derived secondary metabolites",level:"2"},{id:"sec_13_3",title:"2.1.1 Antibacterial activity",level:"3"},{id:"sec_14_3",title:"2.1.2 Anti-inflammatory activity",level:"3"},{id:"sec_15_3",title:"2.1.3 Anticancer activity",level:"3"},{id:"sec_16_3",title:"2.1.4 Antiviral activity",level:"3"},{id:"sec_17_3",title:"2.1.5 Hepatoprotective activity",level:"3"},{id:"sec_18_3",title:"2.1.6 Important present-day drugs derived from plants secondary metabolites",level:"3"},{id:"sec_19_3",title:"2.1.7 The pharmacological activities of cardiac glycosides",level:"3"},{id:"sec_20_3",title:"2.1.8 The pharmacological activities of flavonoids and phenolic compounds",level:"3"},{id:"sec_21_3",title:"2.1.9 The pharmacological activities of tannins",level:"3"},{id:"sec_22_3",title:"2.1.10 The pharmacological properties of terpenoids",level:"3"},{id:"sec_24_2",title:"2.2 The pharmacological activities of fungal-derived secondary metabolites",level:"2"},{id:"sec_24_3",title:"2.2.1 Some important drugs of fungal origin",level:"3"},{id:"sec_24_4",title:"2.2.1.1 Antibiotics",level:"4"},{id:"sec_25_4",title:"2.2.1.2 Antifungal agents",level:"4"},{id:"sec_26_4",title:"2.2.1.3 Immunosuppressive agents",level:"4"},{id:"sec_27_4",title:"2.2.1.4 Potential antiviral agents",level:"4"},{id:"sec_28_4",title:"2.2.1.5 Potential antidiabetic and antimalarial agents",level:"4"},{id:"sec_31_2",title:"2.3 The pharmacological activities of bacterial-derived secondary metabolites",level:"2"},{id:"sec_33",title:"3. The role of secondary metabolites in enhancing agricultural productivity",level:"1"},{id:"sec_34",title:"4. Folkloric usage of secondary metabolites based on reliable sources of information and genuine scientific investigations",level:"1"},{id:"sec_34_2",title:"4.1 Some reported medicinal uses of secondary metabolites",level:"2"},{id:"sec_34_3",title:"4.1.1 Alkaloids",level:"3"},{id:"sec_35_3",title:"4.1.2 Anthraquinones",level:"3"},{id:"sec_36_3",title:"4.1.3 Flavonoids",level:"3"},{id:"sec_37_3",title:"4.1.4 Cardiac glycosides",level:"3"},{id:"sec_38_3",title:"4.1.5 Saponins",level:"3"},{id:"sec_39_3",title:"4.1.6 Terpenes and steroids",level:"3"},{id:"sec_40_3",title:"4.1.7 Alkylresorcinols",level:"3"},{id:"sec_46",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Daviss B. Growing pains for metabolomics. The Scientist. 2005;19(8):25-28'},{id:"B2",body:'Jordan KW, Nordenstam J, Lauwers GY, Rothenberger DA, Alavi K, Garwood M, et al. 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Safety aspects of herbal remedies. Journal of Royal Society of Medicine. 1998;91:294-296'},{id:"B96",body:'Nwude N, Ibrahim MA. Plants used in traditional veterinary medical practice in Nigeria. Journal of Veterinary Pharmacology and Therapeutics. 1980;3:261-273'},{id:"B97",body:'Akinyemi B. Recent concept in plaque formation. Journal of Clinical Pathology. 2000;30:13-16'},{id:"B98",body:'Newman DJ, Cragg G, Snader KM. The influence of natural products upon drug discovery. Natural Product Reports. 2000;17:175-285'},{id:"B99",body:'Ghani A. Introduction to Pharmacognosy. 1st ed. Zaria, Nigeria: Ahmadu Bello University Press; 1990. p. 58'},{id:"B100",body:'Rates SMK. Plants as source of drugs. Toxicon. 2001;39:603-613'},{id:"B101",body:'Soldati F. The registration of medicinal plant products, what quality of documentation should be required? The industrial point of view. In: World Congress on Medicinal and Aromatic Plants for Human Welfare 2, Abstracts. Mendoza: ICMPA/ISHS/SAIPOA; 1997. p. L-48'},{id:"B102",body:'Anjaria JV. Traditional (indigenous) veterinary medicine project. Final report, Livestock evelopment project. Sri Lanka Asian Development Bank. Gannoruwa, Peradeniya: Sri Lanka Veterinary Research Institute; 1986. pp. 15-24'},{id:"B103",body:'Umashankar DD. Plant secondary metabolites as potential usage in regenerative medicine. The Journal of Phytopharmacology. 2020;9:270-273'},{id:"B104",body:'Rauf A, Jehan N. The folkloric use of medicinal plants in public health care. In: Public Health. Madrid, Spain: SM group; 2015. pp. 1-12. Available from: www.smgebooks.com'},{id:"B105",body:'Huang Q, Lu G, Shen HM, Chung MCM, Ong CN. Anti-cancer pr operties of anthraquinones from rhubarb. Medical Research Review. 2007;27:609-630. DOI: 10.1002/med.20094'},{id:"B106",body:'Li S, Yang WTC, Lai CC, Huang SH, Liao JM, Wan L, et al. Antiviral activity of aloe-emodin against influenza A virus via galectin-3 up-regulation. European Journal of Pharmacology. 2014;738:125-132. DOI: 10.1016/j.ejphar.2014.05.028'},{id:"B107",body:'International Agency for Research on Cancer (IARC). Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 82. Lyon, France: IARC Press; 2002'},{id:"B108",body:'Metodiewa D, Kochman A, Karolczak S. Evidence for antiradical and antioxidant properties of four biologically active N, N,diethylaminoethyl ethers of flavanone oximes: A comparison with natural polyphenolic flavonoid (rutin) action. Biochemistry and Molecular Biology International. 1997;41:1067-1075'},{id:"B109",body:'Farnsworth NF. Biological and phytochemical screening of plants. Journal of Pharmaceutical Sciences. 1966;55:225-276'},{id:"B110",body:'Just ML, Recio MC, Giner RM, Cuéllar MJ, Marĩez S, Bilia AR, et al. Anti-inflammatory activity of unusual lupane saponins from Bupleurum fruticescens. Planta Medica. 1998;64(5):404-407'},{id:"B111",body:'Abed El Aziz MMA, Ashour AS, Melad ASG. A review on saponins from medicinal plants: Chemistry, isolation, and determination. Journal of Nonomedicine Research. 2019;7(4):282-288'},{id:"B112",body:'Kaiser R. The Scent of Orchids: Olfactory and Chemical Investigations. Basel: Editiones Roche; 1993'},{id:"B113",body:'Harper DJ. Early Chinese Medical Literature: The Mawangdui Medical Manuscripts. London: Kegan Paul Intern; 1998'},{id:"B114",body:'Evangelista LF (managing editor). MIMS Annual. 1995. p. 1082'},{id:"B115",body:'Mikail HG, Karvouni H, Kotsiou A, Tesseromatis C, Magiatis P. New alkylresorcinols from a lipophilic extract of Urginea indica L. bulbs showing experimental trauma healing activity. Fitoterapia. 2015;101:41-45'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hudu Garba Mikail",address:"mghudu@yahoo.com;, hudu.mikail@uniabuja.edu.ng",affiliation:'
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IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
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Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
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This chapter exclusively summarizes the properties of biochar, its interaction with soil microflora, and its role in plant growth promotion when added to the soil.",book:{id:"7305",slug:"biochar-an-imperative-amendment-for-soil-and-the-environment",title:"Biochar",fullTitle:"Biochar - An Imperative Amendment for Soil and the Environment"},signatures:"Jyoti Rawat, Jyoti Saxena and Pankaj Sanwal",authors:null},{id:"46355",doi:"10.5772/57469",title:"Phytoremediation of Soils Contaminated with Metals and Metalloids at Mining Areas: Potential of Native Flora",slug:"phytoremediation-of-soils-contaminated-with-metals-and-metalloids-at-mining-areas-potential-of-nativ",totalDownloads:8589,totalCrossrefCites:14,totalDimensionsCites:87,abstract:null,book:{id:"3854",slug:"environmental-risk-assessment-of-soil-contamination",title:"Environmental Risk Assessment of Soil Contamination",fullTitle:"Environmental Risk Assessment of Soil Contamination"},signatures:"Paulo J.C. Favas, João Pratas, Mayank Varun, Rohan D’Souza and\nManoj S. Paul",authors:[{id:"169746",title:"Dr.",name:"Paulo",middleName:null,surname:"Favas",slug:"paulo-favas",fullName:"Paulo Favas"},{id:"169747",title:"Dr.",name:"Manoj",middleName:"Stephen",surname:"Paul",slug:"manoj-paul",fullName:"Manoj Paul"},{id:"169952",title:"Dr.",name:"Joao",middleName:null,surname:"Pratas",slug:"joao-pratas",fullName:"Joao Pratas"},{id:"169953",title:"Dr.",name:"Mayank",middleName:null,surname:"Varun",slug:"mayank-varun",fullName:"Mayank Varun"},{id:"169954",title:"Dr.",name:"Rohan",middleName:null,surname:"D'Souza",slug:"rohan-d'souza",fullName:"Rohan D'Souza"}]},{id:"61845",doi:"10.5772/intechopen.77987",title:"Montmorillonite: An Introduction to Properties and Utilization",slug:"montmorillonite-an-introduction-to-properties-and-utilization",totalDownloads:5495,totalCrossrefCites:44,totalDimensionsCites:77,abstract:"Clay mineral is an important material available in nature. With an increasing understanding of clay structure, montmorillonite is realized viable for an enhanced performance in a variety of materials and products in the areas of catalysis, food additive, antibacterial function, polymer, sorbent, etc. Significant development in the use and application of montmorillonite is seen in recent time. This chapter provides an overview of montmorillonite, structure, and properties and particularly discusses its recent utilization in important materials. Montmorillonite is introduced in terms of its natural sources, chemical structure, physical and chemical properties, and functional utilization. The important physical and chemical properties are summarized as particle and layered structure, molecular structure and cation exchange effect, barrier property, and water sorption. This is followed by the important functional utilizations of montmorillonite based on the effects of its chemical structure. The important functional utilization of montmorillonite includes food additive for health and stamina, for antibacterial activity against tooth and gum decay, as sorbent for nonionic, anionic, and cationic dyes, and the use as catalyst in organic synthesis. The environment concerns, to date, do not indicate the adversity for particles used as additive. Studies will be useful which are clearly based on any montmorillonite structure to describe environmental effects.",book:{id:"6561",slug:"current-topics-in-the-utilization-of-clay-in-industrial-and-medical-applications",title:"Current Topics in the Utilization of Clay in Industrial and Medical Applications",fullTitle:"Current Topics in the Utilization of Clay in Industrial and Medical Applications"},signatures:"Faheem Uddin",authors:[{id:"228107",title:"Prof.",name:"Faheem",middleName:null,surname:"Uddin",slug:"faheem-uddin",fullName:"Faheem Uddin"}]}],mostDownloadedChaptersLast30Days:[{id:"46032",title:"Soil Contamination, Risk Assessment and Remediation",slug:"soil-contamination-risk-assessment-and-remediation",totalDownloads:14013,totalCrossrefCites:22,totalDimensionsCites:62,abstract:null,book:{id:"3854",slug:"environmental-risk-assessment-of-soil-contamination",title:"Environmental Risk Assessment of Soil Contamination",fullTitle:"Environmental Risk Assessment of Soil Contamination"},signatures:"Muhammad Aqeel Ashraf, Mohd. Jamil Maah and Ismail Yusoff",authors:[{id:"25185",title:"Dr.",name:"Muhammad Aqeel",middleName:null,surname:"Ashraf",slug:"muhammad-aqeel-ashraf",fullName:"Muhammad Aqeel Ashraf"},{id:"101988",title:"Dr.",name:"Ismail",middleName:null,surname:"Yusoff",slug:"ismail-yusoff",fullName:"Ismail Yusoff"},{id:"169931",title:"Prof.",name:"Mohd Jamil",middleName:null,surname:"Maah",slug:"mohd-jamil-maah",fullName:"Mohd Jamil Maah"},{id:"169932",title:"Dr.",name:"Ng Tham",middleName:null,surname:"Fatt",slug:"ng-tham-fatt",fullName:"Ng Tham Fatt"}]},{id:"71931",title:"Open Pit Mining",slug:"open-pit-mining",totalDownloads:1744,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Open pit mining method is one of the surface mining methods that has a traditional cone-shaped excavation and is usually employed to exploit a near-surface, nonselective and low-grade zones deposits. It often results in high productivity and requires large capital investments, low operating costs, and good safety conditions. The main topics that will be discussed in this chapter will include an introduction into the general features of open pit mining, ore body characteristics and configurations, stripping ratios and stripping overburden methods, mine elements and parameters, open pit operation cycle, pit slope angle, stability of mine slopes, types of highwall failures, mine closure and reclamation, and different variants of surface mining methods including opencast mining, mountainous mining, and artisan mining.",book:{id:"8620",slug:"mining-techniques-past-present-and-future",title:"Mining Techniques",fullTitle:"Mining Techniques - Past, Present and Future"},signatures:"Awwad H. Altiti, Rami O. Alrawashdeh and Hani M. Alnawafleh",authors:[{id:"313182",title:"Prof.",name:"Rami",middleName:null,surname:"Alrawashdeh",slug:"rami-alrawashdeh",fullName:"Rami Alrawashdeh"},{id:"313522",title:"Dr.",name:"Awwad",middleName:null,surname:"Altiti",slug:"awwad-altiti",fullName:"Awwad Altiti"},{id:"313523",title:"Prof.",name:"Hani",middleName:null,surname:"Alnawafleh",slug:"hani-alnawafleh",fullName:"Hani Alnawafleh"}]},{id:"64027",title:"Stages of a Integrated Geothermal Project",slug:"stages-of-a-integrated-geothermal-project",totalDownloads:4497,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"A geothermal project constitutes two big stages: the exploration and the exploitation. Each one has a single task whose results allow defining the feasibility of a geothermal project, until achieving the construction and operation stage of the power generation plant. The first stage contains the area recognition, its limitation to the target, and elimination of external factors until defining a geothermal zone with characteristics to be commercially exploited. The main studies and analysis that can be applied during the exploration stage are listed, and the major indicator to continue with the project or suspend is the prefeasibility report. The major risks in the exploration stage are due to studies that are carried out on the surface; at this stage, the costs can be considered low. The main results of the exploration are the selection of sites to drill three or four initial wells. Each well provides a direct overview of the reservoir: depth, production thicknesses, thermodynamic parameters, and production characteristics. The drilling of three to four exploratory wells is recommended, as far as there is certainty of the feasibility of the project, and the development of the field begins with drilling of sufficient wells to feed the plant. In this stage, the cost increases, but the risks decrease.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Alfonso Aragón-Aguilar, Georgina Izquierdo-Montalvo,\nDaniel Octavio Aragón-Gaspar and Denise N. Barreto-Rivera",authors:[{id:"258358",title:"Dr.",name:"Alfonso",middleName:null,surname:"Aragón-Aguilar",slug:"alfonso-aragon-aguilar",fullName:"Alfonso Aragón-Aguilar"}]},{id:"65070",title:"Biochar: A Sustainable Approach for Improving Plant Growth and Soil Properties",slug:"biochar-a-sustainable-approach-for-improving-plant-growth-and-soil-properties",totalDownloads:6959,totalCrossrefCites:60,totalDimensionsCites:99,abstract:"Soil is the most important source and an abode for many nutrients and microflora. Due to rapid depletion of agricultural areas and soil quality by means of ever-increasing population and an excessive addition of chemical fertilizers, a rehabilitated attention is a need of the hour to maintain sustainable approaches in agricultural crop production. Biochar is the solid, carbon-rich material obtained by pyrolysis using different biomasses. It has been widely documented in previous studies that, the crop growth and yield can be increased by using biochar. This chapter exclusively summarizes the properties of biochar, its interaction with soil microflora, and its role in plant growth promotion when added to the soil.",book:{id:"7305",slug:"biochar-an-imperative-amendment-for-soil-and-the-environment",title:"Biochar",fullTitle:"Biochar - An Imperative Amendment for Soil and the Environment"},signatures:"Jyoti Rawat, Jyoti Saxena and Pankaj Sanwal",authors:null},{id:"39170",title:"Study of Impacts of Global Warming on Climate Change: Rise in Sea Level and Disaster Frequency",slug:"study-of-impacts-of-global-warming-on-climate-change-rise-in-sea-level-and-disaster-frequency",totalDownloads:6702,totalCrossrefCites:14,totalDimensionsCites:32,abstract:null,book:{id:"2206",slug:"global-warming-impacts-and-future-perspective",title:"Global Warming",fullTitle:"Global Warming - Impacts and Future Perspective"},signatures:"Bharat Raj Singh and Onkar Singh",authors:[{id:"26093",title:"Dr.",name:"Bharat Raj",middleName:null,surname:"Singh",slug:"bharat-raj-singh",fullName:"Bharat Raj Singh"},{id:"118426",title:"Prof.",name:"Onkar",middleName:null,surname:"Singh",slug:"onkar-singh",fullName:"Onkar Singh"}]}],onlineFirstChaptersFilter:{topicId:"10",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83032",title:"Introductory Chapter: Solar Photovoltaic Energy",slug:"introductory-chapter-solar-photovoltaic-energy",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.106259",abstract:null,book:{id:"9862",title:"Solar Radiation - Measurements, Modeling and Forecasting for Photovoltaic Solar Energy Applications",coverURL:"https://cdn.intechopen.com/books/images_new/9862.jpg"},signatures:"Mohammadreza Aghaei, Amir Nedaei, Aref Eskandari and Jafar Milimonfared"},{id:"82963",title:"Evolution of Radio Source Components and the Quasar/Galaxy Unification Scheme",slug:"evolution-of-radio-source-components-and-the-quasar-galaxy-unification-scheme",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.106244",abstract:"In this work, a theoretical model is developed for explanation of temporal evolution of extragalactic radio sources via beaming, orientation effects and asymmetries. Equation of the form D≈P±q1+z−m is used to account for the D ∼ P/z relation. Also, D≈D01+z−1+z1+z2 accounted properly for Ω0=1 cosmology than the Ω0=0 counterpart in linear size versus redshift of radio sources. Similarly, D=Dc1∓lnPPc1/2 model explained redshift-luminosity relationship of extragalactic radio sources. The results from the regression analyses are q = +0.003 (r = 0.04) for sources with z < 1 and q = −1.59 (r = −0.6) for all z≥1 sources. A critical linear size, Dc of 316kpc which matches the maximum theoretical linear size, Dmax of 0.15D0 at a critical redshift zc∼1 and a critical luminosity Pc=26.33WHz−1 are obtained. The indication of all these results is that the linear size of radio sources evolves up to a certain limit in D–P plane and thereafter decreases with increasing luminosity as predicted in this work.",book:{id:"11737",title:"Astronomy",coverURL:"https://cdn.intechopen.com/books/images_new/11737.jpg"},signatures:"Costecia Ifeoma Onah, Augustine A. Ubachukwu and Finbarr C. Odo"},{id:"82981",title:"Wood Quality and Pulping Process Efficiency of Elite Eucalyptus spp. Clones Field-Grown under Seasonal Drought Stress",slug:"wood-quality-and-pulping-process-efficiency-of-elite-eucalyptus-spp-clones-field-grown-under-seasona",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106341",abstract:"The objective of the present study is to evaluate the wood quality of five elite Eucalyptus spp. clones at 4 years of age from a clonal test installed in a region of seasonal drought stress in central-western Brazil focusing on pulp production. A total of 25 trees were systematically felled and disks and logs were obtained along the trunk. Wooden disks were used for density and fiber analyses and the logs were converted into chips for application in the pulping process. For the denser genotype, clone D (E. grandis x E. urophylla x Eucalyptus tereticornis), a thicker cell wall associated to thinner fibers results in a negative effect on the fiber quality. In contrast, clone B (Eucalyptus pellita x E. grandis), which has relatively inferior pulping performance, displayed the lowest wood density associated to wider lumen and fibers. The best growth performances in response to acclimatization and adaptation to the site strongly influences the pulp productivity, which is identified as the parameter of greatest variance between genotypes, and highlighting clone E (E. grandis x E. urophylla).",book:{id:"11840",title:"Arid Environment - Perspectives, Challenges and Management",coverURL:"https://cdn.intechopen.com/books/images_new/11840.jpg"},signatures:"Deborah Rodrigues de Souza Santos, Camila Sarto, Rafael Fernandes dos Santos, Júlia Lôbo Ribeiro Anciotti Gil, Carlos de Melo e Silva-Neto, Regina Maria Gomes, Evandro Novaes, Carlos Roberto Sette-Junior, Mario Tomazello-Filho, Rafael Tassinari Resende and Matheus Peres Chagas"},{id:"82957",title:"The Socio-Economic Factors of the Covid-19 Pandemic in Turkey: A Spatial Perspective",slug:"the-socio-economic-factors-of-the-covid-19-pandemic-in-turkey-a-spatial-perspective",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.106048",abstract:"This study investigates the role of various socioeconomic determinants and vaccination rates in the spread of Covid-19 in a spatial setting in Turkey. For this aim, we employ the 41 sub-indicators of Life Index in Provinces data provided by the Turkish Statistical Institute which is obtained based on the Organization for Economic Cooperation and Development (OECD) Better Life Index approach. Our results indicate no global interactions in the transmission process of the disease among Turkish provinces. This means that the infection burden in the neighboring province does not significantly affect the infection burden of a given state. Yet, we show that vaccination rates and the median age of a neighboring province significantly affect the number of total cases in a given province. We find that as the vaccination rates of a neighboring province rise, the number of total cases in a given province also increases. This finding can be attributed to the “neighbor–reliant immunity” concept. It seems that people with vaccine hesitancy toward Covid-19 feel safer without a vaccine when their neighbors are mostly vaccinated. Last, people with a higher satisfaction rate with their health status are more likely to catch the disease due to underestimation of negative consequences.",book:{id:"11488",title:"GIS and Spatial Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11488.jpg"},signatures:"Sevgi Eda Tuzcu and Esra Satıcı"},{id:"82652",title:"Intra-Plate Dynamics and Active Tectonic Zones of the Indian Plate",slug:"intra-plate-dynamics-and-active-tectonic-zones-of-the-indian-plate",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.105647",abstract:"The tectonic framework of the Indian Plate started to evolve since the break-up of Gondwanaland in the Late Triassic. It evolved mainly during the time between its separation from the African plate in the Early-Cretaceous and its collision with the Eurasian plate on the north in Late-Middle Eocene and with the Burmese plate in the northeast in Late-Oligocene. Present active tectonic zones, responsible for earthquake generation, were created by the collision pattern and subsequent plate motion. Continued subduction and plate motion due to ridge push and slab pull are responsible for the activation of primordial faults in the inherent structural fabric of the craton depending on the related stress field. Major tectonic zones of the Indian continental plate are related to the collision fronts and the reactivated intra-cratonic faults along the resurgent paleo-sutures between the proto-cratons. Major Tectonic Zones (TZ) are Himalayan TZ, Assam-Arakan TZ, Baluchistan- Karakoram TZ, Andaman-Nicobar TZ, and Stable Continental Region (SCR) earthquake zone. The structure of the continental margins developed during the break-up of Gondwana continental fragments. Western margin evolved during the sequential separation of Africa, Madagascar, and Seychelles since the Late-Triassic to Late Cretaceous time. The Eastern margin structure evolved during the separation of Antarctica in Mid Cretaceous. The orogenic belt circumscribing the northern margin of Indian plate is highly tectonised as the subduction of the plate continues due to northerly push from the Carlsberg Ridge in the SW and slab-pull towards northeast and east along the orogenic and island arc fronts in the NE. This stress pattern induced an anticlockwise rotatory plate motion. The back thrust from the collision front in the direction opposite to the ridge push put the plate under an overall compressive stress. This stress pattern and the plate motion are responsible for the reactivation of the major intra-cratonic faults. While the tectonised orogenic belts are the zones for earthquake nucleation, the reactivated faults are also the strained mega shear zones across the plate for earthquake generation in SCR. These faults trending WNW-ESE are apparently the transform faults that extend across the continent from Carlsberg ridge in the west to the collision zones in the northeast. As such, they are described here as the ‘trans-continental transform faults’. Three such major fault zones from north to south are (i) North Kathiawar fault - Great Boundary fault (along the Aravalli belt) zone, (ii) South Saurashtra fault (extension of Narmada fault) – SONATA-Dauki-Naga fault zone, and (iii) Tellichery-Cauvery-Eastern Ghat-T3-Hail Hakalula-Naga thrust zone. All these trans-continental faults, which are mega-shear zones, are traceable from western offshore to the northeastern orogenic belts along mega tectonic lineaments across the continent. The neotectonic movements along these faults, their relative motion, and displacement are the architect of the present geomorphic pattern and shape of the Indian craton. The overall compressive stress is responsible for strain build-up within these fault zones and consequent earthquake nucleation. The mid-continental Sonata-Dauki shear zone follows the Central Indian Suture Zone between Bundelkhand Proto Continent (BPC) and Deccan Proto Continent (DPC). With the reactivation of this shear zone, the two proto-cratonic blocks are subjected to relative movement as the plate rotates anticlockwise. The kinematics of these movements and their implications are discussed here with a special reference to the recent 2001 Bhuj earthquake.",book:{id:"11490",title:"Advances in Plate Tectonics",coverURL:"https://cdn.intechopen.com/books/images_new/11490.jpg"},signatures:"Sanjib K. Biswas and Gaurav D. Chauhan"},{id:"82525",title:"Perspective Chapter: Daphnia magna as a Potential Indicator of Reservoir Water Quality - Current Status and Perspectives Focused in Ecotoxicological Classes Regarding the Risk Prediction",slug:"perspective-chapter-daphnia-magna-as-a-potential-indicator-of-reservoir-water-quality-current-status",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105768",abstract:"Several types of stressors come into natural water bodies, degrading their quality, and having harmful effects on aquatic biota. As a result, many attempts have been made to develop complementary techniques to those imposed by the Water Framework Directive (WFD) to improve the water quality assessment strategy in a shorter time and be more faithful to the components and contaminants of the ecosystem. Daphnia magna has been extensively used as a model organism for ecotoxicity testing, and its ecotoxicological responses to several disturbance factors have been being well characterized. From this perspective, this work aimed to evaluate the applicability of the feeding bioassays with D. magna, as well as early distress tools (biochemical biomarkers), in the assessment of water quality of natural waters of reservoirs. Samplings were performed in several sites in three Portuguese reservoirs and were conducted in the spring of 2020. Bioassays and biomarkers results showed sensitivity to different reservoirs since the sites are minimally or moderately impacted. Biological responses can be related to several environmental factors, such as surrounding areas, seston composition, and chemical analysis (WFD), among others not quantified. This set of biological responses has presented good concordance with the ecological potential of the reservoirs.",book:{id:"11662",title:"Limnology - The Importance of Monitoring and Correlations of Lentic and Lotic Waters",coverURL:"https://cdn.intechopen.com/books/images_new/11662.jpg"},signatures:"Sara Rodrigues, Ivo Pinto, Sandra Nogueira and Sara C. Antunes"}],onlineFirstChaptersTotal:133},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:"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"}}}},{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"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. 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