\r\n\tWith this goal in mind, together with the US Prof. John M. Ballato and the InechOpen publishing house since 2011 we have published in 2011, 2013, 2015 and 2017 4 books of our serial “Optoelectronics” and the book “Excitons”, edited in 2018 by Prof. Sergei L. Pyshkin. Publishing the new book “Luminescence” we are pleased to note the growing number of countries participating in this undertaking as well as for a long time fruitfully cooperating scientists from the United States and the Republic of Moldova.
\r\n\tSpecialists from all over the world have published in edited by us books their works in the field of research of the luminescent properties of various materials suitable for use in optoelectronic devices, the development of new structures and the results of their application in practice.
Increases and decreases of synaptic activity in the brain are accompanied by proportional changes in capillary perfusion and local glucose consumption. These changes in glucose consumption are the effect of changed activity or density of the afferent nerve terminals in that region. Loss of neurons may result in decreased glucose consumption in distant brain regions by deafferentiation, while also increased regional glucose consumption by increased activation of afferent neurons can occur. The PET tracer [18F]fluorodeoxyglucose (FDG) allows the measurement of glucose consumption. FDG is a glucose analog with physiological aspects almost identical to glucose. It is transported from the blood to the brain by a carrier-mediated diffusion mechanism. FDG and glucose are phosphorylated by hexokinase as the first step of the glycolytic process. FDG differs from glucose in that a hydrogen atom replaced the hydroxyl group at the second carbon atom of the molecule. Glucose is then phosphorylated to glucose-6-PO4, and continues along the glycolytic pathway for energy production. However, FDG is phosphorylated to FDG-6-PO4, which is not a substrate for further metabolism and trapped in tissues. As glucose is the only source of energy for the brain it reflects the neuronal integrity of underlying brain pathology. Since FDG is a competitive substrate with glucose for both transport and phosphorylation, it is important for tracer uptake to avoid high blood glucose levels during an FDG-PET scan in subjects with diabetes.
In neurodegenerative brain diseases, specific brain regions degenerate and specific patterns of metabolic brain activity develop. This happens before clear structural changes can be detected with imaging techniques.
Measurement of glucose consumption with FDG PET imaging thus allows us to identify disease-specific cerebral metabolic brain patterns in several neurodegenerative brain diseases at an early disease stage. Since the first FDG PET study in man in 1979 (Reivich, et al. 1979) regional differences in cerebral glucose metabolism have been reported in various neurodegenerative brain diseases including parkinsonian syndromes.
Univariate methods like voxel-based statistical parametric mapping (SPM) analyses have been used to identify group differences between patients with neurodegenerative brain diseases and controls. (Eckert, et al. 2005, Juh, et al. 2004, Yong, et al. 2007).
At the University Medical Center Groningen, The Netherlands we have performed a retrospective study (Teune, et al. 2010) selecting typical patients with 7 different neurodegenerative brain diseases who had had a clinical FDG brain scan at a time point when their diagnosis was not sure yet. These patients developed in the following years the mentioned typical disease states. Images of each of the seven patient groups were separately compared to controls using a two-sample t test. At those early scans, already typical differences between patient - and control groups were found for each disease.
However, Scaled Subprofile modelling/principal component analysis (SSM/PCA), a multivariate method, not only identifies group differences, but is also able to identify relationships in relatively increased and decreased metabolic activity between different brain regions in combined samples of patients and control scans (Eidelberg. 2009, Moeller, et al. 1987). Covariance analysis techniques are considered appropriate methods to explore network activity. In the SSM, a threshold of the whole-brain maximum can be applied to remove out-of-brain voxels, followed by a log transformation. A threshold of 35% is used by the Eidelberg research group resulting in a mask of mainly grey matter (Spetsieris and Eidelberg. 2010). After removing between-subject and between-region averages, a principal component analysis (PCA) can be applied. PCA transformes a set of correlated variables into a new set of orthogonal uncorrelated variables that are called the principal components. Voxels participating in each principal component (PC) may have either a positive or a negative loading. The loadings express the covariance structure (i.e. the strength of the interaction) between the voxels that participate in the PC. They are ordered in terms of the variability they represent. That is, the first principal components represents for a single dimension (variable) the greatest amount of variability in the original dataset. Each succeeding orthogonal component accounts for as much of the remaining variability as possible. They can be very helpful in determining how many of the components are really significant and how much the data can be reduced.
In most studies, the components that together describe at least 50% of the variance are used for further analysis, but this is an arbitrary limit. To identify a covariance pattern that best discriminates a patient group from a control group, each subject’s expression of the selected principal components with the lowest AIC (Akaike information criterion) value (Akaike. 1974) are entered into a stepwise regression procedure. This regression results in a linear combination of the PCs that best discriminated the two groups and is designated as the disease-specific metabolic covariance pattern.
Important for its use in clinical practice is that this metabolic covariance pattern can then be applied to individual patients to test whether they express the pattern or not. Every voxel value in a subject scan is multiplied by the corresponding voxel weight in the covariance pattern, with a subsequent summation over the whole brain volume. The resulting subject score captures to what extent a subject expresses the covariance pattern.
Typical cerebral metabolic patterns in neurodegenerative brain diseases. SPM (t) maps of decreased metabolic activity were overlaid on a T1 MR template thresholded at P< 0.001 with cluster cutoff of 20 voxels. Patient groups are indicated on the vertical axis and on the horizontal axis, seven transversal slices through the brain are shown. PD = Parkinson’s disease: decreased metabolic activity in the contralateral to the most affected body side parieto-occipital and frontal regions; MSA = multiple system atrophy: decreased metabolic activity in bilateral putamen and cerebellum; PSP = progressive supranuclear palsy: decreased metabolic activity in the prefrontal cortex, caudate nucleus, thalamus and mesencephalon; CBD = corticobasal degeneration: decreased metabolic activity in the contralateral to the most affected body side cortical regions; DLB = dementia with Lewy bodies: decreased metabolic activity in the occipital and parieto-temporal regions. AD = Alzheimer’s Disease: decreased metabolic activity in the angular gyrus and other parieto-temporal regions including precuneus extending to the posterior- and middle cingulate gyrus. FTD = frontotemporal dementia: decreased metabolic activity in the superior and inferior frontal gyrus, anterior cingulate gyrus, SMA, sensorimotor area and middle temporal gyrus. Adapted from:
Parkinson’s disease (PD) is characterized by bradykinesia, rigidity, sometimes rest tremor and postural instability. A disturbed α-synuclein protein forming so-called Lewy bodies seems to play a causal role, which was a reason to designate PD as a α-synucleinopathy. The main pathophysiological changes result from degeneration of catecholaminergic, especially dopaminergic cells in brainstem regions.
A characteristic metabolic covariance pattern has been identified in PD patients (PD-related pattern, PDRP) showing regionally relatively increased metabolism in the globus pallidus and putamen, thalamus, pons and cerebellum and relatively decreased metabolism in the lateral frontal, premotor and parietal association areas (Ma, et al. 2007) Network expression in PD patients also increases linearly with disease progression(Huang, et al. 2007b). Tang et al. tried to study network changes in the PD-related motor pattern before symptom onset by studying 15 hemiparkinsonian patients and focusing mainly on the “presymptomatic” hemisphere. They conclude that abnormal PDRP activity antecedes the appearance of motor signs by approximately 2 years (Tang, et al. 2010a). However, this needs to be proven in future research in true presymptomatic patients.
In addition to motor symptoms, cognitive dysfunction is also common in PD, especially executive and visuospatial dysfunction. FDG-PET studies have been performed to study these specific symptoms and their relations with neural network pathophysiology. The Eidelberg research group has shown PD subclassifications related to specific symptoms. Network analysis with the SSM/PCA approach detected a significant covariance pattern in non-demented PD patients that correlated with memory and executive functioning tasks. The expression of this PD-related cognitive pattern (PDCP) in individual patients correlated with severity of cognitive dysfunction(Huang, et al. 2007a).
Alterations in neuropsychological test results in advanced PD were found to correlate with decreases in glucose metabolism in the dorsolateral prefrontal cortex (DLPFC), lateral orbitofrontal cortex (LOFC) ventral and dorsal cingulum (v/dACC) and in Broca area (Kalbe, et al. 2009). In the study of Kalbe et al, PD patients with deep brain stimulation in the subthalamic nucleus (STN-DBS) showed cognitive decline that correlated with decrease in glucose metabolism in these areas. In another study in STN-DBS treated patients, STN DBS was found to activate glucose metabolism in the frontal limbic and associative territory (Hilker, et al. 2004). Interestingly, cortical areas that show hypometabolism in patients with depression (Mayberg HS. 1994) are similar to the regions that show restored glucose metabolism after STN DBS. This finding agrees with the clinical observation that PD-related depression tends to improve after STN DBS.
Mure et al. identified a spatial covariance pattern associated with Parkinson tremor which was characterized by covarying increases in the cerebellum/dentate nucleus and primary cortex and to a minor degree in the caudate/putamen (Mure, et al. 2011).
Hallucinations in PD have been related to relative frontal hypermetabolism compared to PD patients without hallucinations(Nagano-Saito, et al. 2004). However, another study showed hypometabolism in occipitotemporoparietal regions in PD patients with hallucinations, sparing the occipital pole, while no significant increase in regional glucose metabolism was detected (Boecker, et al. 2007). Interestingly, in patients with dementia with Lewy bodies (DLB), who also suffer from hallucinations, glucose metabolism was also decreased in occipitoparietal regions, however without sparing of the occipital pole (see DLB section).
Multiple system atrophy is a sporadic neurodegenerative brain disease which affects both men and women and generally starts in the sixth decade of life. The main clinical features are parkinsonism, autonomic failure, cerebellar ataxia, and pyramidal signs in any combination. However, two major motor presentations can be distinguished. Parkinsonian features predominate in 80% of patients (MSA-P subtype) and cerebellar ataxia is the main motor feature in 20% of patients (MSA-C subtype) ((Gilman, et al. 2008, Wenning, et al. 1997)
In MSA-P the striatonigral system is the main site of pathology but less severe degeneration can be widespread and normally includes the olivopontocerebellar system. In MSA-C pathological changes are mainly seen in the olivopontocerebellar system and involvement of striatum and substantia nigra are less severe (Wenning, et al. 1997). The discovery of glial cytoplasmic inclusions in MSA brains highlighted the unique glial pathology as biological hallmark of the disease. Their distribution selectively involves basal ganglia, supplementary and primary motor cortex, the reticular formation and pontocerebellar system. Glial cytoplasmic inclusions contain besides classical cytoskeletal antigens also α-synuclein, which is a presynaptic protein present in Lewy Bodies, and this accumulation seems to play a central part not only in MSA but also in other α-synucleinopathies such as PD and DLB.
Disease-related metabolic patterns were also present in MSA consisting of hypometabolism in putamen and cerebellum in MSA (Eckert, et al. 2008). Poston et al. found that differences in expression of the MSA-related pattern correlated with clinical disability (Poston, et al. 2012).
The clinical picture of progressive supranuclear palsy (PSP) has been first described by Steele, Richardson and Olszewski (Steele JC, Richardson J,Olszewski J. 1964) and is characterized by progressive parkinsonism, early gait and balance impairment, vertical gaze palsy and more profound frontal cognitive disturbances. PSP is one of several neurodegenerative diseases characterised by accumulation of hyperphosphorylated tau (tauopathy), forming abnormal filamentous inclusions in neurons and glia in the precentral and postcentral cortical areas but also in the thalamus, subthalamic nucleus, red nucleus and substantia nigra. Other neurodegenerative brain diseases which show disturbances in tau protein handling are corticobasal degeneration (CBD) and frontotemporal dementia (FTD) but there is also overlap in pathology with Alzheimer’s disease (AD).
However the metabolic brain patterns in these tauopathies are quite different. The covariance pattern of PSP consists of decreased metabolism in the prefrontal cortex, frontal eye fields, caudate nuclei, medial thalamus and upper brainstem (Eckert, et al. 2008). Brain stem atrophy and atrophy of the medial frontal cortical regions have also been reported in histopathological studies (Hauw, et al. 1994).
The most striking features of patients with corticobasal degeneration (CBD) include marked asymmetrical parkinsonism and apraxia but also postural instability, limb dystonia, cortical sensory loss, dementia and the alien limb phenomenon. CBD is one of the tauopathies and clinical diagnosis is complicated by both the variability of presentation of true CBD and the syndromes that look alike but are caused by other tauopathies with parkinsonism like PSP or FTD (Josephs, et al. 2006). However with functional neuroimaging a clear distinction can be made. In CBD a typical pattern of hypometabolism is seen in cortical regions contralateral to the affected body side, including parieto-temporal regions, prefrontal cortex and motor cortex. Furthermore, a decrease can be found in the contralateral caudate nucleus, putamen and thalamus (Eckert, et al. 2005, Teune, et al. 2010). No covariance pattern has been described using the SSM/PCA technique in CBD.
Interestingly, Tang and co-workers studied the potential role of FDG PET in the individual diagnosis of 167 patients who had parkinsonian features but uncertain clinical diagnosis (Tang, et al. 2010b) After FDG PET imaging, patients were assessed by blinded movement disorders specialists for a mean of 2.6 years before a final clinical diagnosis was made (gold standard). SSM/PCA analysis can quantify the expression of an obtained covariance pattern in each subject which allows assessing the expression of a given pattern on a single case basis. Using this automated image-based classification procedure and the previously defined disease related covariance patterns in PD, MSA and PSP, individual patients were differentiated with high specificity.
However, blinded, prospective imaging studies (ideally involving multiple centers, a larger validation group, repeat imaging, and more extensive post-mortem confirmation) are needed to establish the accuracy and precision of this pattern-based categorisation procedure. These studies are currently undertaken.
For routine clinical practice, this knowledge of disease specific patterns of regional metabolic activity in neurodegenerative brain diseases can be a valuable aid in the differential diagnosis of individual patients, especially at an early disease stage.
Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease accounting for 50-60% of cases of dementia. AD is characterized by a severe decline in episodic memory together with general cognitive symptoms such as impaired judgement, decision making and orientation (McKhann, et al. 1984). A correct clinical diagnosis can be difficult, especially in early disease stages or in patients with for example comorbid depression, high education or young age (Bohnen, et al. 2012). FDG-PET imaging can be used to assist in the differential diagnosis, because for different dementia syndromes, a separate pattern of hypometabolism can be found. In Alzheimer’s disease (AD), decline of FDG uptake in posterior cingulate, temporoparietal and prefrontal association cortex was related to dementia severity (Herholz, et al. 2002). Foster et al used visual interpretation of an automated three-dimensional stereotactic surface projection technique of patients with AD and FTD. They showed that visual interpretation of FDG-PET scans after training is more reliable and accurate in distinguishing FTD from AD than clinical methods alone (Foster, et al. 2007).
Although multivariate analytical techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study neural correlates of Alzheimer’s Disease or cognitive impairment. Because cognitive processes are the result of integrated activity in networks rather than activity of any one area in isolation, functional connectivity can be better captured by multivariate methods. A study from Habeck et al. examined the efficacy of multivariate and univariate analytical methods and concluded that multivariate analysis might be more sensitive than univariate analysis for the diagnosis of early Alzheimer’s disease (Habeck, et al. 2008).
Scarmeas et al. were the first to derive an AD related covariance pattern using H215O to measure brain perfusion (Scarmeas, et al. 2004). It consisted of relatively increased perfusion in the bilateral insula, lingual gyri and cuneus with bilaterally decreased flow in bilateral inferior parietal lobule and cingulate in AD patients. However, using this PET tracer they found a sensitivity of 76-94% and a specificity of 63-81% with considerable overlap in pattern expression among AD patients and controls. Therefore they concluded that the derived H215O pattern cannot be used as a sufficient diagnostic test in clinical settings. Specific FDG covariance patterns to distinguish early AD-related cognitive decline using multivariate methods have yet to be specified.
Frontotemporal dementia (FTD) is one of the neurodegenerative diseases commonly mistaken for AD. FTD patients do not have a true amnestic syndrome but can present with either gradual and progressive changes in behaviour, or gradual and progressive language dysfunction. Gross examination of the post-mortem brain from a patient with FTD usually reveals frontal or temporal lobar atrophy or both, but the distribution or severity of brain atrophy are not specific for a particular neurodegenerative brain disease. Jeong et al. and Diehl-Schmid et al. analysed FDG-PET scans of FTD patients on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM). They found hypometabolism depending on disease stage in the frontal lobe, parietal and temporal cortices (Diehl-Schmid, et al. 2007, Jeong, et al. 2005).
The clinical overlap of dementia and parkinsonism is highlighted in Dementia with Lewy Bodies (DLB). These patients show besides dementia extrapyramidal motor symptoms and marked neuropsychiatric disturbances including visual hallucinations, depression, variability in arousal and attention (McKeith. 2006). Consistent observation of a metabolic reduction in the medial occipital cortex in DLB patients (Minoshima, et al. 2001, Teune, et al. 2010) using FDG-PET imaging suggests the use of FDG-PET in the differential diagnosis of AD and DLB and of PD and DLB. Minoshima et al. found that the presence of occipital hypometabolism distinguished DLB from AD with 90% sensitivity and 80% specificity when using post-mortem diagnosis as the gold standard diagnosis (Minoshima, et al. 2001).
Huntington’s disease (HD) is characterized by progressive dementia and chorea, starting around 30-40 years of age. HD is caused by a dominantly inherited CAG repeat expansion mutation that generates lengthening of the protein huntingtin, with size-dependent neurotoxicity. Several PET studies have shown hypometabolism in the caudate nucleus, both in symptomatic and asymptomatic mutation carriers (Grafton, et al. 1992) (Antonini A., et al. 1996) In asymptomatic carriers, metabolic decreases were also significantly associated with the CAG repeat number (Antonini A., et al. 1996). Furthermore, it was found that FDG uptake in the caudate nucleus provided a predictive measure for time of onset of the disease, in addition to the mutation size (Ciarmiello A., et al. 2012).
Another study applied network analysis of FDG-PET scans in presymptomatic mutation carriers (Feigin, et al. 2001). They found a HD related metabolic covariance pattern (HDRP) characterized by caudate and putamenal hypometabolism, but also including mediotemporal reductions as well as relative increases in occipital regions. Disturbances of these striatotemporal projections may underlie aspects of the psychiatric and cognitive abnormalities that occur in the earliest stages of HD, before the onset of motor signs (Cummings JL. 1995).
Dystonia is a movement disorder characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures. The most common forms of primary torsion dystonia (PTD) are DYT1 and DYT6, both caused by autosomal inherited mutations with a reduced penetrance.
Functional neuroimaging techniques have been applied in different dystonic disorders including primary generalized dystonia, mainly DYT1 and DYT6 and dopa-responsive dystonia, as well as focal dystonic syndromes such as torticollis, writer’s cramp and blepharospasm. A common finding is abnormality of the basal ganglia, cerebellum and associated outflow pathways to sensorimotor cortex and other regions involved with motor performance. However, controversial results have been found in imaging dystonias, partly attributed to methodological differences but also to the heterogeneity of the dystonias. Using the SSM/PCA approach a reproducible pattern of abnormal regional glucose utilization in two independent cohorts of DYT1 carriers have been found (Eidelberg D. 1998)(Trost M., et al. 2002).
This torsion-dystonia related metabolic pattern is characterized by increases in the posterior putamen/globus pallidus, cerebellum and SMA. Interestingly, also in clinically non-manifesting mutation carriers this pattern was found, suggesting a cerebral “vulnerability to develop dystonia” network change. Also in manifesting and non-manifesting DYT 6 carriers abnormal network activity has been identified. A difference between DYT1 and DYT6 metabolic patterns can be seen in the putamen, where glucose metabolism is increased in DYT1 and decreased in DYT6, possibly do to cell loss in DYT6. Furthermore, the cerebellum shows increased activity in DYT1 and normal activity in DYT6 (Carbon M., et al. 2004).
The TDRP network is not expressed in patients with Dopa-responsive dystonia (DRD) (Trost M., et al. 2002).
DRD is characterized by an early onset of dystonic symptoms and later appearance of parkinsonian symptoms. A defining feature is a marked and sustained response to low doses of levodopa, suggesting that the lesion may be functional in the presynaptic dopaminergic system rather than anatomical. The DRD related metabolic pattern is characterized by relative increases in the dorsal midbrain, cerebellar vermis,and SMA, assiocated with covarying decreases in putamen, lateral premotor and motor cortical regions (Asanuma, et al. 2005b). This DRD related pattern is not apparent in DYT 1 and 6 carriers supporting the hypothesis that the pathophysiology of DRD differs from that of other forms of dystonia. They also found that the Parkinson-related metabolic pattern is not apparent in DRD patients. Thus FDG-PET can be useful to distinguish PD related dystonia from dopa-responsive dystonia with parkinsonism (Asanuma, et al. 2005a).
Tourette syndrome is characterized by the presence of chronic motor and vocal tics that develop before the age of 18. Comorbid behavioural abnormalities are common in Tourette syndrome, most notably obsessive-compulsive disorder and attention deficit/hyperactivity disorder (Lebowitz, et al. 2012). The neurophysiology remains poorly understood with varying and inconsistent neuropathological and neuroimaging findings, possibly due to the clinical heterogeneity of the disorder. Pourfar et al. identified a Tourette syndrome related pattern characterized by reduced metabolic activity of the striatum and orbitofrontal cortex associated with relatively increased metabolic activity in the premotor cortex and cerebellum. A second metabolic brain pattern was found in patients with Tourette syndrome and obsessive compulsive disorder characterized by reduced activity in the anterior cingulate and dorsolateral prefrontal cortex and relative increases in primary motor cortex and precuneus. Subject expression correlated with symptom severity. These findings suggest that the different clinical manifestations of the Tourette syndrome are associated with different abnormal brain networks (Pourfar, et al. 2011).
FDG-PET imaging is increasingly available for routine clinical practice and has remained the only available radiotracer to detect accurately and reliably the cerebral glucose metabolism. As glucose is the only source of energy for the brain it reflects the energy needs of underlying brain neuronal systems. The SSM/PCA method can identify relationships in relatively increased and decreased metabolic activity between different brain regions in combined samples of patients and controls. The expression of an obtained covariance pattern can be quantified in an individual patient and this resulting subject score captures to what extent a patient expresses the covariance patterns. The disease-related metabolic brain patterns can therefore be a valuable aid in the early differential diagnosis of individual patients with neurodegenerative brain diseases.
The intrinsic circadian system synchronizes basic physiologic functions such as temperature regulation, appetite, and hormonal homeostasis and is responsible for the stable sleep and wake states that occur at regular times with respect to day and night. The term circadian derives from the Latin words “circa,” meaning approximately, and “diem,” meaning day, which emphasize that the intrinsic cycle is usually not exactly 24 hours in length [1]. The average circadian cycle length is generally 24.2 hours, which means that the cycle always requires entrainment to the environment because the day is exactly 24 hours long. Light is the most potent mechanism of entrainment, but meals and exercise also have an impact on entrainment [1, 2, 3]. Dysynchrony between a person’s internal circadian system and their desired wake and sleep periods can lead to one of 6 different types of circadian rhythm sleep–wake disorders (CRSWDs). These disorders can present clinically with symptoms of insomnia and/or excessive daytime sleepiness, along with impairments in cognitive, emotional, and social functioning. A key feature of these conditions is that re-alignment of the intrinsic circadian period to the desired circadian period leads to resolution of symptoms.
CRSWDs may be due to a primary problem with the circadian system, such as altered sensitivity of the circadian system to light, and genetic and/or age-related factors that disrupt the intrinsic period of the system.
The diagnosis of CRSWDs can be difficult, due to the overlapping symptoms with other sleep disorders and medical conditions. Recognizing consistent patterns in abnormal sleep schedules is key to helping differentiate CRSWDs from other disorders. CRSWDs are primarily clinical diagnoses and use of a detailed sleep diary is an important part of the evaluation. Other objective measures such as actigraphy and melatonin measurements can supplement information obtained from the patient’s history [4]. Polysomnography is usually not indicated unless there is a suspicion for a comorbid sleep disorder, such as a sleep-related breathing disorder.
Management of circadian rhythm sleep–wake disorders involves a combination of behavioral interventions, light therapy, and timed melatonin therapy. Treatment is individualized to the specific circadian rhythm sleep–wake disorder [5]. The goal of therapy is to gradually realign the patient’s sleep and wake times with the desired schedule. The timing of light and melatonin therapies is critical to determining their biologic effects. The key biologic markers are the dim light melatonin onset (DLMO), which typically occurs approximately two hours prior to habitual sleeptime, and the core body temperature minimum (CBT-min), which typically occurs 2-3 hours prior to habitual wake up time. Exposure to light prior to the body temperature minimum will cause the circadian rhythm to delay (i.e. the next night, there will be a tendency to go to bed and wake up later). Light exposure after the core body temperature minimum will cause the circadian system to advance (i.e. the next night, there will be a tendency to go to bed and to wake up earlier). The effect of light is most potent when it is in the blue spectrum and administered close to the CBT-min. Melatonin has the opposite phase response relationship that light has; melatonin given prior to the CBT-min will cause the circadian rhythm to advance (i.e., the next night, there will be a tendency to go to bed and wake up earlier) whereas melatonin administration after the CBT-min will cause the circadian system to delay (i.e., the next night, there will be a tendency to go to bed and wake up later).
The International Classification of Sleep Disorders, third edition (ICSD-3), has the following three diagnostic criteria for all circadian rhythm sleep–wake disorders [6]:
A disrupted sleep–wake pattern, thought to be due to misalignment or malfunction of the circadian system;
A complaint of insomnia, excessive sleepiness, or both;
Suboptimal performance in an important area of functioning (e.g. occupation, education, social life, mental or physical life).
Intrinsic CRSWDs include the following: 1) advanced sleep–wake phase disorder (extreme early bird), 2) delayed sleep–wake phase disorder (extreme night owl), 3) non-24-hour sleep–wake rhythm disorder (drifting circadian rhythm), and 4) irregular sleep–wake rhythm disorder (no rhythm). The two circadian disorders caused by extrinsic factors are 1) shift work disorder and 2) jet lag disorder, both of which are due to behaviorally mediated misalignments of circadian system.
Circadian rhythm disorders can result in clinically significant symptoms of insomnia, excessive daytime sleepiness, and cognitive impairment. In addition, a drastic misalignment of one’s circadian clock with societal norms can often have implications for one’s emotional well-being and social functioning. There are 6 major categories of circadian rhythm sleep–wake disorders which are grouped based on patterns of sleep time:
ICSD-3 Diagnostic Criteria [6]:
An advance (early timing) in the phase of the major sleep episode in relation to the desired or required sleep time and wake-up time, (i.e. the patient feels sleepy too early and wakes up too early).
Symptoms are present for at least three months.
When the patient sleeps of his/her own accord, sleep quality and duration are improved with a consistent but advanced timing of the major sleep episode.
Sleep log and, whenever possible, actigraphy monitoring for at least seven days show a stable advance in sleep period. Both work/school days and free days must be included during the actigraphy monitoring period.
The patient’s symptoms are not better explained by another current sleep, medical, neurological disorder or mental disorder.
Clinical Characteristics: ASWPD is an intrinsic defect of the circadian system in which sleep duration and quality are normal, but where sleep and wake up times are earlier than desired or socially acceptable. Generally, the intrinsic circadian rhythm period is actually shorter than normal.
Patients with ASWPD often report that they are unable to stay awake past 7 PM and tend to wake up around 2-5 AM. If a patient is able to set their own schedule they will obtain adequate sleep and feel refreshed in the morning. However, since due to social obligations they often stay up later than naturally desired while still waking early. This can lead to a sleep deficit over time that leads to daytime sleepiness.
ICSD-3 Diagnostic Criteria [6]: A delay (late timing) in the phase of the major sleep episode in relation to the desired or required sleep time and wake-up time (i.e. the patient does not feel sleepy at bed time and wakes up too late).
The symptoms are present for at least three months.
When patients sleep of their own accord, sleep quality and duration are improved with a consistent but delayed timing of the major sleep episode.
Sleep log and, whenever possible, actigraphy monitoring for at least seven days show a stable delay in sleep period. Both work/school days and free days must be included during the actigraphy monitoring period.
The patient’s symptoms are not better explained by another current sleep, medical, neurological disorder or mental disorder
Clinical Characteristics: DSWPD is one of the most common circadian rhythm sleep–wake disorders, often affecting adolescents and young adults when eveningness tendencies are typically the strongest. This is a defect of the circadian system whereby the sleep/wake cycle is misaligned with the patient’s desired schedule by more than 2 hours. Individuals go to sleep and wake up at substantially later times than desired, which can lead to social consequences such as chronic tardiness at work or school. Delayed bedtimes (usually between 1 and 6 AM), coupled with early awakenings to meet social/occupational/academic obligations, result in a sleep debt that accumulates over time. There is often a high prevalence of comorbid depression, and higher degrees of circadian misalignment correlate with greater severity of depression.
The intrinsic circadian period is generally longer than normal. DSWPD typically emerges during adolescence and can continue into adulthood.
ICSD-3 Diagnostic Criteria [6]:
Chronic or recurrent pattern of irregular sleep and wake episodes throughout the 24-hour period.
Symptoms are present for at least three months.
Sleep log and, whenever possible, actigraphy monitoring for at least seven days, show no major sleep period and multiple irregular sleep bouts (at least three) during a 24-hour period.
The patient’s symptoms are not better explained by another current sleep, medical, neurological disorder or mental disorder.
Clinical Characteristics: ISWRD is characterized by a temporally disorganized sleep and wake pattern such that there are no clearly defined periods of wake and/or sleep. Multiple sleep and wake periods can occur throughout the day, and usually consist of 3 or more short intervals, approximately 1-4 hours each. The longest period generally occurs in the morning between 2 and 6 AM; however, the distribution of sleep and wake periods can vary per individual. The total sleep duration throughout a 24-hour period is generally normal for the individual’s age. Because of the fragmented nature of sleep, individuals can experience frequent napping, excessive daytime sleepiness, and difficulty staying asleep at night.
ICSD-3 Diagnostic Criteria [6]:
History of insomnia, excessive daytime sleepiness, or both, which alternate with asymptomatic episodes, due to misalignment between the 24-hour light–dark cycle and the non-entrained endogenous circadian rhythm of sleep–wake propensity.
Symptoms persist over the course of at least three months.
Daily sleep logs and actigraphy for at least 14 days, preferably longer for blind persons, show a pattern of sleep and wake times that typically delay each day.
The patient’s symptoms are not better explained by another current sleep, medical, neurological disorder or mental disorder.
Clinical Characteristics: N24SWD, also known as non-trained rhythm disorder, is characterized by chronic cycles of sleep and wake that are not always synchronized with the 24-hour environment. There is a gradual, but consistent drift of sleep and wake times later into the day. Attempting to maintain a regular sleep–wake schedule can lead to symptoms of excessive daytime sleepiness, chronic fatigue, early morning awakenings and insomnia. These symptoms alternate with days to weeks in which the patient is asymptomatic, owing to the patient’s endogenous circadian system coinciding with the external 24-hour cycle. Napping is common, and patients often report impairment of social and occupational functioning due to non-entrained sleep–wake schedule.
N24SWD occurs most often in blind individuals. Onset of symptoms usually occurs in 2nd or 3rd decade of life, and men are disproportionally affected compared to women at a ratio of >2: 1 [7].
ICSD-3 Diagnostic Criteria [6]:
Insomnia and/or excessive sleepiness, accompanied by a reduction of total sleep time, which is associated with a recurring work schedule that overlaps with the usual time for sleep.
Symptoms are present and associated with the shift work schedule for at least three months.
Symptoms cause clinically significant impairment in mental, physical, social, occupational, education, or other important areas of functioning.
Sleep log and, whenever possible, actigraphy monitoring for at least 14 days (work and free days) demonstrate a disturbed sleep and wake pattern.
The patient’s symptoms are not better explained by another current sleep, medical, neurological disorder or mental disorder.
Clinical Characteristics: Individuals who work night shift experience difficulty with sleep and alertness at desired times, and are at greater risk for the variety of adverse health outcomes associated with poor sleep. Shift workers generally report 30-90 minutes less sleep compared to those not working shifts, and their sleep quality tends to be more fragmented and of poorer quality. Shift workers also experience difficulty falling and staying asleep, with as many as 20% of shift workers having clinically significant insomnia [8]. During waking hours, night shift workers are more prone to increased sleepiness, decreased neurocognitive function and more significant changes to mood than their non-night shift counterparts.
ICSD-3 Diagnostic Criteria [6]:
Insomnia or excessive daytime sleepiness associated with a reduction of total sleep time coinciding with jet travel across at least two time zones
Impaired daytime function, general fatigue, or somatic symptoms that begin within two days of travel
The sleep disturbance cannot be explained by another disorder.
Clinical Characteristics: JLD occurs when an individual travels through time zones faster that the endogenous circadian rhythm can adjust, resulting in desynchrony between the external light–dark cycle and one’s internal clock. Symptoms of JLD include difficulty falling and staying asleep, excessive daytime sleepiness, generalized fatigue, impaired daytime performance, and various somatic symptoms (most commonly gastrointestinal) that begin 1 to 2 days post-travel [8].
In addition to number of time zones traveled, the severity of jet lag is affected by the direction of travel. Eastward travel leads to more difficulty with falling asleep and is more difficult to adjust to, while westward travel is more disruptive to sleep maintenance.
Genetic studies have shown possible links to mutations in the
The pathophysiology of DSWPD is multifactorial [2, 3] l. It is hypothesized that certain exogenous factors, such as increased exposure to evening light and greater sensitivity to evening light may play a role in development of DSWPD. Genetic factors may play a role, but their exact contribution is less understood than is the case for ASWPD.
DSWPD typically emerges during adolescence and can continue into adulthood. Males and females seem to be affected equally. Peak age appears to be 21 years old in males and 17 years old in females. There is a large variability in its reported prevalence, with population study estimates ranging from <1% up to 10% [1, 2, 3]. Patients with hepatic cirrhosis are also affected at much higher rates (33%).
ISWRD is most commonly seen in individuals with neurodegenerative conditions, particularly those with Alzheimer’s disease and late-afternoon sundowning [1, 2, 3]. It is also more common in those with traumatic brain injury, in children with developmental delay, in patients with schizophrenia, and particularly in patients who are institutionalized. It is hypothesized that intrinsic circadian dysfunction, coupled with decreased exposure to external synchronizing agents such as light and social activity, are factors in ISWRD.
The etiology of N24SWD is related to disruption of the portion of the circadian system responsible for capturing photic stimuli in the retina. Pathologies that lead to vision loss often but not necessarily impact this system. Thus, N24SWD occurs most often in blind individuals, with reports of 50% of blind patients diagnosed with N24SWD and up to 70% of blind individuals having symptoms of chronic sleep disturbance [2, 3, 7]. Men are disproportionally affected compared to women at a ratio of >2:1. N24SWD is rare, but has been reported, in sighted individuals. In sighted individuals, N24SWD is thought to be a severe form of delayed sleep phase disorder where entrainment to light can no longer be effective [7].
The mechanism behind SWD is thought to be governed by disruptions of 2 physiologic processes [1, 2, 3]. The first is related to one’s homeostatic drive for sleep, which increases throughout wakefulness. The second is one’s intrinsic rhythmic oscillations for sleep and wake periods, which is governed by the circadian pacemaker. This latter process is calibrated by environmental clues such as light. Both the homeostatic process and the circadian process are disrupted in SWD.
Individuals at greatest risk for SWD are those that work rotating night shifts, rather than permanent night shifts, because they are never able to adapt to a stable sleep–wake pattern [8]. In addition, those with other sleep comorbidities can have synergistic effects of sleep disturbance, which lead to symptomatic worsening.
JLD results from desynchrony between the external light–dark cycle and an individual’s internal clock when travel across time zones occurs more quickly than the endogenous circadian rhythm can adjust. The prevalence of this condition is poorly defined [8]. Factors that affect jet lag severity include the direction of travel and number of time zones traveled, the person’s ability to sleep during travel, individual variations in circadian timing, presence of light cues at destination, and intake of alcohol and caffeine.
ASWPD is a clinical diagnosis and should be suspected in individuals who have a history of early sleep onset and wake times. It is important to obtain a detailed sleep history that addresses sleep patterns, napping habits, and daytime symptoms of sleepiness, cognitive changes, or mood changes. Targeted questions should be asked about difficulty falling or staying asleep and sleep quality both during the patient’s current schedule and during times when he/she has followed the preferred schedule. Obtaining collateral history from a bed partner is often useful.
Patients with suspected ASWPD should keep a sleep log for at least 7 days, preferably 14 days, including both weekdays and weekends (Figure 1). Actigraphy is helpful to supplement the sleep diary, especially if the history is unreliable. Melatonin levels, through salivary or plasma sampling, may show early melatonin onset or earlier phase of melatonin metabolite excretion via urinary 6-sulfatoxymelatonin, although these tests are not widely available for clinical purposes [2, 3, 9].
This 14-day sleep diary of a patient with advanced sleep–wake phase disorder (ASWPD) depicts an early sleep onset (7-8 pm) and early wake time (3-4 am). The total duration of sleep time (shaded box) remains normal at 7-8 hours. Individuals with ASWPD usually do not have symptoms if they are allowed to sleep per their preferred schedule; however, when tasked with staying up later than their usual bedtime, they can have significant difficulty. This circadian rhythm is more prevalent in older adults who may not have the same work or school obligations (“ret” represents “retired”) that can contribute to other circadian rhythm disorders, such as delayed sleep–wake phase disorder.
DSWPD is a clinical diagnosis and should be suspected when individuals report consistent bedtime and wake times that are significantly later than social norms. Bedtimes are often more informative than wake times, which are usually dictated by social or work/school obligations. It is also helpful to ask about sleep patterns during weekends, and during unrestricted periods such as vacations, when patients are able to sleep based on their own circadian preference (Figure 2). Sleep logs of at least 7 days, including both school/workdays and weekends, are needed to identify specific patterns [9]. It is important to inquire about other social factors, such as caffeine use later in the day, or excessive use of light-emitting devices before bedtime, which can also delay sleep onset.
This 14-day sleep diary of a patient with delayed sleep–wake phase disorder (DSWPD) depicts variable sleep depending on the day of the week. The upwards arrow indicates “time in bed” while the downwards arrow indicates “time out of bed”. The shaded area represents sleep time of the patient. For example, in this diagram, the individual goes to bed between 9 and 10 pm on school days but is not able to sleep until 2-3 am. Due to his fixed school start time, he has to get out of bed between 6 and 7 am, leaving only 4-5 hours of sleep time (shaded box). However, on weekends (Friday and Saturday nights), he goes to sleep at his desired time of 2-3 am and wakes up at his desired time between 1 and 2 pm, accounting for a total sleep time of 10-11 hours. This variation in sleep pattern, based on day of the week, is classic for DSWPD, and results in the symptoms described by those with this condition.
Wrist actigraphy is another means of obtaining more quantitative data [9]. If the actigraph has a photo sensor it can provide information about the correlation between an individual’s light exposure and sleep time. Polysomnography is not typically indicated, unless there is clinical suspicion for another comorbid sleep disorder, such as sleep-disordered breathing. Salivary melatonin assays are available; however, these assays are used primarily as research tools and not for clinical diagnosis.
The diagnosis of ISWRD is made by clinical history, with supplemental information from wrist actigraphy. There must be a reported chronic or recurrent pattern of irregular sleep and wake episodes throughout a 24-hour period, with a minimum of 3 cycles occurring during that time (Figure 3). A sleep log, and/or actigraphy must document these cycles for at least 7 days (preferably 14 days), and symptoms must be present for at least 3 months [9].
This 14-day sleep diary of a patient with irregular sleep-wake rhythm disorder (ISWRD) depicts an irregular pattern of sleep throughout each 24-hour period. During each day, there are at least 3 sleep cycles occurring in a recurrent, but irregular fashion. The total sleep duration (shaded box) is usually normal for an individual’s age, however there is no clearly defined pattern. This disorder is more prevalent in older individuals and in those with dementia.
Polysomnography is not usually indicated, unless there is concern that the sleep disturbance is better explained by another disorder (e.g., a sleep-related breathing disorder).
Sleep diary and actigraphy are important in confirming a non-entrained sleep pattern and will also show a gradual drift of onset and offset of the sleep–wake rhythm (Figure 4). In order to appreciate the drift, this data should be obtained for at least 2 weeks, and symptoms should be present for at least 3 months [9].
This 14-day sleep diary of a patient with non-24 sleep–wake phase disorder (N24SWPD) depicts a gradual drift in onset and offset of the sleep duration (shaded box), usually by 30 minutes each day. In order to best appreciate this drift, a sleep diary or actigraphy should be obtained for at least 2 weeks, and ideally more if possible. This circadian rhythm disorder is most prevalent in individuals who are blind.
Other measurements such as continuous core body temperature or serial measurements of melatonin can be confirmatory as they also exhibit a similarly non-24-hour drifting rhythm. However, these procedures are not required to make the diagnosis of N24SWD.
Attention should be paid to distinguish N24SWD from DSWPD, as these patients can display a similar evening phenotype and up to 25% of N24SWD are often initially misdiagnosed as DSWPD [2, 3, 9].
SWD is best assessed through careful sleep history and sleep diary. Particular attention should be paid to a patient’s occupation, history with shift work disorder with prior jobs, and impaired task performance at work. Factors specific to the patient’s home environment (i.e. lack of dedicated dark space for sleeping, noise levels during the day, etc.) can further reduce the likelihood that the patient can obtain restorative sleep. The clinical history should also inquire about features of other comorbid sleep, medical, and mental disorders. A sleep diary should be obtained for at least 2 weeks and should capture both work and non-work days [9]. Validated questionnaires, such as the Insomnia Severity Index and Epworth Sleepiness Scale, can be used but are not required to diagnose SWD.
Wrist actigraphy, especially when performed with an actigraphy that includes a photosensor, can better quantify sleep duration. There is no need for polysomnography unless there is a clinical suspicion for a comorbid sleep disorder, such as a sleep-related breathing disorder. Melatonin sampling is done in research settings, but is not routinely used in the clinical setting.
Clinical history is the most important tool. The clinician should specifically obtain information about number of time zones crossed and the timeline of symptom occurrence. JLD is often confused with travel fatigue since there are many overlapping symptoms; however, the distinction is that travel fatigue is not dependent on the number of time zones traveled and tends to resolve quicker.
Since JLD is transient, and clinical history is usually clear, there is typically no role for formal diagnostic testing.
Bright light therapy in the early evening is the primary treatment for ASWPD, with the goal to delay the circadian phase so it is better aligned to desired sleep and wake times [5, 9]. Patients should use a bright light that filters out ultraviolet rays (2,500 to 10,000 lux) for 1-3 hours per day, starting at the time when they first experience sleepiness in the evening (usually around 7-9 pm). This should be done to gradually delay bedtime by 1-2 hours each day until desired times are met (Figure 5).
For individuals with advanced sleep–wake phase disorder (ASWPD), bright light therapy should be given for 1-3 hours per day in the evening starting at the time of sleepiness. This will gradually shift the sleep time until the desired schedule is met.
There is no strong evidence to support pharmacologic therapy in ASWPD. Melatonin in the morning can theoretically shift the clock to a later phase, however the sedating effect of melatonin often limits morning use. Early morning hypnotics to resume sleep can lead to daytime grogginess and hangover effect and thus are generally discouraged.
Management of DSWPD consists of
For those who fail to respond to behavioral therapies alone, timed melatonin can supplement these behavioral modifications. One reasonable approach would be to take melatonin daily, approximately 3-5 hours prior to desired sleep time [5]. Doses may vary from 0.5-5 mg, though it is best to use the lowest effective dose. Melatonin dose and timing can be strategically adjusted based on clinical response. Relapse tends to occur in high rates (80-90%) once melatonin is discontinued [3, 5].
Morning light therapy can be coupled with the above interventions. Commercial light boxes that either contain a broad spectrum of white light or narrow spectrum of blue light (2,000-10,000 lux) should be used every morning between just after typical wake-up time, with gradual advancing of the sleep–wake time until the desired time is reached [5, 9]. Care should be taken to avoid light exposure earlier than 2-3 hours before the habitual wake up time because light prior to the core body temperature minimum may cause further delays in circadian phase (Figure 6).
For individuals with delayed sleep–wake phase disorder (DSWPD), treatment can consist of low-dose melatonin (to be taken ~3-5 hours prior to desired sleep time), along with phototherapy in the morning upon awakening. This combination can cause gradual advancement in sleep phase.
Treatment of ISWRD involves using behavioral strategies to restructure an individual’s daily routine, and to optimize sleep hygiene to better consolidate sleep times and improve daytime alertness. It is important to create a cognitively enriched and socially interactive environment during the day to maintain alertness and prevent excessive napping. At night, measures should be taken to reduce noise and light, and to prevent sleep disturbances caused by other factors (e.g., nocturia).
Light therapy remains the most effective intervention during the day. Exposure to 3,000-5,000 lux of light for at least 2 hours in the morning has been shown to improve daytime alertness, reduce napping, and consolidate nightly sleep [5].
Melatonin can also be used for management of ISWRD, though positive results with melatonin use are less consistent than with treatment of other CRSWDs. Melatonin doses of 1-5 mg can be used 30 min prior to bedtime to facilitate sleep, and melatonin is more effective if used in conjunction with light therapy [3, 5]. Controlled-release formulation can be more effective than immediate release in this specific patient population with ISWRD.
Treatment for N24SWD includes attempting to re-synchronize the circadian pacemaker using behavioral approaches and pharmacologic therapy. Education regarding proper sleep hygiene and maintenance of regularly scheduled timing of meals, social activities and physical exercise is important.
Tasimelteon, a melatonin agonist with affinity for the MT1 and MT2 receptors, is Food and Drug Administration (FDA) approved for use in N24SWD [5]. Melatonin can also be used to achieve gradual re-alignment. Higher doses (3-10 mg) may be given 1-2 hours prior to the desired bedtime for the first month. Entrainment usually occurs within 5-10 weeks, after which low-dose melatonin (0.5-1 mg) should be maintained to prevent relapse [5, 7].
Less robust evidence exists for bright light therapy, though it has been shown to be effective in sighted individuals with N24SWD and can be used in the early morning after awakenings.
Management of SWD should first start with changes to work schedule, if possible, with adjustments to sleep hygiene. A regular daytime sleep schedule that can be followed, even during non-working days, is recommended to promote stability to the circadian system. This can be organized around an individual’s personal schedule, but should ideally incorporate at least a 5 to 6-hour block of uninterrupted sleep. The sleep environment should be optimized to reduce sound, light, unfavorable temperatures and other factors that can interfere with sleep. Light blocking window shades can be used, and a temperature setting between 65 and 70 degrees Fahrenheit is optimal.
While at work, individuals can use continuous exposure to high-intensity light (2,000-10,000 lux) for as little as four 20-minute periods during the first part of the nigh [8] t. Use of blue light-blocking goggles in the morning and general avoidance of morning light help the circadian rhythm remain adapted to the shift work schedule. Additionally, short naps (<45 minutes) prior to the start of the work shift are a low-risk intervention that can be used to promote wakefulness during the shift.
If these behavioral measures fail, medication therapy is the next step. Modafinil (200 mg) and armodafinil (150 mg) are FDA approved for shift work disorder and can be used during the first part of the night [5, 8]. Small doses of caffeine (100-250 mg, equivalent to a small cup of coffee) can also be used during the first part of the night. Short-acting hypnotics such as zolpidem and zaleplon can be used to promote sleep during the daytime; use of hypnotics must be introduced cautiously to prevent nocturnal grogginess (during work hours). Exogenous melatonin 30 min prior to desired bedtime can be used, although the evidence for this is poor [5].
The treatment strategy depends on the length of trip, number of time zones traveled, and direction of travel [9]. Trips less than 3 days are usually too short to create problematic jet lag symptoms. Treatment planning is best done in anticipation of travel.
For eastward travel on trips longer than 3 days and up to 7 time zones, a strategy using timed light exposure and melatonin can help advance the circadian rhythm (making natural bedtime and wake time earlier) to the new time zone. Bright light therapy can be started up to 3 days prior to departure to start the advancing process. Individuals should wake up about 1 hour prior to usual wake-up time and expose themselves to bright light for at least an hour. Upon arrival at destination, strategic light exposure throughout the afternoon and light avoidance during the early morning can help with this circadian realignment. The specific timing of light exposure is based on when the patient’s habitual core body temperature minimum (CBT-min) occurs, which is usually 3 hours before habitual wake-up time. Light exposure after the CBT-min causes circadian phase advancement, whereas light exposure before the CBT-min causes a circadian phase delay and is thus counterproductive for eastward travel [8].
Timed melatonin (3-5 mg) taken at the desired destination bedtime can be used concurrently with prescribed light exposure. Melatonin should first be taken on the evening of arrival and continued for up to 5 days. Hypnotics have been used by patients during travel, but these medications can lead to impaired daytime performance, and thus are generally not recommended for management of JLD. Caffeine can help mitigate daytime sleepiness. Other stimulants (e.g. modafinil, armodafinil) can offset daytime sleepiness though these medications are not FDA approved for JLD. For eastward travel that crosses more than 8 time zones, it is often easier to pursue a circadian phase delay, rather than a circadian phase advance, to mitigate symptoms of JLD. This approach generally involves seeking out early morning light at the destination and avoiding light exposure in the afternoon.
Westward travel requires a delay in the circadian rhythm (later bed times and wake times) to adjust to the destination time zone. It is advised to seek bright light before the calculated CBT-min at the destination (based on the home time zone). For example, if one’s habitual wake up time in Boston is 8 am Eastern Standard Time (EST), the habitual CBT-min will be at 5 am EST. If that individual travels to Westward to Hawaii (5-hour time zone delay), the CBT-min will occur at midnight EST, thus bright light exposure should be given prior to that time. Melatonin or hypnotics are generally not required in JLD associated with westward travel.
Resources such as www.jetlagrooster.com and the British Airways jet lag advisor [10] can help individuals plan light and melatonin exposure including in preparation for travel.
Treatment of circadian rhythm sleep wake disorders can often be challenging, and requires an individualized and multimodal approach, incorporating behavioral strategies such as directed light exposure, and appropriately timed melatonin. Overall effectiveness can be improved by combining these measures with chronotherapy, which gradually and progressively shifts the circadian clock.
Patients tend to respond well initially, however often require significant personal investment to maintain their newly desired schedule, and relapse to prior sleep schedule is not uncommon. It is essential to have the support of family, friends, teachers and coworkers to establish and maintain a sustainable new sleeping schedule.
When treating circadian rhythm sleep wake disorders, it is important to optimize the treatment of other comorbid medical conditions, especially psychiatric and mood disorders. This is especially true in adolescents and older patients. The importance of addressing sleep hygiene and one’s sleep environment cannot be overstated as a critical component of treatment.
The treatment of CRSWDs remain a challenge, in part because of the scarcity of large, multicenter placebo-controlled trials using phototherapy and pharmacotherapy. However there have been recent rapid advances in our understanding of the genetics of circadian rhythm regulation, which may lead to improved diagnostic tools and treatments. For example, technology involving DNA manipulation has been used to generate Cry1/Cry2 knockout animals to further study the expression of specific genes on circadian function [11]. This opens up avenue for new therapeutic approaches in many disorders, specifically neuropsychiatric conditions, associated with circadian rhythm disturbance.
Circadian rhythm disorders are common conditions that occur as a result of misalignment between an individual’s intrinsic time-keeping system, and extrinsic cues. There are usually multifactorial contributions, including genetic influences, and behaviorally induced elements. Effective treatment approaches largely revolve around strategically timed melatonin and phototherapy to shift one’s sleep phase to a more desired time. Consultation with a sleep medicine clinician may be helpful if symptoms persist, or to clarify a suspected circadian rhythm disorder.
The authors wish to acknowledge faculty at the Northwestern University Center for Circadian & Sleep Medicine, and the UCLA Sleep Disorders Center for their significant contributions towards our training and sleep medicine education.
Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. 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Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. 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He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null}]},{type:"book",id:"7839",title:"Malaria",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7839.jpg",slug:"malaria",publishedDate:"December 11th 2019",editedByType:"Edited by",bookSignature:"Fyson H. Kasenga",hash:"91cde4582ead884cb0f355a19b67cd56",volumeInSeries:4,fullTitle:"Malaria",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga",profilePictureURL:"https://mts.intechopen.com/storage/users/86725/images/system/86725.jpg",biography:"Dr. Kasenga is a graduate of Tumaini University, Kilimanjaro Christian Medical College, Moshi, Tanzania and Umeå University, Sweden. He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). Dr. Kasenga is married to Grace and blessed with three children, a son and two daughters: Happy, Lettice and Sungani.",institutionString:"Malawi Adventist University",institution:{name:"Malawi Adventist University",institutionURL:null,country:{name:"Malawi"}}}]}]},openForSubmissionBooks:{paginationCount:7,paginationItems:[{id:"11476",title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg",hash:"8d41fa5f3a5da07469bbc121594bfd3e",secondStepPassed:!0,currentStepOfPublishingProcess:4,submissionDeadline:"March 24th 2022",isOpenForSubmission:!0,editors:[{id:"335401",title:"Prof.",name:"Margherita",surname:"Mori",slug:"margherita-mori",fullName:"Margherita Mori"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11460",title:"Pluralistic Approaches for Conservation and Sustainability in Biodiversity",coverURL:"https://cdn.intechopen.com/books/images_new/11460.jpg",hash:"ab014f8ed1669757335225786833e9a9",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 22nd 2022",isOpenForSubmission:!0,editors:[{id:"101105",title:"Dr.",name:"Gopal",surname:"Shukla",slug:"gopal-shukla",fullName:"Gopal Shukla"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11475",title:"Food Security Challenges and Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11475.jpg",hash:"090302a30e461cee643ec49675c811ec",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 5th 2022",isOpenForSubmission:!0,editors:[{id:"292145",title:"Dr.",name:"Muhammad",surname:"Haseeb Ahmad",slug:"muhammad-haseeb-ahmad",fullName:"Muhammad Haseeb Ahmad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11450",title:"Environmental Impacts of COVID-19 Pandemic on the World",coverURL:"https://cdn.intechopen.com/books/images_new/11450.jpg",hash:"a58c7b02d07903004be70f744f2e1835",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"63465",title:"Prof.",name:"Mohamed Nageeb",surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11477",title:"Public Economics - 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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