\r\n\tAlthough the microorganism was later described by several other researchers with multiple synonyms, Escherich was recognized as the first, establishing the definitive name of the microbe as Escherichia coli in 1954.
\r\n\tIn 1933, Alfred Adam showed that certain serotypes of "dyspepsia Koli" (as he called the diarrheagenic E. coli strains) were implicated in epidemics of pediatric diarrhoea. In 1944, Kauffman proposed a classification scheme that is still in use today for the purpose of differentiating commensal types from pathogens and subclassifying them.
\r\n\tEscherichia coli, in its natural habitat, lives in the intestines of most healthy mammals. It is the main facultative anaerobic organism of the digestive system. In healthy individuals, that is, if the bacterium does not acquire genetic elements that encode virulent factors, the bacterium acts as a commensal forming part of the intestinal microbiota and thus helping the absorption of nutrients.
\r\n\tIn humans, E. coli colonizes the gastrointestinal tract of a neonate by adhering to the mucus of the large intestine within a few hours of birth. Since then, it remains in a relationship of mutual benefit. However, these commensal strains can cause infections in immunosuppressed patients.
\r\n\r\n\tPathogenic strains of E. coli, on the other hand, as soon as they colonize a healthy host, can cause infections of varying severity in the intestine, urinary tract, meningitis, and sepsis, among other infections.
\r\n\tDiarrhea caused by pathogenic strains of E. coli is an important cause of death in children under 5 years of age, especially in sub-Saharan Africa and South Asia, where it is one of the four most important causes of moderate and severe diarrhea, potentially lethal An increase in mortality is associated with enteropathogenic strains.
\r\n\tUrinary tract infections are more common in women because of the short length of the urethra (25 to 50 mm) compared to men (about 15 cm). Among the elderly, urinary infections tend to be of the same proportion between men and women.
\r\n\tBecause the bacteria invariably enter the urinary tract through the urethra (an ascending infection), poor hygiene habits can predispose to infection; however, other factors become important, such as pregnancy, benign or malignant hypertrophy of the prostate, and in In many cases, the initiating event of the infection is unknown. Although ascending infections are the cause of lower urinary tract infections and cystitis, this is not necessarily the cause of upper infections such as pyelonephritis, which may have a hematogenous origin.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that is increasingly prevalent in young adults. Patients with MS have multiple causes of poor sleep, and potential triggers may be related to MS-related symptoms, co-morbidities and adverse effects from drug therapy.
\nMajor sleep disorders have been reported to be associated with numerous co-morbid conditions, including heart disease, obesity, stroke and diabetes [1].
\nThe poor sleepers among patients with MS are more likely to report fatigue (one of the most frequent symptoms in MS) and pain (a co-morbid condition to MS-related fatigue but is confounded by depression and medication for treating pain or pain-induced sleep disorder) [1].
\nAll the symptoms are intermixed, and it is not possible to discern the precipitating factor and the perpetuating factor. In this respect, sleepiness and fatigue may converge in some situations [1].
\nInsomnia is present in mood disorders (depression and anxiety), restless leg syndrome (RLS), pain, nocturia and others [1]. RLS is also an important cause of pain in patients with MS. Sleep disorders may occur independently of demographic factors such as gender and clinical-demographic factors. High psychological burden has been said to be independently associated with poor sleep patients with increased risk of co-morbid conditions such as heart disease, obesity and diabetes, which may have a profound impact on long-term health. The reverse situation is also possible.
\nThe frequency of sleep disturbances in MS and their impact on the patients’ quality of life are unknown. The prevalence of sleep problems in the MS population ranges from 47 to 62%, with a higher prevalence in women [2, 3, 4, 5]. Sex hormones and genetic mechanisms, psychosocial factors, certain physical factors that disrupt sleep, such as pain or bladder dysfunction may contribute to sleep differences between women and men [5].
\nObstructive sleep apnea (OSA), RLS and chronic insomnia in particular are frequent problems in the MS population, and play a key role in the development of debilitating fatigue and other poor functional outcomes in MS. Yet, despite their impact, sleep disorders in MS remain critically under-recognized in most clinical settings. A recommended approach to the fatigued patient with MS is also highlighted [6].
\nSleep disorders during the course of MS may be secondary to numerous symptoms arising from the disease itself or can be primary with a common biological link. In either of the two cases, a bidirectional relationship exists between these co-morbid conditions [7].
\nSleep disturbances have been associated with increased risk of mortality, cardiac disease, obesity and diabetes [8] and can contribute to the depression, pain and fatigue symptoms that are commonly seen in MS patients, which are often disabling [3, 9].
\nSleep disorders are under-recognized in persons with MS. These sleep disorders can contribute significantly to fatigue, other daytime dysfunction and poor quality of life. A systematic, practical approach that takes into account clinical features of MS is recommended to enhance recognition of these conditions and facilitate appropriate treatment. Clinicians caring for patients with MS should routinely screen for sleep disturbances and initiate diagnostic workups, if clinically indicated.
\nSleep specialty referrals should be considered for management of conditions that require polysomnography (PSG) diagnosis, for complex patients who present a diagnostic challenge and for patients who do not respond to first-line treatments. Clinicians should also routinely ask about sleep when forming a comprehensive care plan for patients with MS.
\nSleeplessness or insomnia is an inability to fall asleep or to stay asleep as long as desired. Insomnia is described as a complaint of prolonged sleep-onset latency, disturbance of sleep maintenance or the experience of non-refreshing sleep [10]. Episodic insomnia can usually be traced to an acute psychological stressor or an environmental change. Chronic insomnia may be related to a combination of factors including depression, poor sleep hygiene, learned sleeplessness, sleep-disordered breathing, nocturia, drugs or extrinsic factors such as noise [6, 11].
\nPatients with MS face a high risk of insomnia of around 40% [6] compared to roughly 10–15% in the general population [12]. Awakening too early in the morning is the most common symptom (58%) [13].
\nPrimary symptoms of MS that can condition the onset of insomnia are neurogenic bladder (nocturia), spasticity, sexual dysfunction, neuropathic pain, paroxysmal phenomena, depression and anxiety [7].
\nInsomnia affects daytime activities, because of fatigue, mood disturbances (depression and anxiety), attention, concentration and memory impairment [7]. Higher fatigue scores have also been found to correlate with insomnia, especially middle insomnia [13].
\nPatients with insomnia may complain of difficulty falling asleep, difficulty staying asleep or waking up sooner than desired [10]. There are screening tools to identify such patients.
\nThe Pittsburgh Sleep Quality Index (PSQI) measures seven domains: subjective sleep quality, latency, duration, habitual efficiency, disturbances, use of sleep medication and daytime dysfunction over the last month. Each of these seven domains is self-rated by the individuals. The score of each question is based on a scale from 0 to 3, in which a score of 3 demonstrates the negative extreme on the Likert Scale. A global sum of 5 or greater indicates a poor sleeper (sensitivity of almost 100% for insomnia) [14, 15].
\nInsomnia Severity Index (ISI): a seven item questionnaire designed to assess the nature, severity, and impact of insomnia in adults. Scores >15 reflect moderate clinical insomnia. It is also a useful tool to monitor the effects of insomnia interventions [6].
\nAthens Insomnia Scale (AIS): a psychometric instrument designed for quantifying sleep difficulty. It consists of eight items: the first five pertain to sleep induction, awakenings during the night, final awakening, total sleep duration and sleep quality; while the last three refer to well-being, functioning capacity and sleepiness during the day. Either the entire eight-item scale (AIS-8) or the brief five-item version (AIS-5), which contains only the first five items, can be used. The score of each question is based on a scale from 0 to 3, where a score of 3 indicates the negative or normal extreme on the Likert Scale. A cut-off score of ≥6 on the AIS is used to establish the diagnosis of insomnia [16].
\nAfter detecting insomnia, amelioration of any precipitating causes of insomnia is a cardinal step in its management. Medications or substances that may contribute to insomnia should be reduced or discontinued, if possible, there should be a check on which drugs the patient is taking (medications used to alleviate MS-related symptoms, including over-the-counter medications).
\nSelective serotonin reuptake inhibitors, while helpful for depressive symptoms, may worsen insomnia.
\nStimulants and wake-promoting agents, which are commonly used for fatigue, may interfere with sleep initiation if taken during the late afternoon or early evening hours.
\nAntihistamines, which are used as sleep aids by up to 25% of patients with MS, have the potential to worsen RLS, and thereby worsen sleep-onset insomnia [6].
\nCo-morbid symptoms must be identified and treated: neuropathic pain (tricyclic antidepressants and the α-2-δ ligand pregabalin), spasticity (baclofen or tizanidine) and urinary urgency (anticholinergics) [6].
\nCognitive behavioral therapy (CBT) is an innovative psychotherapy approach. CBT treatment could reduce anxiety and depression by changing thoughts and beliefs and consequently reduce the symptoms of insomnia [6, 17].
\nPharmacological therapies can be considered if more conservative strategies have been exhausted or are not fully effective: benzodiazepines, benzodiazepine agonists, melatonin receptor agonists and orexin receptor antagonists.
\nExcessive daytime sleepiness (EDS)/excessive daytime drowsiness disrupt daily performance.
\nHypersomnia may be due to acute thalamus injuries, mental disorders, especially depressive symptoms, sleep deprivation or as a consequence of received treatments.
\nThe Epworth Sleepiness Scale (ESS) is a screening tool that assesses sleepiness and has eight items. ESS values equal to or greater than 10 indicate excessive daytime sleepiness (EDS), and in this case, patients should undergo polygraphy or PSG (screening for sleep apnea) [18].
\nAll fatigued patients should be asked about sleepiness and fill in the Epworth Sleepiness Scale (ESS) as these are not always associated with sleepiness.
\nMagnetic resonance imaging (MRI) should be performed because of the need to identify structural lesions in the brain.
\nAfter detecting hypersomnia, the physician should check for any medications involved and withdraw them if possible, treat acute lesions of multiple sclerosis with corticosteroids, indicate adequate sleep hygiene and assess whether specific treatment is needed to improve daily performance.
\nThe four main criteria for diagnosis of RLS are: (1) unpleasant sensations in the legs; (2) worsening of the symptoms during rest; (3) relief of the symptoms by movement and (4) exacerbation of the symptoms in the evening or at night [19].
\nThe periodic limb movement disorder (PLMD) includes repetitive periodic shaking episodes lasting between 0.5 and 5 seconds that occur during sleep every 20–40 seconds; mainly in the legs, but sometimes in the arms.
\nRLS and PLMD are motor disorders of sleep considered separate clinical entities, both conditions have the potential to cause disrupted sleep, share similar pathogenesis and have an increased prevalence among persons with MS. PLMD also frequently occur in the absence of RLS.
\nMost RLS patients (80–90%) have periodic leg movements PLM during sleep. They can cause arousals or micro-arousals leading to non-refreshing sleep, daytime sleepiness and fatigue. The prevalence of RLS in the general population ranges from 1 to 12% [20]. The prevalence of RLS in MS patients is two to five times higher than in the general population [21, 22, 23, 24].
\nDifferentiating RLS from other sensory and motor symptoms of MS can be difficult, as MS patients frequently suffer from spasms, dysesthesia, paraesthesia and spasticity in the legs, which worsen with immobility [25].
\nPredictive factors for RLS in MS patients include: older age, longer disease duration, progressive primary forms, greater disability as measured by the Expanded Disability Status Scale (EDSS), especially in the pyramidal and sensory subscales and shaking of the legs before onset of sleep [26]. Furthermore, RLS symptoms are more severe when associated with MS than when not associated with MS.
\nMS patients with RLS have more cervical cord lesions than those patients without RLS. These lesions possibly disrupt the ascending and descending pathways with cerebrospinal disconnection leading to these symptoms [10].
\nPrimary RLS is a genetic form of RLS with autosomal dominant transmission [27]. Four genes have been associated with this syndrome [28] but no crossing over of those involved in MS [10].
\nPathogenesis of RLS and PRLS shows dysfunction of downstream dopaminergic pathways, namely diencephalospinal and reticulospinal pathways, that project to the spinal cord. These pathways,
Certain medications used in the management of persons with MS, such as antiemetic drugs, antipsychotic dopamine antagonists, antidepressants and antihistamines can also cause or worsen RLS [6, 10].
\nMany descriptors can be used by patients to describe the restless sensation, including creeping, crawling, itching, burning, tightening, tingling or pain.
\nSymptoms of leg tightness relieved by voluntary movement suggest RLS, whereas involuntary spasms, even if a circadian component is endorsed, suggest spasticity. Rhythmic involuntary movements triggered by stretching or certain leg positions suggest clonus.
\nThe Restless Legs Syndrome Diagnostic Index (RLS-DI) is a 10-item questionnaire. Scores range from −22 (no RLS) to +20 (definite RLS). A score of +11 yields 93.0% sensitivity and 96.1% specificity to accurately diagnose RLS [6].
\nDiagnosis of PLMD requires overnight PSG to assess for the presence of leg movements [6, 10].
\nThe RLS Rating Scale is a useful tool to track treatment response and is a 10-item self-administered scale. Scores of 11–20 reflect moderate RLS.
\nIron supplementation should be implemented for a ferritin level of less than 50 ng/ml.
\nReduction or discontinuation of medications and substances that can cause or worsen RLS or PLMD (dopamine antagonists, lithium, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antihistamines, tricyclic antidepressants, alcohol, tobacco and caffeine) is recommended.
\nDopamine agonists (pramipexole, ropinirole and rotigotine), and the α-2-δ ligand gabapentin and anticonvulsants are first-line treatments.
\nBenzodiazepines and opioid agents (oxycodone and methadone) are second line treatments.
\nTreatment for refractory RLS, or augmentation in response to dopaminergic therapy, is also likely to be optimized by sleep specialty care [6].
\nSleep-disordered breathing is characterized by episodes of nocturnal hypopnea and apnea resulting in a reduction or a cessation of airflow in the upper airway.
\nPatients with sleep-disordered breathing may complain of “fatigue,” decreased concentration, mood changes, erectile dysfunction, nocturia and mood changes, all these complaints are similar to those experienced in MS [29].
\nApneas and hypopneas may be caused by a collapse of the tissues and muscles in the pharynx (obstructive apnea/hypopnea) or a failure in the medullary respiratory signal (central apnea/hypopnea) [10].
\nMaintenance of upper airway patency during sleep requires an increase in pharyngeal tone that is primarily mediated by efferent motor output from cranial nerves X and XII to the palatal and genioglossus muscles, respectively. This process is largely influenced by afferent sensory input from pressure receptors in the upper airway, peripheral chemoreceptors in the aortic and carotid bodies, and brainstem respiratory generators. Pathophysiological processes that disrupt these tightly regulated brainstem pathways have the potential to impair nocturnal respiration. The medullary reticular formation is responsible for controlling automatic breathing during sleep [10].
\nCausative factors include obesity, craniofacial abnormalities, enlarged tonsils, congestive heart disease and degenerative central nervous system (CNS) disorders, to name a few [10].
\nSuch apnea and hypopnea episodes may lead to nocturnal hypoxemia, frequent awakenings and daytime somnolence. When the apneas are associated with respiratory effort, the term obstructive apnea is used, and central apnea is used when there is a lack of respiratory effort [10].
\nCentral sleep apnea is diagnosed when more of 50% of the events are central in patients with both central and obstructive apneas.
\nObstructive sleep apnea is characterized by repeated episodes of upper airway obstruction and hypoxia during sleep [6].
\nThe incidence of OSA in patients with MS is 2–21% and is one of the most common respiratory disorders [10].
\nPatients with MS who have a diagnosis of OSA and those at an elevated risk of OSA have increased fatigue and diminished quality life compared with undiagnosed or low-risk patients [6].
\nSleepiness is primarily a result of acutely or chronically reduced sleep time, or poor sleep quality. Apnea severity may correlate with impaired cognition in MS [6].
\nQuestions must be asked about symptoms of snoring, pauses in breathing witnessed by a bed partner, gasping or choking upon awakening, non-restorative sleep, excessive daytime hypersomnolence or fatigue, cognitive disturbances and nighttime awakenings, any of which may arise in part from underlying OSA [6].
\nDysarthria or dysphagia, obesity, increased neck circumference, crowded oropharyngeal inlet, retrognathia, or micrognathia are common physical exam findings [6].
\nThe STOP-Bang questionnaire is a screening tool consisting of eight questions and measures that form the acronym snoring, tired, observed apnea, Blood Pressure-Body Mass Index, age, neck circumference and gender. Scores of 3 or higher indicate an elevated risk of OSA [6].
\nA full-night PSG is necessary to demonstrate the presence of obstructive respiratory events during sleep to confirm the diagnosis of OSA. These events may be partial (hypopneas) or complete (apneas), but must demonstrate evidence of a reduction in airflow during sleep, despite continued effort to breathe [6].
\nManagement strategies for sleep-disordered breathing should take into account the patient’s primary apnea subtype, apnea severity, co-morbidities and behaviors, and other MS-specific symptoms or limitations. Guidance by a sleep medicine physician is often helpful [6]. Discontinuation of medication, such as opiates, antispasmodics or CNS depressants medications [6].
\nPositive airway pressure (PAP) therapy is delivered by a mechanical device and mask to splint the upper airway open during sleep. Supplemental oxygen, bi-level PAP and adaptive servo ventilation are other improvements that these devices have [6].
\nOral appliances work by repositioning the mandible in the anterior and inferior position [6]. By improving nocturnal oxygen saturation and sleep quality, PAP therapy effectively reduces fatigue and can be effective in the treatment of depression. This is especially important given the link between fatigue and depression in MS [6, 18].
\nDisease-modifying therapy use, in particular emerged as a strong predictor of
Central sleep apnea (CSA) is rare, and the prevalence is unclear in the general population. CSA involves repeated complete or partial reduction of airflow, caused by an intermittent lack of respiratory effort by failure in the medullary respiratory signal [10].
\nWhile the prevalence of CSA is less than that of OSA, patients with CNS disorders that affect pontine and medullary respiratory generators, including MS, may be at increased risk for this condition as well even nocturnal death (Ondine’s curse) [6, 10].
\nCNS and brain stem-related nocturnal respiratory abnormalities such as central sleep apnea, paroxysmal hyperventilation, hypoventilation, respiratory muscle weakness and respiratory arrest have all been described and should be considered in this patient population in the evaluation of symptoms of daytime somnolence, increased fatigue and non-refreshing sleep [11].
\nIn patients with symptoms of daytime somnolence, increased fatigue and non-refreshing sleep, the physician must ask about nocturnal respiratory abnormalities [11] and look for evidence of reduction in airflow in the absence of respiratory effort in an overnight PSG.
\nIn patients with both central and obstructive apneas, central sleep apnea is diagnosed when more than 50% of the events are central. The coexistence of OSA or CSA and MS has been described by several authors [2, 10, 30].
\nIn the cases of central sleep apnea not symptomatic or central sleep apnea during sleep-wake transition (20% of central sleep apnea cases resolve spontaneously) observation is recommended.
\nIn other cases, PAP treatment, adaptive servo ventilation, oxygen, added dead space, carbon dioxide inhalation and overdrive atrial pacing are needed.
\nSleep disturbance is associated with outcomes such as increased risk of falls and mortality. Nocturia may both precipitate poor sleep and perpetuate insomnia (awakenings associated with nocturia may themselves be perpetuating factors) [31].
\nOveractive bladder (OAB) syndrome is a condition that accompanies urgency (a significant factor for sleep disruption), with or without incontinence, frequently with increased daytime frequency and nocturia [32]).
\nNocturia is defined by the International Continence Society as the complaint that an individual has to wake at night one or more times to void. It reflects the relationship between the amount of urine produced while asleep, and the storage by the bladder of urine received. Nocturia is a symptom rather than a disease and causative categories have been proposed and is the most common storage symptom in the general population [32].
\nNocturia can occur as part of lower urinary tract dysfunction (LUTD), notably in overactive bladder syndrome (OAB). Nocturia can also occur in association with other forms of LUTD, such as bladder outlet obstruction or chronic pelvic pain syndrome [33].
\nNocturia is due to nocturnal polyuria, a decreased nocturnal bladder capacity or a mixture of the two. Various duplicating factors for nocturia have been reported, including pathological conditions such as diabetes, LUTD, cardiovascular disease, primary sleep disorders and sleep apnea [32].
\nNocturia is a feature of systemic conditions affecting water and salt balance, leading to excessive production of urine at all times (global polyuria) or primarily at night (nocturnal polyuria), so that nocturia can be a systemic symptom such as cardiovascular, endocrine and renal disease can affect water and salt homeostasis, leading to an increased rate of urine production [33].
\nNocturia can significantly influence quality of life, efficiency, vigor and awareness of health, primarily due to sleep disruption.
\nAsking how many times the patient wakes up at night because of nocturia, whether urinary urgency exists and the characteristics of urination, quantity of fluid intakes, physical exercise, medication being taken, etc. is also necessary
The use of specific questionnaires such as the PSQ, ISI and ASI for the diagnosis of insomnia or the ESS for the diurnal hypersomnia helps the physician to approach the functional repercussion of the problem.
\nThe study occasionally needs to be completed with ultrasound studies, urodynamics, MRI and urinary sediment to identify LUTD or OAB problems.
\nInterventions targeting nocturia may potentially improve sleep quality [31].
\nHygienic measures such as reduced fluid intake at the end of the evening and frequently going to the bathroom during the day can help. Adequate treatment of co-morbid conditions such as diabetes mellitus, congestive heart failure or sleep apnea requires direct intervention for improvement nocturia.
\nAnticholinergics, mirabegron, a-blockers, 5-a reductase inhibitors, oral phosphodiester-ase-5 inhibitors, desmopressin, diuretics, sleep-promoting agents and phytotherapy are used to treat urinary problems [33]. Half of MS patients with moderate to severe overactive bladder symptoms are treated with an anticholinergic medication [18].
\nAntimuscarinic drugs (Solifenacin), the most appropriate treatment for OAB, inhibited bladder stimulation may originate a decrease of drive to the brain stem, improve urination urgency and frequency and effectively reduce involuntary contractions and increase bladder capacity in patients with storage symptoms. The night time dosing of antimuscarinic drugs may improve tolerance compared to daytime dosing [32].
\nAntidiuretic therapy using clinician-directed dose titration has been reported to be more effective than placebo in terms of reduced nocturnal voiding frequency and duration of undisturbed sleep [33].
\nNocturia severity improvement contributes to overall improvements in health-related quality of life [33].
\nThe impact of treatment for nocturia in MS fatigue is unknown [18]. Non-pharmacological therapies such as cognitive behavioral therapy for nocturia (CBT-N) act on the abovementioned perpetuating factors. Sleep restriction entails reducing the excessive time in bed (a common occurrence in insomnia) and thereby improves sleep efficiency.
\nSleep disturbances have been associated with increased risk of mortality, cardiac disease, obesity and diabetes [8] and can contribute to the depression, pain and fatigue symptoms that are commonly seen in MS patients, which are often disabling [3, 9, 10].
\nFatigue is defined as a subjective lack of physical or mental energy perceived by the patients or their caregivers which interferes with desired activities of daily living and it is the most frequent symptom in MS [18].
\nBetween 80 and 97% [6] of patients report chronic fatigue, and more than 33% of patients rate this symptom as the most disabling [34, 35, 36].
\nFatigue may occur at any stage of the disease and can even precede MS onset by several years. Fatigue affects the social and professional capabilities of patients, is a major reason for early retirement, reduced employment and is considered to be one of the main causes of impaired quality of life among MS patients, regardless of depression or disability [18].
\nFatigue starts early in the morning and increases during the day. The perception of fatigue is exacerbated with environmental temperature and humidity [25], with age, [36] greater EDSS, mental or physical activity, infections and food ingestion [37].
\nFatigue also deteriorates cognitive domains, such as information processing, memory and attention, [35] and it has significant socioeconomic consequences, including loss of work hours and in some instances, loss of employment, as well as family relationships and leisure time [36].
\nFatigue is a symptom in MS patients and may have multi-factorial causes such as immunologic abnormalities (pro-inflammatory cytokines such as INF-α), endocrine influences (cortisol and dehydroepiandrosterone (DHEA)), axonal loss, altered patterns of cerebral activation, sleep disorders (RLS, chronic insomnia, sleep-disordered breathing and altered sleep microstructure), depression and medications used to treat MS symptoms or immunomodulatory and immunosuppressive treatments [7, 38, 39].
\n“Primary” fatigue is related to the pathological changes of the disease itself, and results from a spectrum where one pole is the inability to generate the force required to perform the task due to a failure of force production at the muscle level “
“Central fatigue” can be the result of both cognitive and physical exertion and can reflect either a subjective sensation (fatigue) or an objective change in performance (fatigability) [37]. Dopamine imbalance plays a major role in developing fatigue. Central fatigue is a failure of the non-motor functions of the basal ganglia.
\nThe subjective feeling of fatigue is related to inflammation and increased levels of cytokines such as interleukin-1 (IL-1), IL-6 and TNF-alpha [40].
\n“Secondary” fatigue attributed to mimicking symptoms, co-morbid sleep, irritable bowel syndrome, migraine, mood disorders, depression and anxiety and medication side effects [36, 37]. Persons with secondary fatigue report greater levels of fatigue than those with isolated primary fatigue [36].
\nThere is a great variability in MS lesions from extensive areas of destruction during MS attacks, healing processes of and neuroplasticity. The clinical manifestations of fatigue do not seem to exclusively depend on the structural damage, but rather on the balance between restorative and inflammatory/degenerative processes and the rupture of the neural network [37].
\nIn this respect, there is evidence that supports these hypotheses, linking fatigue with structural or functional abnormalities (atrophy in the thalamus, corpus callosum, cortical gray matter regions: superior frontal and inferior parietal gyrus, parietal lobe) within various brain networks (the cortico-subcortical circuit as a substrate for MS fatigue and the involvement of a “fronto-striatal network”), greater activation of the premotor area ipsilateral to the movement with functional MRI (fMRI), decreased N-acetylaspartate-creatine ratio (NAA/Cr) as a marker of axonal dysfunction. Resting-state fMRI studies show changes in functional connectivity (FC) of the basal ganglia including reward processing and motivation. In addition to motor functions, the abovementioned aspects are involved in the pathophysiology of fatigue [18].
\nPatients with MS report being fatigued very often, sometimes it is just the feeling of lack of energy but in others it interferes with their work or their daily life. There are tools that help quantify the degree of fatigue which are described below.
\nSeverity Scale (FSS): is a self-administered questionnaire with nine items (questions) investigating the severity of fatigue in different situations during the previous week. Grading of each item ranges from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement and the final score represents the mean value of the 9 items. A total score of less than 36 suggests that you may not be suffering from fatigue [24].
\nModified Fatigue Impact Scale (MFIS): The full-length MFIS consists of 21 items (total score 0–84, 38 as a cutoff to discriminate fatigued from non-fatigued individuals) while the abbreviated version has 5 items (0–20.). The abbreviated version can be used if time is limited but the full-length version has the advantage of generating physical, cognitive and psychosocial functioning subscales. The MFIS is one of the components of the MS quality life inventory [37].
\nMS patients, regardless of their fatigue level, have a significantly high frequency of RLS, higher Epworth sleepiness scale (ESS) scores, and higher PSQI scores. The time in bed, wake time after sleep onset %, total arousal index, limb movement arousal index and periodic limb movement arousal index are abnormal. The sleep efficiency index and sleep continuity index are lower in fatigued MS patients than non-fatigued MS patients. The PSQI results also suggest more disrupted sleep in fatigued MS patients. For all of the reasons above, quality of sleep studies should be performed with fatigued MS patients.
\nOnce the patient has been identified with fatigue, it is necessary to investigate whether other co-morbidities are present (depression, anxiety, sleep disturbance, diabetes, heart disease, obesity, anemia, thyroid disease and nocturnal urinary disorders), what factors influence perpetuating fatigue and what situations can be modified in their lifestyle [6].
\nInterventions targeting fatigue may potentially improve sleep quality and quality of life [31].
\nPharmacological interventions are also reviewed and if there is evidence that a drug is involved in fatigue, it should be suppressed or the dose decreased [18]. Disease-modifying treatments (DMTs) are generally used to reduce relapses and progression and they occasionally cause an increase in fatigue, and in these circumstances it is important to change the medication for another DMTs [40].
\nHygienic measures such as energy conservation programs, specific rehabilitation interventions physical (endurance, resistance, aerobic and combined training), aquatic therapy, cooling therapies, Tai chi, stretching, mindfulness-based interventions, yoga, acupuncture, progressive muscle relaxation and sleep hygiene advice (dependent on the nature of the sleep disorder) are more effective than pharmacological interventions [41].
\nAdequate treatment of co-morbid conditions such as diabetes mellitus, congestive heart failure, obesity, sleep apnea and other sleep disorders, depression and anxiety with pharmacological, psychological, behavioral and educational interventions is recommended [40, 41]. Pharmacological interventions for fatigue that are effective for reducing fatigue in patients with MS include amantadine, pemoline, prokarin (1 pilot study, side effects not reported), modafinil and pemoline combined with aspirin are efficacious for reducing fatigue in patients with multiple sclerosis. Carnitine has a discreet effectiveness. In general, the risk benefit of the drugs used for fatigue makes their recommendation be evaluated in each patient, highlighting them to the amantadine [37, 41]. Aminopyridines and coenzyme Q10 have an effect on fatigue by improving nerve conduction.
\nNowadays, non-invasive brain stimulation (NIBS) techniques are gaining interest in the treatment of MS fatigue [37].
\nPromotion of health behaviors such as quitting smoking, physical activity (a high level of physical activity was borderline significantly associated with a decrease in co-morbidity) [42] and healthy eating may prevent some co-morbidities which were slow to show improvement in fatigue after the intervention, but they are effective [36].
\nCognitive impairment is a frequent feature of MS affecting up to 65% of patients [43] at both the earlier and later stages of the disease [44] and it tends to worsen over time [45].
\nMS negatively affects several aspects of cognitive functions, including attention, information processing [46], learning and memory, executive function and visuospatial abilities [47], having an important impact on quality of life [48], employment status [49], daily functioning, independence [50] and participation in social activities [51, 52].
\nSeveral factors have a negative influence on cognition in MS patients, such as depression [53], fatigue and sleep disturbances. Proper sleep is important for memory consolidation [54], and sleep deprivation has been related to impaired functioning in various cognitive domains [55].
\nSleep disturbance causes a decrease in sustained attention [56], interferes with information processing and executive functioning [52]. Sleep disturbed patients reported higher levels of subjective cognitive problems compared to patients with normal sleep [52].
\nOSA and sleep disturbance are significantly associated with diminished visual memory, verbal memory, executive function (as reflected by response inhibition), attention, processing speed and working memory [52].
\nExcessive daytime sleepiness can lead to poor attention, poor memory, mood disturbances and increased risk of accidents [29].
\nIn subjects with insomnia, a functional magnetic resonance imaging (fMRI) showed hypoactivation of the medial and inferior prefrontal areas during a cognitive task, in relation to the control subjects, which returned to normal values after treatment. Insomnia or superficial sleep produces less activation of the hippocampus and less connectivity is observed in the thalamus than in the control subjects. Damage to the hippocampus and thalamus (e.g., lesions and atrophy) in MS is associated with worse cognition. In controls, both regions may be related to sleep and cognition [52].
\nMS patients performed worse on all cognitive tests compared to controls. MS patients had less normalized gray matter (GM) volume, normalized white matter (WM) volume, hippocampal volume and thalamic volume. The hippocampus and thalamus showed increased functional connectivity (FC) in patients compared to controls, but lower FC was observed in patients with sleep disturbances (32%) [52].
\nNeuropsychological manifestations can even be detected in patients during early stages of the disease. The Brief Repeatable Battery-Neuropsychology (BRB-N) [57] test was developed as a short and sensitive test to identify disturbances of cognitive domains in MS patients. The BRB-N has become the most widely used neuropsychological battery for MS, [58] and it is now being applied in clinical trials to monitor cognitive changes.
\nDifferent cognitive impairment criteria have been used: <1.0 SD, <1.5 SD and <2.0 SD in one, two or three subtests of the battery, respectively [59, 60].
\nStrategies to optimize sleep could improve cognitive function in patients with MS.
\nIn the case of insomnia, relaxation techniques such as autogenic training or progressive muscle relaxation can help the patient fall asleep earlier and have a longer sleep. But they do not improve sleep, so it has no sleep recovery effect. Behavioral therapies can improve sleep, but not prolong it. A combination of relaxation techniques and behavior therapy could be the most appropriate therapy for certain sleep disorders.
\nThe general strategies for insomnia treatment include aspects of sleep hygiene such as extensions of night time in bed and frequent naps during the day. Pharmacological treatment is usually administered with stimulants such as amphetamines, methylphenidates, pemoline and modafinil [61].
\nAs regards sleep hygiene, it is often necessary to make some lifestyle changes such as dinner should not be too late, nor too spicy or copious, maintain a regular sleep schedule, do not spend too much time in bed other than bedtime, do not drink caffeinated beverages such as coffee, black tea or cola, or caffeine medications, 4–6 hours before bedtime, do not smoke before going to bed or during the night, try to get enough rest and darken the bedroom, ventilate the bedroom, the temperature should not exceed 18°, do not do any physically demanding sport immediately before sleep because otherwise it will stimulate too much circulation, do not drink alcohol before going to bed or avoid sleeping too much during the day.
\nPatients with fatigue should organize daily routine and workloads. The physician also needs to improve the efficiency of information processing and working memory in these patients with fatigue [40].
\nAnxiety, depression, difficulty in sleeping and fatigue may have an impact on cognitive problems. If a person with MS experiences these symptoms and has problems with memory and cognition, they need to be provided with assessment and treatment (occupational therapist and neuropsychologist).
\nThe concept of mental toughness (MT) has recently been recognized for its psychological importance not just in coping with stress but also for its association with increased physical activity (PA), and for its impact on both stress and objective sleep quality. MT consists of four key factors such as control (of own life and emotions), commitment, challenge and confidence (in own abilities and in other people); thus covering a range of cognitive-emotional processes closely involved in coping with stress, emotions, unexpected events and social setting [62].
\nPatients who suffer from problematic sleep and/or fatigue (with or without anxiety) may be more likely to experience higher depressive symptoms [63].
\nDepression is a mental illness that causes feelings of sadness and loss of hope, changes in sleeping and eating habits, loss of interest in your usual activities and pains that have no physical explanation.
\nA trans-diagnostic approach to symptoms may be more effective than targeting each symptom separately, such as depression treatment or pain treatment alone. Trans-diagnostic models explain how multiple co-morbid symptoms or disorders develop rather than create disorder or symptom specific models [63].
\nA trans-diagnostic treatment is an intervention that targets a range of diagnoses or problems through the use of treatment strategies targeting psychological processes that are common across disorders. It may be useful to consider all five factors such as depression, pain, anxiety, sleep and fatigue in designing a treatment plan. Treatments for the constellation of biopsychosocial concerns affecting many people living with MS.
\nThe beneficial effects on depression of CBT targeting insomnia highlight a need for a comprehensive assessment of multiple concerns such as depression, anxiety, sleep problems or fatigue when treating people with MS who report higher levels of pain [63].
\nThe mechanism by which sleep disorders trigger an acute MS relapse might be multi-factorial. Normal sleeping plays an important role in maintaining the normal function of the immune system. Various studies have shown that sleep disorders are associated with elevated serum levels of pro-inflammatory cytokines and markers of oxidative stress [15].
\nThe circadian regulation of cytokine output produces a daily rhythm in the inflammatory profile, with a pro-inflammatory state occurring at night. Disrupted sleep can interfere with this pattern leading to prolonged periods of inflammation throughout the day, thereby exacerbating symptoms. Furthermore, the circadian rhythmicity of key components of the immune system has been shown to be dysregulated in MS patients [64].
\nThe central circadian pacemaker, located in the hypothalamic suprachiasmatic nuclei, is responsible for regulating the timing and expression of various circadian rhythms [65].
\nSleep dysfunction and disruption in the circadian system alter the synchrony between these transcriptional and translational feedback loops, resulting in increased cellular permeability, which is thought to be an important underlying mechanism for initiating the inflammatory cascades causing a disease flare. In addition, the presence of pro-inflammatory cytokines has been proven to suppress the activity of circadian genes [65].
\nMelatonin is produced by the pineal gland that regulates circadian and seasonal rhythms. Secretion of melatonin is suppressed during daylight and enhanced during the night, promotes sleep by reducing sleep latency, decreasing wake time and increasing overall sleep quality [65].
\nMelatonin promotes anti-inflammatory states: it inhibits nitric oxide production, nuclear factor-κB activation and tumor necrosis factor- α, it reduces COX-2 expression and matrix metalloproteinase activity (modulating apoptosis) [65].
\nCircadian sleep disorders are common in MS patients and could be linked to a disruption in melatonin production, which is important in sleep-wake cycle regulation. Melatonin helps dampen the overactive immune system and low levels are associated with relapse [64].
\nAccording to studies on an animal model, sleep deprivation is associated with an accelerated autoantibody production rate and increases oxidative stress (toxic effect on oligodendrocytes causing oligodendrocyte death and myelin damage). Chronic sleep deprivation breaks down blood-brain barrier (BBB) thereby increasing permeability [15].
\nSleep disorders also result in an elevated serum concentration of interleukin-6 (IL-6), which further activates polyclonal B cells and triggers an autoimmune reaction. The serum concentration of IL-6 is significantly associated with the number of relapses in female patients with relapsing-remitting multiple sclerosis (RRMS) [15]. In the study of Sahraian et al. [15], the group in relapse had worse scores of global PSIQI for the previous month than remission group (87.5% were poor quality sleepers). Age, gender, EDSS and disease duration did not associate with sleep quality in either group.
\nCo-morbidities have been shown to affect MS progression, time to initiation of the disease-modifying therapy (DMT), as well as treatment compliance, which may be related to the increased mortality of these patients as compared to the general population.
\nCo-morbidities can negatively impact sleep in MS patients, which can, in turn, lead to a worsening of symptoms, especially fatigue and pain.
\nPatients with sleep disorders are at risk of co-occurrence of other problems like vascular diseases, obesity and diabetes that would threaten the health of patients in the long term [17].
\nCircadian disruptions occur in shift workers and appear to contribute to hypertension, diabetes, breast cancer, lung cancer and elevated prostate-specific antigen. Shift work entails changes in diet, exercise and tobacco use, which can confound circadian rhythm and sleep disturbance studies [65].
\nNarcolepsy is classified as a chronic sleep disorder associated with sleep attacks and other features attributed to abnormalities of rapid eye movement sleep, such as hypnagogic/hypnopompic hallucinations, cataplexy, sleep paralysis and disrupted nocturnal sleep. The usual PSG features include a mean sleep latency of less than or equal to 8 minutes and two or more sleep onset rapid eye movement periods [6]. There is a high variability in the prevalence across different geographic areas, which is thought to be related to differences between the populations and current study methods [10].
\nNarcolepsy is estimated to affect 0.02–0.05% of the general population, the overall prevalence of narcolepsy among persons with MS is unknown [6, 10].
\nThere are two subtypes of primary narcolepsy which are described below.
\nNarcolepsy type 1(immune-mediated loss of hypocretin-secreting cells in the lateral hypothalamus) [6, 10] is characterized by the presence of cataplexy (a reliable clinical marker for hypocretin deficiency) and hypocretin deficiency in CSF (<110 pg./dl).
\nNarcolepsy type 2: normal hypocretin levels [6, 10].
\nThe secondary causes of narcolepsy show that MS is the fourth most common cause of narcolepsy after inherited disorders, CNS tumors and brain injury, and it has been found that 12% of the cases of secondary narcolepsy were due to MS [6, 10, 66].
\nIn terms of genetics, 95% of narcoleptic patients and 50–60% of MS patients are positive for DR2 haplotype. The human leukocyte antigen (HLA) DQB1*0602, a known genetic risk factor for narcolepsy, also influences the presence and severity of MS. Therefore, both diseases are closely related to the same genes of the human leukocyte antigen (HLA) system, which is the basis for labeling for most autoimmune diseases. This relationship suggests that similar autoimmune factors may be at work in the development of each disorder and might be partially responsible for symptoms of fatigue and sleepiness [6, 10, 67].
\nThe aforementioned findings merit further attention given the potential impact of sleep disorders on the health and quality of life of MS patients [10].
\nA diagnosis of narcolepsy requires PSG and CSF hypocretin assays (only performed at a few academic institutions).
\nNarcolepsy cannot be established in the presence of concomitant OSA, insufficient sleep, shift work or another circadian sleep disorder [10].
\nIn such cases, adequate treatment of concomitant sleep disorders must be confirmed prior to the multiple sleep latency testing.
\nThe usual PSG features include a mean sleep latency of less than or equal to 8 minutes and two or more sleep onset rapid eye movement periods [6].
\nIt is necessary to perform MRI studies to rule out secondary causes of narcolepsy [6].
\nPatients with suspected narcolepsy are usually referred for diagnosis and management by sleep specialists: wake-promoting agents or stimulants may be used to increase wakefulness and vigilance.
\nSodium oxybate (an endogenous metabolite of gamma-aminobutyric acid (GABA) may be used in selected cases.
\nREM-suppressing antidepressants may be useful for cataplexy and sleep paralysis.
\nIn cases of secondary narcolepsy when new hypothalamic lesions are identified, a trial of high-dose steroids should be considered [6].
\nBeing overweight is having more body fat than is optimally healthy. The degree to which a person is overweight is generally described by the body mass index (BMI). Overweight is defined as a BMI above or equal to 25 and below 30.
\nObesity is defined as a BMI over 30. The prevalence of overweight and obesity in patients with multiple sclerosis ranges from 19 to 55%. These differences are due to the distinct prevalence in the general population, differences in geographic origin, population type (military veterans or hospital users) and/or age group. It is notable that the American population has the highest numbers of obesity. Besides which, it is worth mentioning the different methodology used, including overweight with obesity in some studies [42, 68].
\nSpanish data (NARCOMS study) have shown that overweight people with MS had lower general and mental health scores compared to those with normal weight and found no differences in other quality of life scales of the SF-36 [69].
\nDepression levels were higher in the overweight versus normal weight MS Spanish patients. This finding is due to pathophysiological mechanisms common to both depression and obesity, given that chronic low-grade pro-inflammatory states can generate various abnormalities in different neural networks [69].
\nBMI was significantly related to levels of disability, with obese participants 1.4 times more likely to have moderate/severe disability while controlling for age, gender, time since diagnosis and number of co-morbidities. As the BMI increases, the number of co-morbidities increases with higher odds for disability and prior relapse and lower health-related quality of life [42].
\nCentral obesity, as defined by increased waist circumference, absolute waist circumference >102 cm in men and >88 cm in women or waist-hip ratio (the circumference of the waist divided by that of the hips) of >0.9 for men and >0.85 for women, is often indicative of metabolic syndrome, and is suggested to be a more potent risk factor (cardiovascular disease, Alzheimer’s diseases and type 2 diabetes) than body mass index alone.
\nWeight, height, BMI = weight (kg)/height (m2), waist circumference and waist-hip ratio.
\nPatients who are overweight and obese are usually referred for diagnosis and management by a multidisciplinary team such as specialist nutritionist, physiotherapists, surgeons and neuropsychologists.
\nGradual weight loss and gentle physical exercise and stretching are recommended. Small meals and small amounts of food, low in animal fats and fresh fruits. Bariatric surgery may be necessary in severe cases of obesity.
\nCo-morbidities have been shown to be associated with increased hospitalization, rate of progression to disability, decreased quality of life and increased mortality risk which is why they have to be properly treated [42].
\nAdverse health behavior including being overweight and obese, smoking and sedentary behavior are common in people with MS [42]. These behaviors can be modified and may significantly change the level of health. Health professionals should be focused on achieving these behavioral changes in patients with MS.
\nThe therapeutic approach to multiple sclerosis involves pharmacological, rehabilitative, psychological, lifestyle modifying interventions, etc. These can be used independently or coordinated with each other with a holistic view. This approach involves changes in the structure of sleep, which are not always beneficial.
\nTherapeutic options to treat MS relapses include oral glucocorticosteroids [70, 71] or their intravenous administration at a high dose as first line and therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) as second line treatments in glucocorticosteroids unresponsive patients [72], corticotrophin injection and Acthar [73].
\nThe action mechanisms of glucocorticosteroids in the immune system are pleiotropic, induced apoptosis of peripheral blood leucocytes and down-regulation of T-cell activity delayed for 7–10 days after a 5-day course of administration [72].
\nTPE is the removal of circulating antibodies, cytokines, immune complexes and complementary factors, all of which are assumed to be involved in immune-mediated neuroinflammation.
\nIVIG reduces or prevents the activation of inflammatory cells and alters antibody responses.
\nOptimal treatment of relapses increases the chance of limiting or avoiding residual deficits which have been related to the progression of disability in MS [72].
\nSleep disturbance (insomnia) might be one of the side effects of corticosteroid therapy during an acute exacerbation in MS. Benzodiazepines are useful during these periods [74].
\nInterferons are DMTs that produce major alterations of sleep, mainly by the flulike reaction, fever, headache, alteration of the mood and fatigue. It is imperative to treat these effects to improve the patient’s quality of life including finding what time is best to administer the treatment. The monoclonal antibody Natalizumab could reduce fatigue [37].
\nSpecific treatment of symptoms of MS manifestations occasionally interferes with sleep quality, leading to insomnia or drowsiness. The treatments the patient is receiving need to be reviewed in the event of any sleep disturbance.
\nSelective serotonin reuptake inhibitors, while helpful for depressive symptoms, may worsen insomnia. Stimulants and wake-promoting agents, which are commonly used for fatigue, may interfere with sleep initiation if taken during the late afternoon or early evening hours. Antihistamines, which are used as sleep aids by up to 25% of patients with MS, have the potential to worsen RLS, and thereby worsen sleep-onset insomnia.
\nPatients suffering from fatigue symptoms are often treated with antidepressants due to the strong association between depression and fatigue. Modafinil, amantadine and aminopyridine are known as fatigue treatment options, although the physician must monitor the real effect on sleep and adjust the administration schedules so as not to mask the effect on fatigue.
\nMedications used to alleviate MS-related symptoms, including over-the-counter medications, also have the potential to interfere with sleep. Given the high frequency use of these medications in this population, the physician should carefully consider screening for these medications and assessing possible effects on sleep.
\nThe first approach includes reviewing the list of drugs being taken by the patient and adjusting doses or suspending them if necessary to avoid interference with other situations of the patient. In this respect, the multidisciplinary approach to the patient is important.
\nSleep disorders in patients with MS are frequently underdiagnosed. Clinicians caring for patients with MS should routinely screen for sleep disturbances.
\nAll the symptoms are related, many of them share the same pathophysiology where it is not possible to identify the precipitating factor and the perpetuating factor. Sleep disturbances increase the risk of mortality, co-morbidities (cardiac disease, obesity and diabetes) and can contribute to the depression, pain, cognitive impairment and fatigue symptoms which are disabling and worsen the prognosis of multiple sclerosis.
\nThe therapeutic approach to sleep disorders in MS involves pharmacological, rehabilitative, physical, psychological, educational and lifestyle modification interventions. These can be used independently in combination, with combined therapies being more effective.
\nThe list of drugs being taken by the patient should always be reviewed and doses should be adjusted or suspended if necessary to avoid interference with sleeps disorders.
\nMontserrat González Platas and María Yaiza Perez Martín report no conflicts of interest concerning the manuscript
Typical SSCs are equipped with state-of-the-art technologies to support the new and modern lifestyle. Communication technologies are the primary enabler of most electronic interactions and associated operations. The European Parliament states, “A smart city seeks to address public issues via information and communication technology (ICT) solutions.” The Japanese definition concentrates on energy, infrastructure, ICT, and lifestyle. Navigant Research [1] pointed out that investment in smart cities covers smart government, smart building, intelligent transport, innovative communications, and smart utilities. Wireless communication using electric signals is the core for accessibility and availability of communication everywhere within the city and at all times. The UN projected that 66% of the world’s population will be urban by 2050, and cities consume most of the world’s resources, such as 75% of the total energy. They will generate 80% of the greenhouse gases, causing adverse environmental effects. Smart cities with their inherent moderation and control of resource consumption are the ideal solution to address these challenges, population growth, deterioration of energy sources, environmental pollution, etc. The International Organization for Standardization (ISO) provides standards to assure a wide range of smart cities’ quality, safety, and performance. Adherence to these standards benefits deploying, managing, and controlling smart cities. Implementing these standards requires embedding sensors within the involved devices and having these devices connected to a local network to establish inter-sensors communications using ICT. Nathali et al. [2] proposed a generic and universal bottom-up smart city architecture for real-world deployment. The architecture comprises four layers: sensing, transmission, data management, and application. Embedded communication means within each layer are critical and mandatory to ensure cooperation and synchronization among the various components of city sustainability.
ICT allows setting energy targets, observing, and enforcing them by deploying sensor networks covering primary energy consumption sources, such as municipal, industrial, hospitals, and citizens. A tool to identify optimal monitoring locations is available. In a case study, the ICT hotspots identified were heating systems, transport systems, and potential transformation of the buildings and roads enabled by ICT solutions. Studies show that a successful implementation requires the timing of ICT-related decisions in the planning process and the actor-networks needed to implement the ICT solutions and their management. The planning process has several decision points: the property owner, meta-network governance coordination, and traveler information systems. A flexible-work-hub solution case study revealed that mobility management systems encourage environment-friendly transport modes to reduce transport demand with minimum impact. All transportation means should be equipped with efficient navigation systems, and flexible work hubs should be located in local nodes closer to people’s homes.
To provide a practical framework for this chapter, we propose a four-layer concept, an analogy to the OSI seven-layer for communications. Figure 1 depicts the layers model, starting from the bottom with the physical city architecture layer, allowing electric and optical signals free of disturbances and delays. Then the network layer where all the communication equipment, wireline, wireless, antennas, sensors, and IoT are optimally deployed. The intermediate layer contains the protocols and third-party software required to support the application layer and manage the lower-level devices. The upper layer has applications enabling the end-user to enjoy the benefits of a sustainable city, such as energy control and waste and pollution management. Each layer is improving over time; this is presented by the vertical column called trends and developments.
The multi-layer framework for smart city communications.
The global smart cities market size is expected to expand from $1.226T in 2022 to $6.965T registering a CAGR of 24.2% by 2030. Navigant Research [1], based on 443 projects spanning 286 cities worldwide, will contribute nearly $1.7T to the global smart city technology market until 2030. Rapid urbanization led by government initiatives worldwide encourages sustainable and green technologies investment. Asia Pacific market seems to lead with a CAGR of 27.7%. Advanced cities use IoT to manage sustainable operations. For example, pollution, water, and healthcare. Endeavor Business Media announced the launch of smart-building technology embedding intelligence for new constructions and existing commercial buildings. This technological development reduces energy consumption. Major Asian mobile operators take many 5G deployments, and initiatives to resolve the problem of high bandwidth requirements are anticipated to drive the growth. The list of companies promoting smart cities shows that many leading communication vendors appear there, such as Cisco Systems, Inc., Ericsson, General Electric, Honeywell, IBM, Huawei Technologies, Siemens AG Telensa, Verizon, and Vodafone. The introduction of electric vehicles has been well accepted mainly due to their low pollution and modern look. However, it raised a new environmental issue of recharging stations and how to get rid of the big obsolete batteries.
To complement it, intelligent transportation systems (ITSs) [3] became decisive in minimizing congestion, pollution, and parking space. There is still a need for a closed monitoring system to prevent greenhouse gas emissions and promote efficient energy consumption, awareness, attraction, and broadcast decisions. Smart cities market report posted that the innovative utility section, the intelligent infrastructure, and the travel assistance segment are expected to grow at a CAGR of 22.9, 24.3, and 23.4%, respectively, over the forecast period. Endeavor Business Media, 06/21, announced the launch of intelligent construction technology combining smart communication components, reducing energy consumption. Waste management companies deploy sensor networks and data platforms to generate practical insights, route optimization, and analytics decisions. The growing adoption of new technologies in the smart ticketing market, RFID, QR code, BFSI, and healthcare offer smart solutions across sectors.
Businesses look for new ways to engage their customers, streamline operations, and generate revenue, and many are turning to wireless wide area network (WAN) technology. Wireless connectivity is now essential for enabling agile and secure connectivity of people, places, and things, beyond the reach and limitations of traditional wired network connections, managed wireless. The emergence of 5G, with its faster speed, lower latencies, and enhanced network capabilities, catalyzes wireless WAN adoption as businesses seek to make their WANs cellular simple and fiber-fast for true wireless flexibility. This solution provides businesses with the necessary secure and flexible wireless cellular connectivity to any number of fixed sites managed by network experts, helping organizations save time, money, and removing the burden of ongoing management or upfront infrastructure costs. Customers need an agile network that is quick to deploy, highly scalable, secure, and supports a broad WAN use case. They expect a plug-and-play, managed solution that enables simple and fast deployment of wireless connectivity when wired connections are unavailable, lack sufficient reliability, are too costly, only applicable to fixed locations, and require long lead times. Managed wireless WAN is designed to connect thousands of endpoints while providing end-users with fast and secure access to the cloud, datacenter applications, and the internet. It provides employees with safe and reliable access to be productive anywhere without relying on a network provider to deliver a circuit. 5G wireless edge devices offer connectivity, and plans for future additions to the service include support for in-vehicle and internet of things (IoT) use cases and the addition of enhanced routing and security features. Examples of particular use cases have a temporary connection at a branch site, pop-up store, or construction trailer, expanding to new locations, or using a permanent cellular connection as a failover or WAN link for an SD-WAN deployment. It extends the reach of the enterprise to remote areas https://www.computerweekly.com/news/252516487/European-employers-missing-the-opportunity-to-automate-processes-for-hybrid-work enabling innovative use cases.
Advanced communications enable the use of new services covering a variety of life indicators applications, such as shorter commute time, clean air, traffic control, street lighting, smart parking, gathering management, accelerated emergency response time, reduced healthcare costs, decreased water consumption, recycled waste, harmful emissions, sustainability, and other saving potential.
Figure 2 presents several key application types used in a typical SSC for managing, coordinating, synchronizing, and managing all city activities, such as advanced metering of water, electricity, and gas consumption control. Real-time metering of measurable elements, anomaly detection, alert systems, sensor-data collection, machine learning, deep learning methods, and big data analysis. The expected impact is efficient, balanced, cost-efficient, reliable, secured, improved power consumption, low air pollution, and tight coordination among city sectors, such as energy, transportation, water supply, healthcare, education, and culture. In parallel, privacy and security issues are handled, and centralized IoT applications for cost reduction and energy saving of LED lighting controls. Applications for managing surveillance cameras, environmental sensors, electronic billboards, charging stations, WiFi coverage, and smart transit systems reduce cost, improve safety, and routing management improve user experience, onboard WiFi reduce congestion, provide clean air quality, and priority access management. Other applications, sensing flow rates, tank pressure, water levels, remote management solution, monitoring or the components of the IoT, including a range of radio devices, system on modules (SOMs), sensors, water management applications, gateway to supply the connectivity for a range of application needs, water treatment solutions, evaluate critical environmental data, such as groundwater analytics providing recommendations to customers. Remote monitoring and management solution offer hidden visibility of equipment and customers usage of chemicals.
The application layer detailed examples.
A collection of vast applications arsenal is the core enabler of SSC. Following are estimated global market values per application type: [4]. Smart metering for the electricity, gas, and water, market is estimated to reach $39B by 2027. The smart lighting market will grow at a CAGR of 18% to $31B by 2025. Intelligent electric vehicle (EV) charging market is expected to reach $70B by 2026. The solar photovoltaic (PV) market is estimated to grow by 5% annually, reaching $185B.
This layer provides the underlying generic technologies required by the application layer to operate, giving new ideas and capabilities, and empowering the software intelligence to a leading position in the software domain. Figure 3 depicts state-of-the-art technologies enabling AI and other libraries to enrich the applications in the first-layer. The API library contains various generic software components the application layer uses. Big data is another component having a warehouse of data collected over a long period enriched with related market data. Data mining, AI, and BI use this data to identify data patterns, rules, and exciting insights. Machine learning (ML) and deep learning (DL) are two modern tools that are able to learn some insights by processing a given training data. These insights are then used to extrapolate and predict the behavior of the system results. Cloud computing transforms computer-owned usage into services without owning the computer environment. It is disconnecting computer services from the organization’s site. Consequently, the software can be accessed anywhere and anytime free of maintenance, which is an excellent advantage for a smart city. Cyber security is a comprehensive solution to secure the entire system from cyber-attacks.
The intermediate layer detailed examples.
The following are typical qualifications representing SSCs [4], as follows: Technological provision, environmental, social, economic sustainability, economic and social development, air quality, energy transition toward renewables, quality of living, waste per population, water sustainability, human infrastructure & networked markets, ESG performance, and smart city ecosystem. Some of the cities provided data regarding their status. One city deployed over 20,000 sensors for capturing temperature, air quality, mobility data, lighting, noise, and climate. Another city implemented pollution-monitoring sensors and educational campaigns. Some cities stated that all new buildings are built with intelligent controls, low-energy heating, and digitized mobility using accessible WiFi in 755 public spaces. More options are wired bike-sharing, electrical vehicle plug-in spots, activated video feeds in busy intersections to smooth traffic, renewable energy, sustainable mass transit, $70B in total startup valuations, 100 accelerators, incubators, and co-working spaces, using 100% renewable power, implementing real-time meter sensors, reducing emissions from daily commuting by sharing, and deploying sensors for heating, cooling, and lighting based on occupancy. Distribute to the public smart-mobile applications, measure and optimize biogas, energy efficiency, heating and cooling, smart grids, and consider electric buses and green energy systems.
Following are typical declarations of existing smart cities. The city goals are clean air, biodiversity, low carbon, green transportation, waste reduction, artificial intelligence (AI), blockchain, internet of things (IoT), quantum computing helping in their intelligence journey, and cutting 40% of CO2 emissions by 2025. Becoming the leader in smart and sustainable building solutions. Through the $37N green building masterplan, make 80% of the city buildings eco-friendly by 2030, earn 80% of new buildings super low energy (SLE), and achieve an 80% improvement in energy efficiency for green buildings. Becoming a climate-friendly by 2040. Any services that can be digitized will be digitized. Become the world’s first carbon-neutral city by 2025, becoming fossil-fuel-free by 2050.
Some of the recorded achievements are: reducing carbon emissions by 25,000 tons, saving $9.5M, decreasing the electricity consumption of public buildings by 7.8%, reducing overall carbon footprint by 35%, recover 1.64 million tons of municipal solid waste, reducing emissions by about 18,000 T/year, comparable to the electricity use of 4000 residents, Over a third of all transportation, fossil-fuel consumption has been removed through sustainable transport alone, a reduction of 90,000 tons of greenhouse gas emissions each year.
Several publications define the requirements for qualifying a city as an SSC. In all of these publications, we realize that communication and sensors are the key enablers of smart cities. Internet connectivity is crucial for smart cities as almost all activities are via messaging. High capacity, high-speed, efficient, and effective internet connection is a key to achieving the smart cities vision. It complies with the forecast that by 2024, more than 23B devices will be connected to cellular networks. It is possible with high-speed internet connectivity associated with local communication networks. Figure 4 depicts recent trends in modern communication infrastructure, which can cope with a high-volume communication activity. The first component is satellite communications, which is undergoing significant development by SpaceX. The second is cellular 5G, which supports a new magnitude of transmission speed and volume. The third refers to a substantial WiFi version, a newly expanded gateway, and the exploding spread of sensors and IoT devices.
The network layer details.
During the past few years, we are evident the intensive launch of more than 2000 small satellites to the LEO by SpaceX, creating a network of satellites communicating with each other via laser beams. The communication with the earth is by electronic signals transmitted toward ground stations for further distribution via wireline and cellular networks. It is the ultimate achievement of satellite communications.
The evolving spread of 5G provides ultra-fast internet, low latency, and improved reliability. It is the ultimate solution that copes with the expected wireless traffic. 5G network’s speed is 10–30 Gbps, which is 100 times faster than 4G; the capacity is 1000 Gbps/km2 area spectral in dense urban environments, 1000 times more than 4G. It decreases energy consumption by 10% times the higher battery life of associated devices and five times lessened end-to-end delay. 5G integrates with long term evolution (LTE) and WiFi to give all-inclusive high-rate coverage and a seamless user experience. 5G networks have a latency rate of 1 ms vs. 40–50 milliseconds in 4G. 5G networks allow smoother handling of spikes and better network traffic optimization than 4G. Lower power consumption and enhanced capacity and speed are part of sustainability.
WiFi wireless communications transport most wireless traffic in enterprises, public and residential environments cost-effectively and continue improving the efficiency in using precious spectrum resources. The new version 7 is to be released in 2024. It is a significant enhancement of WiFi 6. It is more flexible and efficient, supports 16 streams, has a channel size of 640 MHz, has a data rate of 46 Gbps, has lower latency, and uses network and spectrum resources. WiFi 7 integrates well with 5G and 3GPP-based 5G and other standard communication devices and protocols. It supports distributed and cloud architectures, virtualization, and digitalization in the emerging private wireless networks (PWN). Wi-Fi-7 supports applications that require deterministic latency, high reliability, quality of service (QoS), IoT, IIoT, and video-based applications, such as surveillance, remote control, gaming, AV/VR, smart-home services, and more. WiFi deployment provides communication services that save unnecessary wiring, energy, transportation, and contribute to sustainability.
The evolving new services generated for smart cities require numerous sensors connected to new types of wireless communication networks that meet the specific requirements of smart city needs. Sensors [5] interactions require the transfer of small data packages, energy efficiency, the ability to connect devices in remote areas, a high degree of data protection, and interoperability. Connected end devices must operate for a long time, powered by an embedded battery with no connection to the grid. Terleev et al. [6] recommend LoRaWAN as the best gateway for machine-to-machine communication technology. According to experiments, the coverage area of the LoRaWAN gateway is 1500 m, which is fine for a smart city.
The last component required to complement the network layer is IoT, the internat of things, enabling the data collection from the system endpoints, the sensors, and vice versa, transmitting messages from the system toward an IoT device and among IoT devices.
Smart city communication infrastructure supports intra-city and internet interactions. It comprises wireline and wireless mixture networks. The wireline is a network of fiberoptic channels deployed underground with connected antennas.
Figure 5 depicts the typical new generation of communication hardware required to support modern communication services. It includes satellite and cellular antennas, underground fiberoptics wiring, and the construction materials impacting the electric signals. The number of antennas, location, signal strength, and height depend on the city’s population density. The wireless portion comprises signals from satellites intercepted by the corresponding antennas and signals broadcasted by the cellular antennas and captured by the mobile phones located within the antenna’s spectrum. Wireless signals are disturbed by physical obstacles, such as buildings and other constructions. Therefore, city streets, buildings architecture plans, and used materials should consider optimal deployment of the wireline fiberoptics and the corresponding antenna locations to ensure smooth communication at minimum interference. For example, the building material and the estimated data transmission load apply the suitable communications infrastructure or determine the building’s fabric. We provide the knowledge and guidelines for selecting the appropriate communications technologies fitting the specific SSC’s attributes and vice versa.
The physical layer details.
Electric waves are the core of wireless digital communication at free space and ground contacts. However, the transmitted waves are exposed to obstacles, such as rain, dust, topography, urban surface, and magnetic forces, causing signal attenuation and degrading the transferred signal quality up to data loss. To overcome it, we may request the transmission of stronger signals, which increases the power consumption and shortens the transmitting satellite’s lifespan. Hence, we propose a machine-learning based model, which predicts the proper signal strength and the correct transmission time, having a high probability of reaching the intercepting antenna on the ground. The model analyses the two path sections, from the satellite to free space close to the ground and then to the ground station. We trained our ML system using training data from the genesis satellite. Experiment results show our system’s high accuracy level for frequencies ranging from 2 to 72 GHz.
Several papers cope with the same problem. Some proposed solutions are limited to a geographic region where minimal rain and dust, while others are limited to low frequencies [7]. Analyzed satellite data to discover the elements causing a signal loss in urban environments [8, 9]. Correlate signal loss and construction material [10, 11]. Present materials measurements of low frequencies [12, 13]. Focus on the receiver’s position and height disruption inside a building. Entry loss for 2 GHz is reported in [14, 15, 16, 17, 18]. Discuss signal spread within facilities and [19] calculate the spread delay as a function of elevation and angle. In [20], a new path loss model and [21] present attenuation differences for indoor textures and materials. We selected a concrete building with a horn antenna with vertical polarization. The signal generator, the transmitter, and the receiver are agilent. We use recurrent neural networks (RNN), and MLNNs have a temporal dimension. The MLNN system builds, loads the neural network, trains, and tests the input data. Then it analyzes the data, starting with the input samples reduced in two stages to one instance, identifying the optimal converged parameters. The training results resemble the accurate results. In summary, we provide SSC designers with a tool to determine the optimized materials and positioning of communication equipment so that signal strength will remain effective until it reaches the targeted antennas and mobile devices.
This chapter discusses the role and contribution of communication technologies to sustainable smart cities. For a detailed analysis, we divided the subject into four cumulative aspects piled into four layers, starting with the bottom physical layer up to the applications developed to manage, coordinate, and synchronize the activities required to maintain sustainability in smart cities. This study shows the profound necessity of incorporating communication technology into the management and control mechanisms used to assert sustainable smart cities. Based on the detailed content of the chapter sections, it is clear that everything related to management, control, and interaction among key players of smart cities require communications infrastructure to enable its operations. Figure 6 encapsulates the complete view of the chapter content and its details. Since SSC is still in its beginning stage and still evolving, this chapter may be updated soon to capture the near future developments in this advanced domain.
The multi-layer detailed framework for smart city communications.
The authors declare no conflict of interest.
IntechOpen has always supported new and evolving ideas in scholarly publishing. We understand the community we serve, but to provide an even better service for our IntechOpen Authors and Academic Editors, we have partnered with leading companies and associations in the scientific field and beyond.
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The toxic and allergic reactions of synthetic dyes are compelling the people to think about natural dyes. Natural dyes are renewable source of colouring materials. Besides textiles it has application in colouration of foods, medicine and in handicraft items. Though natural dyes are ecofriendly, protective to skin and pleasing colour to eyes, they are having very poor bonding with textile fibre materials, which necessitate mordanting with metallic mordants, some of which are not eco friendly, for fixation of natural dyes on textile fibres. So the supremacy of natural dyes is somewhat subdued. This necessitates newer research on application of natural dyes on different natural fibres for completely eco friendly textiles. The fundamentals of natural dyes chemistry and some of the important research work are therefore discussed in this review article.",book:{id:"9203",slug:"chemistry-and-technology-of-natural-and-synthetic-dyes-and-pigments",title:"Chemistry and Technology of Natural and Synthetic Dyes and Pigments",fullTitle:"Chemistry and Technology of Natural and Synthetic Dyes and Pigments"},signatures:"Virendra Kumar Gupta",authors:[{id:"305259",title:"Dr.",name:"Virendra",middleName:null,surname:"Kumar Gupta",slug:"virendra-kumar-gupta",fullName:"Virendra Kumar Gupta"}]},{id:"49647",title:"Fiber Selection for the Production of Nonwovens",slug:"fiber-selection-for-the-production-of-nonwovens",totalDownloads:10568,totalCrossrefCites:9,totalDimensionsCites:17,abstract:"The most significant feature of nonwoven fabric is made directly from fibers in a continuous production line. While manufacturing nonwovens, some conventional textile operations, such as carding, drawing, roving, spinning, weaving or knitting, are partially or completely eliminated. For this reason the choice of fiber is very important for nonwoven manufacturers. The commonly used fibers include natural fibers (cotton, jute, flax, wool), synthetic fibers (polyester (PES), polypropylene (PP), polyamide, rayon), special fibers (glass, carbon, nanofiber, bi-component, superabsorbent fibers). Raw materials have not only delivered significant product improvements but also benefited people using these products by providing hygiene and comfort.",book:{id:"5062",slug:"non-woven-fabrics",title:"Non-woven Fabrics",fullTitle:"Non-woven Fabrics"},signatures:"Nazan Avcioglu Kalebek and Osman Babaarslan",authors:[{id:"119775",title:"Prof.",name:"Osman",middleName:null,surname:"Babaarslan",slug:"osman-babaarslan",fullName:"Osman Babaarslan"},{id:"175829",title:"Dr.",name:"Nazan",middleName:null,surname:"Kalebek",slug:"nazan-kalebek",fullName:"Nazan Kalebek"}]},{id:"41409",title:"Surface Modification Methods for Improving the Dyeability of Textile Fabrics",slug:"surface-modification-methods-for-improving-the-dyeability-of-textile-fabrics",totalDownloads:7063,totalCrossrefCites:13,totalDimensionsCites:36,abstract:null,book:{id:"3137",slug:"eco-friendly-textile-dyeing-and-finishing",title:"Eco-Friendly Textile Dyeing and Finishing",fullTitle:"Eco-Friendly Textile Dyeing and Finishing"},signatures:"Sheila Shahidi, Jakub Wiener and Mahmood Ghoranneviss",authors:[{id:"58854",title:"Dr.",name:null,middleName:null,surname:"Shahidi",slug:"shahidi",fullName:"Shahidi"}]}],onlineFirstChaptersFilter:{topicId:"296",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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