Concentration of organic and inorganic pollutants in rural and urban soils in France (values extracted from Ademe [13]).
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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MND is a progressive neuromuscular disease with a fatal outcome; the commonest clinical presentation of MND presentation is ALS, commonly known as Lou Gehrig’s disease. Most of ALS patients pass away within 2–5 years of confirmed a diagnosis. Familial ALS (ALSf) is a hereditary presentation of the disease and accounts for 5–10% of affected people. ALS affects persons of all ethnicities worldwide; no cure for ALS has yet been available at any country. Sometimes, ALS is clinically, pathologically, and genetically associated with fronto-temporal dementia, which is the second cause of dementia in elderly people. In our first book, we reviewed all previous chapters published by INTECH, and in the Introductory Chapter, readers could find summarized information about all publications on ALS made by INTECH. Trying to illustrate the reached progress, we displayed this information grouped by topics and countries in two graphics. As we saw on that book, the number of publications written about ALS increased remarkably for the past 4 years. To have some idea of this phenomenon, be informed that INTECH published more than 40 chapters on ALS in this period of time, and these books “Amyotrophic Lateral Sclerosis,” “Current Advances on Amyotrophic Lateral Sclerosis,” and others are fully available on line, for free. Therefore, why we are going to publish another chapter? All novel information about MND were not published. Therefore, some aspects published in 2012 need to be update because new ideas, proposals, findings, experiences, and many other’s knowledge have been arising despite of this short period of time. Therefore, for the benefit of the readership community, we included update information not reported before, mainly new contribution of aberrant astrocytes to MND damage and death in the SOD1G93A rat experimental model of ALS; novel genetics studies on ALS; an update of the structural and functional consequences of the spinal muscular atrophy-linked mutations of the survival motor neuron protein; stem cell therapy for MND; and the novel treatment for SMA and ALS in the introductory chapter of this book. Compromises have been inevitable to accommodate our visual and factual updated information in a book of his characteristic on top of many chapters about the same issue published recently.
MND does not affect sphincter, sexual function, or eye movements [1]. Although ALS is not associated with thermoregulatory dysfunction, its progression can affect intensively important cerebral regions that control body temperature and affect multiple functions of this homeostatic activity. Nevertheless, experimental ALS animals can display altered thermoregulation as a consequence of affected energy homeostasis. Indirect evidence suggests, performing studies on the body temperature regulatory system, both as a possible modifier of disease progression in ALS and as a potential biomarker [2].
Although edaravone and riluzole do not cure MND/ALS, it seems to be that both medications can slow its progression. The prevalence of ALS in America was 5.2 per 100,000 populations with a total of 16,583 cases identified from January 1 to December 31, 2015 [3].
MND is the most common degenerative disorder, which affects the upper and lower motor neurons at the same time. There are different clinical modalities of MND being ALS the commonest one, and its incidence is around 1–3 patients every 100,000 people [4, 5].
The higher incidence of ALS is in patients with 60 and 70 years of age, but some younger cases (20–30 years of age) have been reported as well [4]. Between 5 and 10% of the patients have a familiar origin due to Mendelian autosomal dominant transmission.
Most of the patients presenting MND in our series complain of muscle weakness, muscle wasting, fasciculation, and spasticity plus cranial nerve disturbances from the lower brainstem.
The most frequent mutation seen in the familial form of ALS (ALSf) occurs on the gene of superoxide dismutase 1 (SOD1) and on the chromosome 9, among others. The decreased endovascular factor and the hereditary hemochromatosis protein are also genetic mutations. Some variations in the number of copies of Genes 1 and 2 that codify the motor neuron survival factors have been reported [6]. No correlation investigations have been done. However, some genome-wide studies in patients presenting ALS show a series of loci confirming a greater susceptibility to develop the disease such as kinase carbohydrate (FGGY), dipeptidyl-peptidase 6 (DPP6), and Type 2 inositol triphosphate receptor [7, 8, 9]. Most of these findings were not able to be replicated in further investigations done. At present, there is not specific cure for this deadly disorder as was mentioned before.
Long time ago, a nitrogenic expansion on the gene C9ORF72 was observed in a number of patients presenting ALS associated with Chromosome 9, which brought more clarity in the ethiopathogenesis of ALS [10, 11], but these findings are also seen in patients presenting fronto-temporal dementia (FTD) and ALS-FTD [10, 11]. Below, we will deliver more comments about this topic.
Future genetic investigations should be focused on non-European populations in order to bring more clarity on new pathogenic loci.
In the forthcoming years, the exome study that is an emerging field will bring novel information about some implicated genes in ALSf.
In 2018, Thompson et al. [12] used a high-throughput proteomic process to distinguish new biomarkers in patient’s cerebrospinal fluid (CSF), and they found that three macrophage-derived chitinases had increased concentration in ALS: chitinase-3-like protein 1, chitotriosidase, and chitinase-3-like protein 2. Elevated CHI3L1 was commonly seen in ALS, while CHI3L2 and CHIT1 levels did not. Their results confirmed the important role of macrophage activity in pathogenesis of ALS.
Decreased cough capacity is almost always present in respiratory tract infection and is the most important cause of respiratory failure in ALS patients. Other authors determined whether the lung function measurement could identify the cough function in ALS patients with respiratory tract infection. After screening 48 patients presenting ALS, they found only four presenting a remarkable cough with no assistance. The data that identified unassisted cough effectiveness are peak cough flow. These investigators highlighted that the effectiveness of assisted and unassisted cough function depends on the peak cough flow reached [13].
It is well known that MND does not affect the motor neurons at the oculomotor nucleus in the midbrain. Because it could be remarkably advantageous if neurons of motor system resilience can be modeled in vitro, some authors reached elevated quantities of oculomotor neurons from embryonic stem cells in mouse through transient over expression of PHOX2A in nerve cell progenitors, and they confirmed, using immunocytochemistry techniques, electrophysiology studies, and RNA sequencing, that in vitro-generated neurons are bona fide oculomotor neuron cells based on their neuron properties and similarity to their counterpart in rodent (in vivo) and human beings [14].
Increased cortical excitability, thought to reflect pathological changes in the balance of local excitatory and inhibitory neuronal influences that are commonly seen in patients presenting ALS and non-invasive brain stimulation (NIBS), has been shown to modulate cortical activity, with some protocols showing effects that outlast the stimulation by months. Therefore, NIBS has been proposed as a probable candidate to approach therapeutically these disorders associated with pathological neurophysiology activity, such as ALS, among others [15].
ALS type 8 (ALS8) is a familial presentation of MND, with an important anterior horn cell degeneration, due to mutation of the vesicle-associated membrane protein-associated protein B. Some authors compare the cognitive function of patients with ALS8 and a control group composed by healthy people in order to screen behavioral features in ALS8 patients. These authors found that ALS8 patients showed minimal deficits in executive functions. The total amount of ALS8 patients and the control group have the same scores of facial emotion recognition. They also determined an important clinical expression of psychiatric disorder such as anxiety and depression in 36 and 27% of patients, respectively. However, behavioral disturbances were present in around 30% of participants. They concluded that these patients had mild executive problems and behavioral problems such as apathy, mood disorder, and stereotypic behavior, which suggest that ALS8 is not a motor disorder only, and it is associated with minor cognitive and behavioral changes [16].
Because one of the most effective clinical strategies for SMA is to protect the anterior horn cell, apart from nusinersen (that is a very expensive medication), one anti-epileptic medication levetiracetam has been used as well.
Kepra (levetiracetam) provoked neurite elongation in SMA-iPSCs-MNs. TUNEL-positive anterior horn cell was significantly decreased by kepra in SMA-iPSCs-MNs. On the other hand, the expression level of cleaved-caspase 3 was diminished by levetiracetam in SMA-iPSCs-MNs. Furthermore, kepra improved impaired mitochondrial function in SMA-iPSCs-MNs. On the other hand, kepra did not modify the expression level of SMN protein in SMA-iPSCs-MNs. These results suggest that kepra has a neuroprotective effect for SMA [17].
For patients presenting SMA (most common reason of inherited infant mortality), the gene therapy seems to be the most effective strategy [18].
Another therapeutic modality to treat ALS is the noninvasive brain stimulation (NIBS), which has been shown to modulate cortical activity, with some protocols leading effects that outlast the stimulation by months. NIBS have been suggested as a potential treatment choice in those processes with associated changes in the cortical neurophysiology [15].
A total of 25 genes associated with ALSf and ALS (sporadic form), mutations in fused-in-sarcoma (FUS) and superoxide dismutase 1 (SOD1) have been intensively studied in the past, focusing on modified excitability of motor neurons. Based on their personal experience, Peikkert et al. [19] proposed that the 4-aminopyridine (4-AP), which is a potassium channel blocker, can be utilized as a probable therapy
One of the clinical presentations of MND is SMA, which encompasses a group of autosomal recessively inherited degenerative neuromuscular diseases. SMA is an inherited disorder that causes progressive lesions on the anterior horn cell leading to weakness or paralysis of the affected limbs, and it is caused by elimination or mutation of survival motor neuron (SMN) 1 gene. It is well known that homozygous damage and loss of functional mutations in the survival motor neuron 1 gene (SMN1) at the chromosome 5q13 are the main cause of SMA, which affect 1 in 11,000 newborn infants.
SMA usually has a very poor prognosis after rapidly progressive weakness and early mortality. However, a new medication named Nusinersen has been released for the treatment of all forms of SMA (not on mechanical ventilation) with very good results. In December 2016, this medication was approved in the United States. Nusinersen, an antisense oligonucleotide (ASO), is administered directly into CSF. It alters
One in 50 asymptomatic people carries this autosomal recessive neuromuscular code causing SMA in one over 10,000 live births [21].
Based on age at onset, the highest milestone reached, and phenotypic severity: SMA has been separated into four different subgroups such as “Nonsitters” (Type I), “sitters” (Type II), “walkers” (Type III), and “adult onset” (Type IV) [22].
At the present moment, many patients got confirmation of diagnose very late, or the treatment is administered in advance stages. Therefore, poor response is often obtained.
Fortunately, some screening programs are available and accurately and then to identify children in pre-symptomatic stages is possible [23]. However, because some children develop their clinical manifestation far from birth then to decide when to initiate the treatment and whom qualify for therapy is a dilemma.
The majority of SMN2 pre-mRNA transcripts undergo alternative splicing due to a nucleotide substitution leading to exclusion of exon 7. Degradation of the resulting truncated SMN protein is very fast, and the overall lack of full-length SMN protein causes permanent damage on anterior horn cell of the spinal cord [23].
In patients with onset of the disease beyond six months of age, large phase 3 trials confirmed improvement in motor activities, very high event-free and remarkable survival in infantile-onset SMA3, also significant improvement in Expanded version of the Hammersmith Functional Motor Scale scores has been recorded [24, 25].
The copy number of the homologous SMN2 gene is inversely correlated with SMA severity and encoded by SMN1 (except for lack of exon 7), which is identical to the cDNA encoded by SMN2.
Currently, for the therapy of SMA, there are pipelines developed by antisense oligonucleotide (ASO), also available for Huntington disease, ALS, spinocerebellar ataxias, Parkinson disease, and Alzheimer disease, among other options, and the pharmaceutical industry on ASO development has been delivering a promising therapeutic approach. The key care concern to MND patients has been developed, and expert consensus guidelines delivered, and best management for lung diseases, nutritional problems, and palliative care has also been reached. However, in this chapter, we will discuss novel aspects related to treatment and other therapeutic procedures later on.
In pre-symptomatic SMA patient’s Types I–III released interim results of a phase 2 trial evaluating the effects of Nusinersen have been done [23].
Some investigators have been working on stage of improvement after the treatment of SMA and confirmed that the first published data supported important good results on the motor function and quality of life from animal models with early restoration of SMN levels for those studied within the first 3 postnatal days. However, for those treated beyond 5 postnatal days, the level of recovery was low, while delivered treatment after 10 postnatal days, it showed no improvement and died [26].
One of the problems found in our preliminary review is the big number of SMA patients diagnosed at late stage. We found Type I patient with 4 months after onset and Type III with 10 months or more after onset [27, 28].
However, newborn screening programs have been a successful process for identifying affected children at an asymptomatic stage, leading to pre-symptomatic initiation of treatment before irreversible anterior horn cell lesion appears. To perform screening methods before birth are certain, and they available and willing to deliver the possibility of distinguish patients at the beginning of pregnancy, giving a chance to perform a prenatal therapeutic management.
Taiwan and Belgium, also have screening programs for SMA, but in America, the leader and an important number of states, further clinical trials have been implemented to evaluate the applicability and economic advantages. Unfortunately, around 5% of mutations in the SMN1 cannot de identified [23].
Chorionic villus sampling or amniocentesis to identify children with higher risk for SMA with an elevated percentage of accuracy can be done, if it is performed during the 10–14 or 15–20 weeks of pregnancy. These procedures can be dangerous for the mother and the baby to be done in
At this stage, it is also important to mention that significant ethical issues are involved in this genetic screening methodology and its need to be considered by the medical community before making these procedures fully available [31]. At the present moment, we are not quite sure how to predict disease severity accurately or even its presence because not all patients present clinical manifestation birth or because only few minimal sings are detectable. Treatment algorithm for SMA patients confirmed by newborn screening based on SMN1 deletion analysis in dried blood spots is available since 2005 [28]. Indications of treatment are based on the clinical phenotype of the patients and correlation of SMN2 copy numbers. All patients presenting 2–3 copies should be treated with the immediate effect according to NBS Multidisciplinary Working Group recommendations even if the child is asymptomatic with only one copy, but when four or more copies are present due to milder course of the disease, the treatment must be delayed [28].
In 2017, some authors studied a big number of SMA patients (
It is important to take into account that those SMA patients (families and siblings) presenting the same amount of SMN2 copies have another phenotype [33]; in the context, SMN1 (homozygous) mutations, SMN2 copies in people free of symptoms and signs, and even in SMA Type I have been found [34]. SMN2 transcripts and the SMN2 copy number do not show any correlation in a series of investigations done between 2001 and 2017 [35, 36, 37, 38].
Following some recommendations delivered by the Phase 1 trial and studies on its pharmacological process, the investigators found that the half-life of nusinersen in the CFS is 163 days, and the ideal way for administration should be intrathecal (at the dosage of 12 mg) every 4 months. After that period of time, patients should receive five intrathecal injections within the first 6 months of treatment. These authors also confirmed that no correlation exits between concentrations of the CSF, age of the patients, and body weight [39, 40].
Based on results published by Luu et al., the doses of nusinersen according to the age of the patients produce more median exposures in the CSF, which suggest that prescribing fixed dosage programs through all age groups is the best choice [40]. For the other hand, Finkel et al. [41] conducted a Phase 2 dose-escalation investigation confirming that a single dose of 12 mg is better than 6 mg. The best way to assess the outcome for these patients is to measure the advantage of motor milestone, depending on ventilator machine, achievement of motor activities, clinical electrophysiological studies, and overall survival. Twenty patients younger than 1 year of age and less than 10 kg of body weight were screened, and these results confirmed the previous postulate [41]. The results from the small group studied in phase 2 clinical trials and the pharmacological studies done can accurately reflect clinical practice, is an interrogation still no responded.
Taking into account the great variability among SMA patients related to the age at disease onset, residual motor function, body weight, and fixed dose at the same intervals for patients, it seems to be remarkably inaccurate [23]. Reliable biomarkers and screening procedures for proper diagnosis at early stage of the disease are need more than ever if we are looking for longer survival and positive modifications of the patient outcome. If reliable biomarkers are not available, then determining the SMN protein level and epigenetic modifiers to provide confident information about the intensity of the process is mandatory. When more than three SMN2 copies are detectable, chance for life-saving treatment is not certain. In summary, novel screening techniques, procedures to predict the intensity of the disease, and reliable biomarkers, which support monitoring of the treatment, have been discovered and recently developed, but unfortunately, none of them provide an unequivocal explanation of the pathophysiology of SMA [23].
To develop more accurate diagnostic procedures including confident biomarkers, better therapeutic approaches, and novel predictors to determine the ideal dosing recommendation, more investigations are required. This is the only way to guarantee a reliable long-term treatment and successful outcome [23].
Two years ago, the European Medicines Agency finally approved nusinersen an antisense oligonucleotide (ASO) as the treatment of choice for SMA, and later, this medication has been considered as part of the treatment for patients with Type 2 SMA as well [23]. In patients with SMA presenting spinal bone deformities, severe contractures, scoliosis, spine fusion surgeries, and respiratory distress, the administration intrathecal of nusinersen could be a great challenge.
Recently, with the intention of assess, the accuracy, and feasibility of nusinersen administrated by lumbar puncture (LP) in young patients, Wurster et al. [42] studied in 93 patients in whom the LP is done, highlighting the amount of attempts performed, site of injection, length of the spinal needle, duration of the procedure, medications used for sedative purposes, local anesthesia, level of O2 saturation in blood, appearance of the CFS, and adverse effects. These results confirm that LP is the best way to administer this medication in adolescent and young adults with later-onset SMA even in candidates with spinal bone deformities and respiratory failure mainly if the patient is managed under a multidisciplinary team.
Nusinersen is not available in Africa as yet but can be found in many European countries for all SMA types.
A few weeks ago, Sansone et al. [43] reported their experience and good results after studied 50 SMA patients treated with intrathecal nusinersen. They concluded that in spite of the severity of the disease and the age of patients, this treatment is feasible, safe, and suitable for SMA patients if they are managed by a good skilled team.
According to the information provided by Gidaro et al., a few weeks ago, in Australia, the commercial availability of the medication from the transition of expanded access programmed its right in corner. While in New Zealand, a broad access to this program is available, and in Canada, negotiators are discussing about the most convenient price at the present moment. However, some problems such as advanced age, patients with respiratory failure depending ventilator machine, and patients presenting spinal fusion still need to be solved [44].
As was mentioned before, the traditional LP for intrathecal administration of nusinersen can be impeded due to deformities of the spinal bone and orthopedic surgical procedures among other impediments commonly seen in SMA patients. However, the accumulated experiences from cervical myelograms serve to recommend this procedure as an ideal approach for cervical intrathecal administration of nusinersen, especially if it can be guided by ultrasound [45]. The same investigators studied 14 patients after the administration of nusinersen by cervical punctured guide by ultrasound with local anesthesia and found that all patients presented no major complications. One of the advantages of this technique is that general anesthesia is no required, and patients can be managed in real-time ultrasound guidance.
The most significant advantage to antisense oligonucleotide (ASO) therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics.
In 2019, Scoles et al. [46] described several therapeutic modalities with ASO and how they can be indicated for medical treatment of SMA, apart from the work done to develop novel ASO therapies looking for better results in the management of neurodegenerative disorders [46]. Novel advances of the genetic studies will allow distinguishing different genetic information for many neurological disorders. The mutated protein found and its chance to be placing into the cellular pathway will support a faster development of way for treatment. For the other hands, new opportunities for reliable treatment have been arising from the new capacities of targeting the disorder gene and RNAs. Among other procedures, to target the expression of RNA, some authors highlighted the utilization of ASOs to treat neurological problems. Treatment based on ASOs varies from 18 to 30 base pairs in length. These investigators changed expression of a target mRNA modifying splicing or by recruiting RNase H (cellular enzyme) that recognizes DNA: RNA hybrids causing target degradation [46].
Apart from nursinersen, other ASO therapeutics approved by FDA are eteplirsen to treat Duchene muscular dystrophy 2 and inotersen for managing patients presenting familial amyloid polyneuropathy. For treatment of Huntington disease, ASOs targeting HTT have been used [47]. As we and other authors reported in other publications, the treatment of choices for ALS is SOD1 and C9ORF72 [48, 49] and MAPT (TAU) in cases affected by Alzheimer disease [50]. Because most of the treatment with ASO does not cross the blood-brain barrier (BBB), it is necessary to administer it by injection into the intraventricular system in mouse and by intrathecal administration in humans.
Some investigators have mentioned that nucleic acids are prompt to nuclease degradation, and its protein binding is weak, leading to inefficient tissue uptake and unreliable use as drugs [26, 51].
Most of these changes modify the pharmacokinetic, pharmacodynamic, or endocytic uptake that controls the specific function of the proteins (cell surface) [51, 52].
Oligonucleotide chemistry, methoxyethyl oligonucleotide, constrained nucleic acids, Stereopure PS ASOs, Peptide nucleic acid, 5′-methylcytosine modification, target fate, mixed chemistry, and gapmers are aspects that are not discussed in this chapter and should be considered by interested readers on this matter. In order to get most complete information about it, we recommend checking the article of Scoles et al. [46].
ASOs are being used for some genetic etiology of ALS. Obviously, these biological pathways affecting the recognized mechanism of production of the disorder also modify the results when ASO is used [53].
In 1994, the idea about the role of the excitatory amino acid neurotransmitter glutamate in the mechanism of production of ALS was prevalent. At that time, some investigators evaluated the safety and accuracy of the antiglutamate agent riluzole, at the dose of 100 mg daily, in patients presenting ALS. They studied 155 outpatients, and after 12 months of treatment, they found that 74% of the patients were still alive (
Without doubt, nusinersen improves motor neuron function, but riluzole by acting on SK channels also causes similar results [55].
Since 1996, it is well known that one of the etiological pathogenesis of ALS is caused by neural damage due to glutamate excite-toxicity. Riluzole is a synthetic benzothiazole drug with glutamine antagonist activity [56, 57].
The first analyses, and at posteriori meta-analyses done on results obtained from controlled trials by randomization, confirm that riluzole extends survival by 2–3 months and augment the possibilities of an additional 12 months of survival by ~9%. Same authors reported improvements in media survival times over 76 weeks for an important number of ALS patients [58].
In 1995, oral riluzole was approved by FDA as part of the treatment of ALS. Riluzole is a well-known presynaptic glutamate release inhibitor, which can provide neural injury and prevent muscle-power worsening. Currently, this medication has been licensed to be prescribed in many places including the European Union [59].
The dose of 50 mg twice, to be taken 1 hour before meal or 2 hours after it, has been approved by the Institute for Health and Care Excellence since 2001 with good results [60].
One good news is that riluzole is now available in oral suspension (Teglutik®) which presentation (5 mg/ml) and has been shown its beneficial for patients presenting bulbar palsy with functional dysphagia allowing longer therapy [61, 62].
Not randomized controlled trials (RCTs) with riluzole for ALS patients have been performed.
However, other RCTs have been done for patients with cervical myelopathy, chronic psychosis, and autistic spectrum disorder [63, 64, 65].
Real-world evidence confirmed that an important prolongation of median survival times in ALS patients treated with riluzole is certain. Based on retrospective/prospective investigations done on large database, these authors concluded that patients under riluzole therapy had better prognosis than those without treatment, mainly at the first stage of the pathological process [58].
Brooks et al. studied two series of ALS patients: one group of 51 patients under riluzole treatment and another group of 241 patients without riluzole (before 1996) and a second series of 112 ALS patients’ riluzole-treated and 65 nontreated patients (after 1996). These authors found that Cox analysis concluded that patients on treatment got an extension of survival (
Retrospective population-based studies on the effect of riluzole on survival of ALS patients done between 1999 and 2008 and made by Lee et al. concluded that Cox multivariate analysis (
Georgoulopoulou et al. and Knibb et al. conducted a prospective population-based study on the survival of 193 patients (between 2000 and 2009) and 575 cases (between 1990 and 2013) consuming riluzole, respectively. According to the Cox multivariate model used during the first series of participants riluzole-treated, they reached a prolonged survival and remarkable delay of pulmonary complications including patients with bulbar palsy and even those with affected four limbs, and the second series of cases riluzole-treated showed a slower progression to pulmonary involvement [71, 72].
Chen et al. also studied a group of ALS patients using the same methodology and concluded that the median survival time in cases riluzole-treated was 268 weeks compared to 256 weeks in nontreated cases (log-rank
Based on meta-analysis of RCTs recently done and all data obtained up to date, riluzole prolonged survival in ALS cases by 8–12 weeks and augmented the chance of additional 52 weeks of survival by ~9%.
Other authors reported that riluzole-treated cases can increase their median survival by up to 76 weeks, after reviewing 10 clinical ALS databases with around ~6000 cases [58].
In a series of patients studied by Inoue-Shibui et al., riluzole therapy was interrupted in 20 cases among 92 patients [74]. The most common cause of discontinuation of riluzole was abnormal of liver enzymes (5.4%), followed by interstitial pneumonia, among other causes.
All adverse events happened within 24 weeks of the beginning of riluzole therapy, with 50% of the adverse events occurring within 2 weeks. In almost all patients, adverse events disappeared after stopping the treatment. In the real-world setting, riluzole has been well assimilated for long periods of up to 7 years or more [75].
Recently, two patients presenting recurrent pancreatitis were communicated to the medical literature. In both cases, the diagnosis was done within the first 3 months after initiated the treatment with riluzole [76], being another strong reason to highlight our recommendation about a careful observation of adverse events in the first 6 months of riluzole administration.
A few weeks ago, Jaiswal et al. also confirmed that riluzole delay progression of ALS in animal model based on their experiences and many experimental drug trials done over the past decades, but riluzole did not show similar results in human beings or results are still nonconcluded under Phase I–III trials, which are quite true, and riluzole is the only available medication with some benefits on survival [77]. Nevertheless, an antioxidant drug (edaravone) has been produced by Mitsubishi Tanabe Pharma, and its effectiveness in halting ALS progression during early stages has been found.
In 2015, edaravone (Ridicut) was launched for the management of patients with ischemic stroke at first and later for the treatment of ALS patients [78]. Edaravone is a drug with a free radical scavenger with no remarkable benefits in ALS patients according to Phase III clinical trial, but edaravone is also a strong antioxidant able to prevent oxidative stress leading to motor neuron fatal damage in ALS. These investigators found another study, which confirmed good therapeutic response to edaravone in diagnosed patients by revised diagnostic criteria (El Escorial) of MND/ALS. Other authors investigated the effect of intraperitoneal administration of edaravone in wobbler’s mice and demonstrated that elevated dose (10 mg/kg) of edaravone therapy remarkable attenuated paresis and muscle contracture on the extremities and stopped denervation atrophy in the proximal muscles and degeneration in the cervical anterior horn cell neurons compared to control group. After large waiting period of 22 years, the Mitsubishi Tanabe Pharma America acquired an US FDA approval for edaravone (Radicava) in May 2017 for the therapeutic approach of ALS.
To low progression of MND/ALS, edaravone is a good indication according to the previous reports delivered to the medical literature. Recent phase three studies done on ALS patients treated with this medication did not confirm remarkable advantage in the Revised ALS Functional Rating score over the control group [79]. Between November 28, 2011 and September 3, 2014, the Writing Group [80] studied 213 cases and selected 192 candidates. Of these, 137 cases completed the first period for close observation: 69 were selected to be edaravone-treated (randomly), and 68 were assigned to control group to be treated with placebo also randomly, both series were included in the primary efficacy analysis. The results observed from the primary outcome demonstrated that the control group change −7.50 (0.66) in ALSFRS-R score compare with −5.01 (SE 0.64) in the group edaravone-treated. In favor of edaravone, the least-square mean confirmed a difference among two series of 2.49 (SE 0.76, 95% CI 0.99–33:
Although there is no available medicine to cure any clinical presentation of MND, during the first semester of this year (2019), a number of medications have been used to treat affected patients. Unfortunately, no remarkable results have been obtained, but some of them still show good action over this disease. In this chapter, we will deliver some comments about the results reached by some authors according to their report to the medical literature. The most common used medications are EH301, 5Fluoroucil, Tryptophan, RNS60, Rasagiline, Tirasemtiv, Aquaporin, Fasudil, and Lunasil.
de la Rubia et al. [84] evaluated the accuracy and feasibility of Elysium Health’s candidate drug EH301 in ALS cases by a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two ALS patients studied underwent for assessment during 4 months. Differences between EH301 and control group were evaluated based on their findings, and EH301 confirmed a remarkable slow progression of ALS compared with nontreated cases and even confirmed clinical benefits in many key outcome measures relative to their baseline.
Searching for drug candidates for ALS, Rando et al. investigated the action of anti-metabolite 5-fluorouracil (5-FU) administered by a single intraperitoneal injection at 150 mg/kg in SOD1G93A model of ALS. Un expectedly, the authors found that 5-FU (anti-cancer drug) increases survival delays of the disorder onset and improves motor function in ALS mice, but they were not able to demonstrate the mechanism of the beneficial 5-FU action in ALS mice. Despite of 5-FU did not improve the modulate motor neuron survival remarkably and did not improve reactive gliosis or change the muscle morphology, their findings recommended that a low dose of 5-FU or its analogs may have good effects on MND/ALS [85].
Other authors postulate that toxic gain of function, spread, and SOD1 misfolding is suggested as part of pathological mechanism of MND/ALS, but the nature of SOD1 toxicity has been hard to describe [86]. Only in SOD1 proteins from humans and other primates, and rarely in other species, a tryptophan residue at position 32 (W32) is predicted to be solvent exposed and to participate in SOD1 misfolding. DuVal et al. considered that W32 is influential in SOD1 acquiring toxicity, as it is known to be important in template-directed misfolding [86].
DuVal et al. highlighted the relevant influence of W32 on cases SOD1 toxicity to upper and lower motor neuron cells morphology and its activities. They assessed pharmaceutical targeting of the W32 residue for rescuing SOD1 toxicity [86]. When RNS60 is administered by IV infusion every 7 days and daily nebulization, it acts as a novel immune-modulator agent able to provide neuroprotective action in MND/ALS preclinical models. Paganoni et al. [87] studied 16 ALS patients during 23 weeks for safety and tolerability. Some investigations were done such as PBR28 positron emission tomography imaging and plasma biomarkers of inflammation. These authors did not find serious reactions, and no participants were removed from the study due to drug-related complications. At the present moment, a large, multicenter, Phase II trial of RNS60 is currently including cases to test the effects of RNS60 on MND/ALS biomarkers and disease deterioration based on the previous findings. They concluded that long-term RNS60 administered by IV infusion (as indicated) is well assimilated by patients and is also accurate [87]. In ALS, the prolong use of immune-modulating therapies has been showing not good results and did not help to understand how the immune system modifies disease outcome [88].
Rasagiline (monoamine oxidase B inhibitor) administered at 2 mg/day has a neuroprotective effect in MNS/ALS cases. In order to verify this postulate, Fernandez et al. performed a trial of 80 ALS patients from 10 hospitals in America. They did not identify any difference between Rasagiline-treated cases and the control group. Therefore, they assumed that Rasagiline did not change disease output compared with control group during 12 months of therapy. Rasagiline was well assimilated, and no serious adverse events were report.
Shefner et al. conducted a multinational clinical trial to study the accuracy of tirasemtiv (125 mg twice daily) using an escalating dosage protocol during 4 weeks [89]. Comparisons between two series of cases with ALS were performed. One group constituted by fast skeletal muscle troponin activator and a second control group by placebo. Of 744 candidates, 565 participants assimilated open-label tirasemtiv and were treated randomly. As a side effect of tirasemtiv, nausea, weight loss, dizziness, fatigue, and insomnia were more often seen. The frequency of severe side effects was seen equally on both series of cases. Obviously, tirasemtiv did not change the decline of slow vital capacity or remarkable impact secondary outcome assessment and weak tolerability of tirasemtiv may lead to poor effect on MND/ALS.
Aquaporin 4 (AQP4) is present in astrocytes in the nervous system as primary water channel and has been postulated to participate in a myriad of acute, chronic brain disorders and the incidence of MND/ALS. Depolarization of AQP4 causes degeneration of the upper and lower motor neurons via GLT-1, and suppressions increase recovery of motor activity in MND/ALS cases probable due to NGF. No clinical trial targeting AQP4 has been done up to date [90].
Studies made with Fasudil (30 mg for IV application) have shown good results in cell culture and animal research of MND/ALS. This medication is a Rho kinase (ROCK) inhibitor, which has been used in Japan (1995) for the management of Reynaud’s syndrome, pulmonary hypertension, and vasospasm secondary to subarachnoid hemorrhage, angina pectoris, and also to treat complications from high blood pressure. Currently, some authors are looking for efficacy, safety and tolerability of a ROCK-ALS of fasudil in MND/ALS cases that started patient recruitment in 2019 [91]. ROCK (serine/threonine kinase) is a novel medication to target for neurodegenerative brain disorders, and it has two isoforms: ROCK1 is mainly for the peripheral nervous system, and ROCK2 is expressed preferentially in nervous central system [92]. Levels of ROCK augment according to age and tissue of MND/ALS cases. Some authors also confirmed increased levels of ROCK2 and downstream targets LIMK1 and coiling [93]. Fasudil also modifies microglia activity [91]. Main side effect of fasudil is intraparenchymal hemorrhage. Nevertheless, in studied population of cases with subarachnoid hemorrhage, the incidence of bleeding did not differ remarkably from the control group. Therefore, hemorrhage is not an expected complication, and it will not put in risk the life in selected patient. Cases with past medical history of intraparenchymal bleeding, congenital or acquire aneurysms or Moyamoya disease should not be included in the therapeutic group.
Lingor et al. confirmed that ROCK-MND/ALS clinical trial provides a well-tolerated, safe, and accurate way of treatment. The biomarker collection associated with this study will deliver additional data as indicators of progression. Finally, we comment about Lunasin a soy peptide that modify histone acetylation in vitro joined to single MND/ALS effect but no remarkable activity on histone acetylation or disorder deterioration in 50 participants treated during 5.5 months by Bedlack et al. [94]. Excellent retention and adherence have been found but not better results than riluzole or edaravone.
As a result of the great interest showed by investigators and participants on different studies done during the first half of this year (2019), today we can see an important number of other therapeutic procedures also looking for the best management of ALS patients. This modality ranges from physical exercises to acupuncture including other choices such as stem cell therapy, treatment for sialorrhea, and spasticity, among others.
In our times, many healthy people do physical exercises on regular basis; some do exercise for slimming purposes, others for prophylactic treatment, rehabilitation, and so forth.
Unfortunately, due to lack of space, these topics will not be included in this chapter.
After reviewing the most recent studies published in the medical literature, we concluded that we still have no curative treatment for MND patients, but a promising future is forthcoming.
Although occupied only a small (<3%) proportion of the Earth’s terrestrial surface, urban soils provide a wide range of ecosystem services to inhabitants of cities [1]. In the current context of population growth and urbanization as well as rapid industrialization, urban soils have largely disappeared and polluted by different types of organic and inorganic pollutants. According to urban scholars, although there is an increase of the cultural levels and diverse with more various cities, urbanization however generally leads to a reduction in biodiversity and ecosystem quality. Over the last decade or more, urban gardening is privileged and growing trend in many cities all around the world. For this development, the inhabitants should be assured of that the land is clean and safe. It is urgent that urban soil remediation projects must be to encourage investments.
\nConventional methods of soil decontamination possess disadvantages in forms of environmental cost and financial burden. This truth leads to the search of ecological technologies for restoration of urban soils. One such approach includes phytoremediation. Phytoremediation is a process that uses plant for biological treatment of both organic and inorganic from polluted soils in non-urban and urban areas. Operating costs are very low, ranging from $ 0.02 to 1.00 per m3 of soil [2]. Phytoremediation is based on the use of plant species to extract, retain, immobilize or degrade pollutants in soils. This technique provides good recovery of soils contaminated with heavy metals, and petroleum hydrocarbons.
\nIn the urban context, there are two challenges in attracting the application of phytoremediation for contaminated soils. First, how do make the application of this approach operate and effective? Second, how do inform and train professionals and also non-professionals of the remediation of the contaminated soils potential offered by phytoremediation approaches. This will encourage the use of an ecologically, viable and socially accepted depollution technique.
\nIn this chapter, we will discuss how to take phytoremediation approaches from a proven technology to an accepted practice in the urban context. An overview of urban soil types is provided following phytoremediation’s application for urban soils with the focus on inorganic and organic pollutants, to provide a frame of reference for the subsequent discussion on better utilization of phytoremediation. At last, we offer suggestion on how to gain greater acceptance for phytoremediation by urban inhabitant.
\n“Urban soils” could have several definitions according to scientific or technic domain considered. For World Reference Base for Soil Resources (WRB), urban soils are composed of “any material within two meters of the Earth’s surface that is in contact with the atmosphere, excluding living organisms, areas with continuous ice not covered by other material, and water bodies deeper than two meters” [3]. The Morel and Schwartz team’s works made it possible to complete the definition by adding that these soils are under strong human influence in the urban and suburban landscape [4–6]. These soils are called Technosols [3]. Their studies begin to be more and more important at the beginning of the 21st century with an exponential increase in the number of publications concerning urban soils (Figure 1). Indeed, before the 2000s, the urban soils were considered too disturbed, polluted and poor fertility. Nevertheless, with the ever-increasing population in the city and the growing public concern about environment and human health, the restoration or rehabilitation and remediation of these soils have become a priority. In the urban area, soil is a key issue, subject to very rapid changes in allocation and use (green space, gardens, peri-urban agriculture, urban and industrial activities). Soils provide many essential ecosystems services in urban area, such as carbon and mineral nutrients storage, biota’s habitat, role in hydrologic cycle by reducing runoff and promoting infiltration, water supply and reduction of pollutant bioavailability.
\nEvolution of the number of annual scientific publications on soils (dark gray histogram) and urban soils (histogram light gray) in the international scientific literature over the period 2000–2019. Evolution of the relative share of publications on soil remediation urban is represented by the black curve, which is estimated as % of the total number of publications on urban soils. Bibliometrics on the state of scientific and technological knowledge on urban soils has been evaluated with two search engines: Web of Science and Medline, using these keywords “urban soil”, “remediation”, “restoration”, “rehabilitation” with different combinations.
The main characteristics of urban soils are strong vertical and horizontal spatial heterogeneity in terms of physical, chemical and biological properties [7]. This strong variability can be explained by differences in occupation and use, such as the soils supporting buildings and infrastructures, landscaping areas. Various anthropogenic factors lead to a modification of the initial state of the soil in urban zones. Moreover, most of urban land are the new soils created through mixing, incorporation, and export of earthy materials, compaction or sealing. Unfortunately, the incorporation of these materials leads to frequent pollution of these soils. In general, urban soils display raised pH values due to addition of calcareous and other waste building materials.
\nDue to the human activities, urban soils are contaminated with various organic and inorganic pollutants. Among which, polycyclic aromatic hydrocarbons (PAH), pesticides, biphenyl-polychlorinated (PCB), metals, metalloids and radionuclides are the most abundant. Their presence in soil is undesirable due to their highly toxic and the environmental disturbances they create. Soils contain natural quantity of potentially toxic metals due to constitution of parent rock materials. Trace metals including lead (Pb), cadmium (Cd), mercury (Hg), chromium (Cr), zinc (Zn), copper (Cu), nickel (Ni) and some metalloids such as arsenic (As), Selenium (Se), manganese (Mn) are toxic for living organisms even at low concentration in soils. Whereas some trace metals such as zinc (Zn), copper (Cu), nickel (Ni) are vital elements for living organisms and their physiological properties (enzyme activators, electron transfer system in photosynthesis and respiration). Moreover, the presence of hydrocarbons and metals in soils affects negatively seed germination and plant growth [8], soil microbial community and activities [9], metabolic capacities of plants and microorganisms [10].
\nNevertheless, since several decades, the anthropogenic origins of all the urbans pollutants are various and mainly attributed to (i) transport sources (traffic, vehicle emission, brake and tyre wear), (ii) commercial and industrial emissions (energy production, electronics, metallurgical and chemical industries, fuel combustion, incineration), (iii) domestic activities (construction and demolition, waste disposal, wastewater), and (iv) agricultural activities (application of fertilizers and pesticides, wastewater irrigation) [11].
\nSoil erosion and storm water runoff in urban areas are the main contributor to diffuse pollution according to the United States Environmental Protection Agency [12]. Moreover, the incorporation of calcareous and other waste building materials into urban soils are no negligible and several inorganic pollutants, especially trace metals, are being introduced into these soils leading their use dangerous for human health. Degradation of trace metals is not possible; therefore, they are accumulated and persist in the soil for many years. The concentration of various pollutants in rural and urban areas in France are presented in Table 1. We can see that the concentrations of the most of pollutants are superior in urban area than in rural area. These data confirm also the heterogeneity of these urban soils and are coherent with the concentrations of urban soils of other metropolises (USA, Spain, China, Ireland, Finland, Algeria, Nigeria and Iran) [7].
\n\n | \n | Data acquired in mainly rural areas | \nData acquired in mainly urban areas | \n|||||
---|---|---|---|---|---|---|---|---|
Family | \nName | \nUnit | \nMin | \nMed | \nMax | \nMin | \nMed | \nMax | \n
Trace metals | \nAs | \nmg/kg | \n1.00 | \n— | \n25.00 | \n1.00 | \n50.20 | \n|
Pb | \nmg/kg | \n2.20 | \n91.50 | \n5.30 | \n650.00 | \n|||
Zn | \nmg/kg | \n275.00 | \n13.00 | \n2600.00 | \n||||
Ni | \nmg/kg | \n78.90 | \n4.00 | \n6200.00 | \n||||
Hg | \nmg/kg | \n0.02 | \n— | \n0.10 | \n0.05 | \n28.00 | \n||
Cd | \nmg/kg | \n<0.02 | \n6.99 | \n0.05 | \n3.63 | \n|||
Cr | \nmg/kg | \n<2 | \n118.00 | \n0.90 | \n111.30 | \n|||
Cu | \nmg/kg | \n<2 | \n27.20 | \n4.20 | \n190.00 | \n|||
HAP | \nNaphtalene | \nmg/kg | \n0.00 | \n1.03 | \n0.01 | \n11.00 | \n||
Acenaphtylene | \nmg/kg | \n0.00 | \n0.53 | \n0.01 | \n15.00 | \n|||
Acenaphtene | \nmg/kg | \n0.00 | \n0.16 | \n0.02 | \n13.00 | \n|||
Fluorene | \nmg/kg | \n0.00 | \n0.25 | \n0.01 | \n6.40 | \n|||
Phenanthrene | \nmg/kg | \n0.00 | \n3.47 | \n0.01 | \n7.80 | \n|||
Anthracene | \nmg/kg | \n0.00 | \n0.56 | \n0.02 | \n33.00 | \n|||
Fluoranthene | \nmg/kg | \n0.00 | \n6.08 | \n0.01 | \n10.00 | \n|||
Pyrene | \nmg/kg | \n0.00 | \n4.37 | \n0.01 | \n0.64 | \n|||
Benzo(a)anthracene | \nmg/kg | \n0.00 | \n2.18 | \n0.01 | \n1.90 | \n|||
Chrysene | \nmg/kg | \n0.00 | \n4.14 | \n0.02 | \n10.00 | \n|||
Benzo(b)anthracene | \nmg/kg | \n0.00 | \n2.22 | \n0.01 | \n0.60 | \n|||
Benzo(k)anthracene | \nmg/kg | \n0.00 | \n1.46 | \n0.01 | \n16.00 | \n|||
Benzo(a)pyrene | \nmg/kg | \n0.00 | \n1.73 | \n0.02 | \n29.00 | \n|||
Indeno(1, 2, 3-cd)pyrene | \nmg/kg | \n0.00 | \n1.83 | \n0.01 | \n1.20 | \n|||
Dibenzo(a,h) anthracane | \nmg/kg | \n0.00 | \n1.13 | \n0.01 | \n0.70 | \n|||
Benzo(g, h, i)perylene | \nmg/kg | \n0.00 | \n1.53 | \n0.01 | \n12.00 | \n|||
PCB | \n— | \n— | \n— | \n|||||
Dioxines/furanes | \nΣ Dioxines/furanes | \n24.75 | \n2095.28 | \n27.58 | \n4678.40 | \n|||
Cyanure | \nCyanure | \nmg/kg | \n— | \n— | \n— | \n0.10 | \n6.10 | \n|
Phenol | \nIndice phenol | \nmg/kg | \n— | \n— | \n— | \n0.01 | \n86.00 | \n|
Hydrocarbures | \nC10, C40\n | \nmg/kg | \n— | \n— | \n— | \n0.50 | \n260.00 | \n
Concentration of organic and inorganic pollutants in rural and urban soils in France (values extracted from Ademe [13]).
The review of the literature indicates that most scientific articles (>80%) focus on metals and little data are available on traditional or emerging organic pollutants that are now being detected. Many studies still need to be carried out to assess the impact of these pollutants on urban soils and consequently on ecosystem services provided by these soils, and more broadly on human health.
\nAs seen earlier in Section 2.1, urban soils are much polluted. It is therefore necessary to treat them before any other use, be it for parks or gardens. Obviously, depending on the nature of the pollutants (organic or inorganic), their concentrations, and the soil physic-chemical properties, the appropriate technique will differ. Moreover, the reason for which monitoring will also be a criterion for the choice of operational staff. The remediation technics used for the depollution of contaminated site can be in situ or ex situ, on site or off site and biological, physical and chemical. They are often employed in combination with each other in order to optimize the system more efficiently and cost-effectively.
\nEcological methods for soil remediation have received considerable interest in the last decade (Figure 1) and exhibit almost 10% of the publications on urban soils. This growing interest has several reasons such as potential cost savings compared to conventional non biological techniques and the benefit effects of this techniques on urban soil that are often polluted with a poor fertility. Ecological methods the most used in urban soils are phytoremediation, microbes-assisted-remediation, and amendment incorporation. Phytoremediation can be used in combination with this other technique.
\nPhytoremediation [10, 11] consists to use of plants to remediate and revegetate contaminated sites. Phytoremediation technique was first developed to clean up heavy metal(loid)s contaminated soils, thus, the first publications on the subject appears at the end of 1980s and beginning of the 2000s for urban soils. Phytoremediation is considered environmentally friendly, esthetically pleasing, non-invasive and cost-effective technology to clean up the sites with low-to-moderate levels of heavy metal(loid)s (see Section 2).
\nAmendment incorporation in urban soils corresponds mainly to organic amendment such as compost or biochar [12, 13]. In urban soils, this technique is used since 2000s for disturbed soils with poor structure and low levels of OM and fertility in order to improve the physical properties (such as bulk density, infiltration rate, hydraulic conductivity, water content, aggregate stability, and porosity) and function (such as water and nutrients available for plants, support for living organisms, etc.). Concerning contaminated urban soils, the studies on biochar has shown its ability to bind metals, decrease their mobility and bioavailability, stimulate microbial activity and promote soil revegetation and recovery (see Section 3.3).
\nMicrobes-assisted-remediation [14] or bioremediation is a method involving the use of microorganisms to breakdown hazardous contaminants/pollutants to nontoxic or harmless forms. This technique was mainly used for organic pollutants. It can be also used for inorganic pollutant to stabilize metals or metalloids into soil or extract them when associated to phytotechnologies. Bioremediation techniques are mainly of two types: in situ (at the site of contamination) and ex-situ. Bioremediation presents several benefits such as economic viability, social acceptability, and eco-friendly (see Section 3.1).
\nInorganic pollutants which include heavy metals and metalloids are release into the environment due to human activities of industry, transportation and also urban activities. In order to remediate the soils polluted by inorganic pollutants, several conventional chemical and physical techniques have been used for decades; however, they are expensive and often hard to set-up. Recently, phytoremediation is admitted as an appropriate method using plants for the depollution of inorganic pollutants. The number of publications related to phytoremediation has only increased since the early 2000s with an average of 700 articles per over the last 5 years (source: Web of science) with 3–5% focused on urban soil. Moreover, 90% of these publications are related to phytoremediation of soils contaminated by trace metals and metalloids.
\nPhytoremediation of inorganic pollutants refers to phytoextraction, phytostabilization, phytovolatilization and rhizofiltration [14, 15]. Phytovolatilization (only for mercury and selenium) and rhizofiltration are still techniques with an experimental approach and mostly under controlled conditions unlike phytoextraction and phytostabilization which have been applied in the field, and most used to rehabilitate urban soils.
\nPhytostabilization consist to cover contaminated soil by plants either by seeding or planting. As a consequence, the biological, physical and chemical properties of the soils will be improved. The presence of vegetal cover, especially dense root system will permit to decrease the dispersion/mobilization of inorganic pollutants by promoting (i) water infiltration rather than runoff, (ii) evapotranspiration which will limit the percolation of water and thus the leaching of contaminants, and (iii) by retaining fine particles. Thus, plants will stabilize inorganic pollutants by accumulating them in the rhizosphere or into roots and will decrease their bioavailability. Phytostabilization, despite these many advantages (improvement of biological, physical and chemical qualities and consequently the increase in soil ecosystem services), is above all more a management strategy for polluted urban soils than a depollution technique since trace metals and metalloids remain in the soil. The application of amendments promotes the heavy metal stabilization in soils. Recently, aided phytostabilization have been used for remediation of urban soils [16–18]. This technique consists in the chemical stabilization of inorganic pollutants with the combined use of a wide range of soil amendments with a selected plant. This soil amendment can be natural mineral (phyllosilicates, zeolites, and oxides), organic substances, industrial or urban wastes and agriculture (manure, straw, and composts). This amendment will increase the soil pH and sorption capacity of soil rhizosphere (see Section 2.3).
\nPhytoextraction is based on the ability of plants to grow on contaminated soils, absorb inorganic pollutants by their roots and then transfer and accumulate them in significant quantities in their aerial organs (stem, leaves, and reproductive organs). The pollutant presented in soils must therefore be bioavailable for plants. Thus, the phytoremediation process will increase the fraction of metals bioavailable for plants depending on a combination between plant physiology, soil microorganisms (see Section 3.1), soil chemistry and the interaction between plant and microbes. There are many reviews that inventory these hyperaccumulators or high biomass accumulating plants used as a function of the major trace metals or metalloids they accumulate [14, 19, 20].
\nMoreover, in order to improve the efficiency of plants involved in phytoextraction process, many authors proposed the transfer of the hyperaccumulator phenotype from small and slow growing hyperaccumulator species to fast growing, high biomass-producing non-accumulator plants. Many genes involved in the acquisition, allocation and detoxification of metals come from bacteria and yeasts [21]. For example, some works on bioengineering have used plants capable of removing methyl-mercury from contaminated mining and urban soils [22], a strong neurotoxic agents, is biosynthesized in Hg-contaminated soils. To detoxify this compound, transgenic plants have been engineered to express modified bacterial genes
In the case of lead (Pb) which is one of the most trace metals presented in urban soils (see Section 2.2), the content of bioavailability lead in the soils is very low and it is difficult for plant to uptake them. Therefore the rehabilitation of soils polluted be lead is often difficulty. To overcome the problem, it is necessary to realize assisted phytoremediation [23]. This technique consists of adding to the soil various chemical compounds that can increase the availability of trace metals or metalloids in the soil solution. The chemical compounds used are generally aminopolycarboxylic acids (APCA), molecules chelating metal cations such as ethylenediamine tetraacetic acid (EDTA), nitrilotriacetic acid (NTA), hydroxyethylenediaminetetraacetic acid (HEDTA) or diethylenepentaacetic acid (DTPA). Nevertheless, it has been shown that the aminopolycarboxylic acids can be toxic for some plants, microorganisms or nematodes. Meanwhile organic acids such as citric or oxalic acids which are less toxic can be used, but they are less effective in increasing the fraction of trace elements easily assimilated by plants. Moreover, transgenic plants have been engineered too to overproduce recombinant proteins and chelating molecules such as citrate, phytochelatins, metallothioneins, phytosiderophores playing roles in chelation and assimilation of metal.
\nDue to increased human activities including urbanization and industrialization, the pollution of organic pollutants in urban areas has been increased over the last decade. Urban and peri-urban soils are often polluted as consequence of human activities. The main sources of the urban organic pollutants are (1) the utilization of the pesticides in the urban environment, (2) the atmospheric deposition of organic pollutants in form gaseous and particulate by transport, (3) the using of urban waste composts as amendments in urban agriculture and (4) the development of urban industry. According to the results of bibliographic research over the last 20 years on website Web of Sciences, phytoremediation of organic pollutants in non-urban and urban soils generally involved several classes of compounds which are mostly polycyclic aromatic hydrocarbons (PAHs) [24, 25], polychlorinated biphenyls (PCBs) [26] and petroleum hydrocarbons (PHCs) [27] and others low molecular weight compounds such as benzene, toluene and xylene [2] (Table 1).
\nPhytoremediation for organic contaminants takes place at two levels: inside and outside of plant cells. Like the mechanisms of phytoextraction (absorption) which is the primary of phytoremediation for inorganic pollutants as described above (see Section 2.1), some low molecular weight organic contaminants can be taken up by root and then to be accumulated and/or degraded
Over recent years, the number of works in phytoremediation for organic contaminants has intensely increased with many encouraging results that have emerged regarding the capacities of several plants to degrade specific organic contaminants. To make phytoremediation for organic compounds successful, it is fundamental to understand (1) the type of soil to be treated, (2) the concentration and the fate of each organic pollutants and (3) the relations between the physical, chemical and biological parameters. Urban soils are known to have particular characteristics that have mentioned above, therefore the application of this technology in urban polluted soils remains a daunting challenge for scientists. An exploratory bibliographic research on the Web of Science from 2000 to 2020 show that a few works use greenery to eliminate the organic pollutants in urban context since its application can be limited by many factors including climate and anthropogenic modifications of the soil (e.g. impacts on soils by urban-rural temperature contrast also known as urban heat islands) [33].
\nThe urban context is very particular with regard to its location, spatial heterogeneity, pollution and usage. Even if urban soils are not intended to be reclaimed, there is still a risk to the health of the local population. It is for this reason that it is necessary to rehabilitate these soils. Many studies present the evidence results in utilization of different ornamental plant species for phytoremediation (e.g. family Asteraceae) can survive under such adverse urban conditions. In situations where the city budgets are limited and no alternative treatment can be carried out, the use of phytoremediated-plants could be affordable, sufficient, economically and community acceptable. Thus, plants play also a significant role in preservation of green spaces through enforcement of environmentally sustainable city planning. This application presents wealth of opportunities for city designers of urban landscapes and a good compromise to enhance urban diversity using phytoremediation in association with water infrastructures and open space on multiple scales. Phytoremediation seems to be a promising technique but there are still many challenges, especially in an urban context. Indeed, the use of this technique is long (several decades) and restricted. Phytoremediation is thus limited by the area explored by plant roots and the low growth and low biomass produced. Moreover, this biomass cannot be used as compost because it is considered as contaminated waste. It is therefore necessary to select the right plant, adapted to urban soils, non-invasive in order not to alter the floristic diversity and capable of mobilizing metals even if they are not bioavailable. Thus, for each urban soil, a risk assessment should be carried out to protect local biodiversity before introducing alien species, but also a study should be carried out to better understand the interaction between the factors in the rhizosphere (metals/soil/microorganisms/plant roots).
\nUrban soils are increasingly being used for urban agriculture, either for private use or for small-scale local production. Thus, one of the big challenges is to cultivate while respecting food security and human health but there is a lack of data. To remediate to its problem, more and more works were focused on the combination of phytoremediation and food production [34]. At present, there are no large-scale studies, and most of this work reports on experiments with crop/phytoremediating plants combinations. There is always the problem of the biomass produced, can it be consumed? Can it be used as compost? Legislation in all countries is very vague or non-existent and needs to be strengthened. Research needs to be further continued to overcome these challenges of establishing food production on urban soils by carrying out studies on the translocation of pollutants in plants and their bioaccumulations, eco-toxicological risk assessment and soil legislation.
\nIn spite of the fact that phytoremediation has a great of advantages in comparison to other technologies, it has also some limitations. The process of the phytoremediation is very slow from a few months to several years. The most of the plant used for phytoremediation have often small aboveground biomass and slow growth rate, and shallow root system, therefore very limits for their application in large-scale operations. Also, the low concentration of contaminants in form bioavailability in soils cause a low ability of contaminant absorption by plants.
\nTo improve these limitations, one alternative that we will mention in this chapter is the use of (1) specific microorganisms such as fungi and bacteria, (2) earthworms, considered as ‘ecosystem engineers’ of soil, and (3) amendment such as biochar. All these complementary methods will permit to increase the growth of plants, biotic and abiotic stress tolerance and all the processes associated, such as mineral nutrient absorption, roots exudation and rhizosphere microbial activities, will be improve the process of the phytoremediation.
\nA fungus (plural: fungi) belongs to the group of eukaryotic organisms. These organisms forms a kingdom that is separate from the other eukaryotic life kingdoms of plants and animals. Fungi are heterotroph, since they obtain carbon and energy from organic matter. Two major functional categories of fungi are saprophytic and mycorrhizal fungi. Saprophytic fungi decompose nonliving organic matter and they are important agents in soil mineralization processes and carbon cycle. Mycorrhiza are symbiotic species associated with vascular plants. There are eight main types of mycorrhizal symbioses based on their morphology and not on a biological reality [35].
\nAccording to pollutant type (organic and inorganic), the mycorrhizal fungi will be different. Whatever the pollutants, the selection of an appropriate host plant with mycorrhizae is of primary importance to improve phytoremediation. For organic pollutants such as polycyclic aromatic hydrocarbons (PAH), endophytic fungi is preferentially used to increase the efficiency of phytoremediation [36, 37]. For example, arbuscular myccorhizal fungi (AMF), belonging to the phylum
For inorganic pollutants such as trace metals or metalloïds, some endophytic fungi, especially AMF that can increase the uptake of arsenic or other metals such as zinc, copper or lead [39]. Nevertheless, it has been shown that the most effective fungi in terms of host plant adaptation are ectomycorrhizae and ericoid mycorrhizae [35, 40, 41]. Indeed, the great development of the extraracinar mycelium allows it to explore a large volume of soil but also to store more metals and transform them into a less toxic form thanks to a wide range of enzymatic activities.
\nThe interaction mycorrhizae-plant symbiosis and inorganic pollutants has three advantages. First, fungi can tolerate a high level of metal toxicity. Second, they are able to remove inorganic pollutants from soil and water. Finally, they promote plant growth even in polluted soils.
\nIn healthy soil, bacteria represents billons of unicellular organism and thousands of different species. Bacteria play a crucial role in ecosystem service of soil such as decomposers. As a consequent, bacteria release nutrients that other organisms could not access. Nevertheless, environmental and structural characteristics of urban soil greatly influence soil microbes. Indeed, anthropogenic impacts such as organic and inorganic pollutants in technosols and in urban runoff can shift the abundance and diversity of bacterial communities [42]. For example, it has been shown that in urban soils the main phyla identified are Acidobacteria, Actinobacteria and Proteobacteria.
\nIn the rhizosphere zones, bacteria interact with plant root in form of commensalism or mutualism. These root associated beneficial bacteria that plays an important role in acquisition for nutrient, tolerance to abiotic stress and also defense against pests are referred to as the plant-growth-promoting rhizobacteria (PGPR) [43]. Therefore, PGPR have been mainly considered to use in phytoremediation in order to increase the efficiency of the phytoremediation. Recently, another bacterial type called plant growth-promoting endophytic bacteria (PGPE) which have been shown to act as PGPR are widely used in phytoremediation [44].
\nIn the phytoremediation context, the microbial mechanisms direct and indirect that can improve the efficiency of phytoremediation are differ depending the pollutant types including organic or inorganic. Generally, root assisted-bacteria are used in order to improve the adaptation of hyperaccumulator plants to suboptimal urban soil conditions (see Section 2.1, 2.2 and 2.3) and ameliorate the efficiency of phytoremediation. For inorganic pollutants including trace metals, the mechanisms employed for enhance the phytoremediation involve improvement of plant growth by increasing mineral contents, plant metal tolerance by phytohormones products, and capacity of absorption and accumulation by producing organic acid and metal-specific ligands (e.g. siderophores) [45]. We can here cite some research works on the phytoremediation of metals facilitated by soil bacteria. The bacterial species
Unlike inorganic pollutants, for organic pollutants whose molecules contain principally carbon, the principal bacterial mechanisms when phytoremediation’s applied is related to pollutant co-metabolism and/or degradation pathways [50]. In fact, exogenous as well as endogenous bacteria have a system of co-metabolism of the organic pollutants as the sole carbon source with amino acid, lipid, fatty acids and organic acids. Alternatively, these bacteria come to colonize in the rhizosphere and benefit the production of root exudates, consisting of sugar, fatty-acid, organic acids, amino acids and other carbon-containing compounds for growth and degrade these organic pollutants [51].
\nAlthough a lot of research points out many advantages this alternative technology, to our knowledge, no work on phytoremediation of pollutants facilitated by soil bacteria in urban areas has been carried out. To apply this technique in urban context, we must take into account all the parameters, consisting of bacterium, plant species, soil composition and nutrient (see Section 2), pollutant type and concentration as well as the competition with other organisms that can limit the use of phytoremediation in the field.
\nEarthworms act as soil ecosystem engineers because of their crucial role in building galleries and in the decomposition of organic matter; therefore they play an important role in agriculture production [52, 53]. In polluted soils, various species of earthworms including
A summary of the mechanisms direct and indirect of earthworm’s effect on soil microorganisms and plants was presented in Figure 2.
\nMechanisms direct and indirect of earthworm’s effect on plant and microorganisms in the phytoremediation context.
Despite a large body of literature on the benefit for soil and plants by earthworm actions, the research on earthworms-assisted phytoremediation has just started on a laboratory scale with some encouraging results [55, 56]. The attention of this research topic is expanding by the time with an increasing the sum of times cited per year according to the citation report from Web of Science Core Collection between 2010 and 2020 (Figure 3). Outdoor experiments up to fields scale need to be investigated and documented.
\nCitation report of the sum of times cited per year on the topic “earthworms” and “phytoremediation” from web of sciences. This report reflects citations to source items indexes within web of science Core collection. Perform a cited reference search to include citations to items not indexed within web of science core collection.
Urban soils are often nutrient poor and polluted. They are degrading more and more quickly with the loss of organic matter and soil permeability that cause the negative impacts on soil structure with increasing in soil density due to soil compaction and other factors. To overcome these deficiencies, the addition of natural organic matter including compost has been recognized to increase the bio-physicochemical qualities of these urban soils [58–60]. Among the different composts, the application of biochar, which is a carbonaceous solid material, is used preferentially for urban soils. Biochar is derived from the pyrolysis of biomass. All cellulose, lignin and other non-carbonic materials gasify and are burned. Only pure carbon remains with approximately 40% of the carbon originally contained in biomass.
\nRather than an amendment (because it is very poor in nutrients), biochar would behave as a soil structure and perhaps as a catalyst, via mechanisms of action that are still poorly understood. The incorporation of biochar decreases the mobility and bioavailability of metals, thus decreasing their translocation in plants while improving the soil characteristics such as infiltration rate, hydraulic conductivity, porosity and therefore the water content. The growing of plants and water cycle is also improved.
\nBiochar, as a carbon-rich, stable and sustainable product, also acts as a carbon sink, which explains why it is attracting growing interest in the context of concerns about human-induced global warming. It could be one of the immediate solutions to the overall negative impact of urban and agricultural activities with the use of fossil carbon in the form of fuels, greenhouse gas emissions and tillage that degrades the carbon sink that humus constitutes.
\nNevertheless, the application of biochar presents possible negative effects. Biochar may contain toxic elements naturally present in its composition and which may lead to an increase in pollution when incorporated. This can affect living organisms and the functioning of the soil. Moreover, because of the dust formed during their application, it present a risk for human health. There is still little data on its negative impacts.
\nTo date, most of the studies has focused on the impact of compost on soil characteristics in agricultural area and relatively little data has been carried out in urban area. Future research should focus on the optimization of compost rates (quantity, depth…) in order to standardize the use of biochar on soil to minimize the bioaccessibility of pollutants and maximize soil/water relations and plants reestablishment [59].
\nThe use of the words acceptability, social acceptance or social reception gives rise to terminological debates [61]. Acceptability is indeed a term vague enough to be used frequently [61]. We can nevertheless consider the social acceptability of a project as a process of social construction born from the confrontation of the arguments of the different actors and which results in an identification of the population concerned with the values carried by the said project. Some stress the fact that this dialog often comes down to the implementation of a communication strategy intended to convince the target audience as part of a top-down conception of a project [62]. The acceptance term is sometimes preferred but can imply a form of resignation of the inhabitants compared to a project conceived in a non-concerted way ([61], according to [63]). Some therefore prefer to use the term “acceptance” [61] after [64], others prefer the term “social reception”. In fact, we can speak of acceptance of a project when it is appropriate by a population that identifies with the objectives pursued and the methods mobilized by it. This appropriation is conditioned by the perception of the project.
\nFor psychology, perception is the function that allows the body to receive, process and interpret information received which comes from the surroundings through the senses. This construction is obviously specific to the type of information, to the individual or group who receives it and to the context in which it is disseminated. Thus a project will be perceived and therefore appropriate differently according to the economic, social, historical context, according to the modalities of diffusion of the information and the nature of this one, and obviously according to the type of actors diffusing and receiving the information and their expectations.
\nIf we particularly consider phytoremediation projects, the perception by the population concerned is influenced by multiple factors: first of all, the identification of the risk associated with soil pollution and the potential benefits expected from phytoremediation [65]. This identification is closely linked to knowledge of the health risks involved. It was highlighted in a Quebec mining site, that the knowledge by all of a strong soil pollution whose effects on the health of populations are clearly highlighted, facilitates the acceptance of phytoremediation projects. In this case, the benefit is clearly identifiable and the populations are extremely favorable to a method of depollution considered as ecological.
\nHowever, if the populations of mining sites are alerted to the health risks linked to these forms of pollution [66] which is not necessarily the case in urban areas where pollution is old and associated with activities considered to be less polluting. Thus, the spreading of Parisian mud on the fields of farmers located in the immediate suburbs of Paris in the 19th century was not initially considered as a polluting activity [67]. In addition, the renewal of the population in a good number of urban regions leads to a lack of knowledge of the history of soils and associated pollution.
\nIn most cases, the esthetic and landscaping criteria has an essential role in the reception that can be given to this type of project [68]. The revegetation of soils in neighborhoods that the image is devalued by an industrial or mining past and the presence of brownfields, constitutes a benefit clearly identifiable by the population who have been living there for a long time or more recently. Revegetation is often equated with an embellishment and an improvement of the living environment from an ecological point of view.
\nThe different phytoremediation methods used, can, however, raise questions about the choice of species (sometimes non-native and poorly accepted by local residents), the fate of pollutants and the time required to obtain results [65]. Phytoextraction raises the question, for example, of the fate of plants that have absorbed a certain amount of pollutants, including trace metals, and their treatment [69].
\nGood reception of the project can be facilitated by working upstream with the inhabitants in order to make them aware of the characteristics of the different phytoremediation methods and their effects. Consultation on the landscapes desired by local residents would make it possible to consider the choice of species that can be used appreciated [61]. This work obviously requires a time of information and consultation that is added to the time necessary to obtain the first effects of the different phytoremediation methods.
\nIt is also difficult to envisage social acceptability without considering the potential economic benefits. In terms of costs, phytoremediation is a much less expensive technique than conventional techniques, however it still seems to be little applied [70]. In this regard, it should be emphasized that local communities such as companies specializing in soil remediation are often ill-informed and poorly trained or little trained in this type of alternative techniques and prefer to apply better known and better controlled methods such as excavation and backfilling of polluted areas. It seems that phytoremediation is struggling to get out of the purely scientific and experimental sphere. The time required to obtain significant results is a constraint both for development companies, local authorities and for the population. In the process of acceptability of phytotechnologies, an articulation between these different temporalities constitutes an issue to be taken up.
\nIn addition, the techniques of economic valuation of the biomass resulting from phytoremediation by the production of energy are still often experimental and little diffused and/or applied. Its transformation into energy, whether by thermodynamic processes (combustion, pyrolyse, roasting) or by biological processes (methanization), poses the problem of becoming pollutants and in particular of the trace metals contained in the biomass, in particular in the case phyto-extraction (ash after combustion, digestate after production of biogas). The acceptability of soil remediation projects through phytoremediation depends on the benefits known to society (population and decision-makers) and the value attributed to them.
\nThe social benefits attributed to phytoremediation can therefore be considered through the prism of ecosystem services. This concept, first imagined by ecologists, has been mobilized and widely publicized since the Millennium Ecosystem Assessment (2015); the objective sought was to promote the protection of ecosystems by assigning economic and social value to the services provided by them [71]. Ecosystem services can therefore be defined as the benefits provided by ecosystems to human societies. A general distinction is made between production (or supply) services, regulation services and cultural services. Despite the reservations which are made by ecologists and sociologists among others with regard to this concept and the reflections as to a “commodification of nature”, this can be useful here to consider the potential economic and social benefits of phytoremediation operations [71, 72]. These are a few lines of inquiry and not an exhaustive analysis. The purpose of phytoremediation is to reconstitute an ecosystem allowing depollution of the soil or stabilization of pollutants in the soil.
\nThe most directly perceptible benefit for the population is undoubtedly landscaped and esthetic. The revegetation of polluted sites, often fallow land can on the one hand radically modify the urban landscape and the image of districts or cities sometimes stigmatized by their industrial or mining past, and thus procure an embellishment to which the local populations are sensitive [61]. On the other hand, this revegetation can in certain conditions and ultimately provide spaces for relaxation and leisure. In this sense, these are the benefits associated with cultural services that can be highlighted.
\nThe benefit most directly sought by this type of project is obviously soil remediation. It can be clearly identified by the population, particularly in regions where health risks are known. Beyond the management of this pollution, it is also the structure and fertility of the soils that will be improved if not restored: the greater permeability of these soils is an asset to limit runoff and potential flooding in certain cases and a restoration of the water cycle more generally, including filtering and purification functions provided by vegetation [13].
\nWe should add that in the context of sustainable city projects, revegetation via phytoremediation can contribute to the objectives of reducing greenhouse gases and improving air quality, plants storing carbon in their tissues via photosynthesis. The plants introduced into phytoremediation operations, whether local or not, participate in the maintenance or dissemination of a certain diversity of flora and therefore fauna and can be integrated into larger projects for the maintenance or development of urban biodiversity. The areas benefiting from these projects can thus be associated with the construction of ecological corridors within the framework of the green and blue frames promoted in recent years at different territorial scales. Phytoremediation can therefore help to provide regulatory services for the restoration of these ecosystems in urban areas.
\nThe valorization of the biomass produced within the framework of these revegetation operations, can in certain cases and in the long term, be envisaged of different forms. Burning and pyrolizing wood products produces gas. Oil from pyrolysis can also be used in the composition of certain fuels, while ash and biochar (vegetable charcoal) can be reincorporated into the soil as fertilizers. The roasting of this woody biomass provides fuel. Non-woody plant waste subjected to anaerobic digestion allows for the production not only of gas but also of digestates; these can also be reintroduced into the soil [13]. These are therefore production or supply services which can be highlighted and fairly easily economically quantifiable.
\nThe assessment of these social and environmental amenities provided by phytoremediation projects are, however, for the most part complex to assess and account for economically, in particular regulation and cultural services. The monetary calculation of the direct or indirect services rendered could however minimize the real costs of soil rehabilitation projects and facilitate their wider implementation.
\nPhytoremediation is a plant-based technology that make us think about the potential eco-garden whom urban residents can profit the green and beautiful landscapes and easily accept it. Ecological gardens can be viewed in two ways depending on the target audience. For city managers, these gardens are installed in a sustainable way to cover polluted soils and thus limit the risks to the population. The plants that will be used are, in general, ornamental plants that will require little maintenance and will be durable over time. A list of ornamental plant species provided (see more in [31]) belonging to different plant groups: trees, shrub, and herbaceous which have a good potential phytoremediation for heavy metal are already used for remediate the polluted soils. For this purpose, the exploitation of ornamental plants could be an additional option. At the top, we raise the points that we need to take care when application of phytoremediation. We propose also that phytoremediation could be successfully exploited in urban territories; in these contexts, many herbaceous and others are suitable for planting because of their ornamental features and adaptability to inhabited areas.
\nFor the surrounding population, these ecological gardens have several roles, first of all a food production role, an educational role by promoting social cohesion. Thus, one of the big challenges is to cultivate while respecting food security and human health. Research needs to be further continued to overcome these challenges of establishing food production in combination with phytoremediation in urban areas by carrying out studies on eco-toxicological risk assessment.
\nPhytoremediation consist of different process and mechanisms such as absorption and accumulation of pollutant in plant as well as degradation. In the case of the contaminants are absorbed and accumulated in plant, risks in allotments are higher because of transfer of pollutants to the food chain [73]. Phytoremediation with degradation process maybe more suitable. In all cases, it is recommended to take precautions when you want to install eco-gardens on the polluted soils with hyper accumulator plants. High precautions has to be paid to parks, playgrounds, kindergartens and urban zones where residents come into close contact with soils. There are various species of ornamental plants in the literature, the choice of plant species depends on the climate, the tastes and traditions of each country.
\nFrom what we can see, phytoremediation is indeed an ecological and economical technology, acceptable and efficient to remediate the polluted soils. However, this technology is not actually widely applied in the urban context but it has many advantages regardless of the technique chosen or the pollutants present. Thus, the redevelopment of urban land in cities has become a priority. Since the implementation in 2006 of the draft European Directive on soil protection, which gives priority to soil diagnosis and remediation, the general objective of the European strategy has been to protect soil and guarantee its sustainable use by preventing its degradation, preserving its functions and restoring degraded soils. Despite these many improvements, legislation on these soils is either non-existent or very vague. Moreover, we have very little experience with trials of remediation of urban soils by the technique of phytoremediation. Nevertheless, the first results are promising with a stabilization of pollution, a decrease in erosion, a decrease in heat islands, and an increase in biodiversity with the implementation of ecological corridors in urban soil management. Research needs to be further continued to overcome these gaps on urban soils.
\nIntechOpen - where academia and industry create content with global impact
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\\n\\nBut, one thing we have in common is -- we are all scientists at heart!
\\n\\nSara Uhac, COO
\\n\\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\\n\\nAdrian Assad De Marco
\\n\\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\\n\\nDr Alex Lazinica
\\n\\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
\\n"}]'},components:[{type:"htmlEditorComponent",content:"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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