179 results on '"Theotokis P"'
Search Results
2. Ontogeny of Skin Stem Cells and Molecular Underpinnings
- Author
-
Iasonas Dermitzakis, Despoina Dimitria Kampitsi, Maria Eleni Manthou, Paschalis Evangelidis, Efstratios Vakirlis, Soultana Meditskou, and Paschalis Theotokis
- Subjects
skin ,stem cells ,epidermis ,hair follicle ,sebaceous glands ,sweat glands ,Biology (General) ,QH301-705.5 - Abstract
Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.
- Published
- 2024
- Full Text
- View/download PDF
3. Skin Development and Disease: A Molecular Perspective
- Author
-
Iasonas Dermitzakis, Despoina Chatzi, Stella Aikaterini Kyriakoudi, Nikolaos Evangelidis, Efstratios Vakirlis, Soultana Meditskou, Paschalis Theotokis, and Maria Eleni Manthou
- Subjects
skin ,epidermis ,appendages ,hair follicle ,sweat glands ,development ,Biology (General) ,QH301-705.5 - Abstract
Skin, the largest organ in the human body, is a crucial protective barrier that plays essential roles in thermoregulation, sensation, and immune defence. This complex organ undergoes intricate processes of development. Skin development initiates during the embryonic stage, orchestrated by molecular cues that control epidermal specification, commitment, stratification, terminal differentiation, and appendage growth. Key signalling pathways are integral in coordinating the development of the epidermis, hair follicles, and sweat glands. The complex interplay among these pathways is vital for the appropriate formation and functionality of the skin. Disruptions in multiple molecular pathways can give rise to a spectrum of skin diseases, from congenital skin disorders to cancers. By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, this narrative review aims to present a comprehensive understanding of these aspects. Such knowledge paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.
- Published
- 2024
- Full Text
- View/download PDF
4. Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery
- Author
-
Xiaolei Zhang, Pantazis I. Theotokis, Nicholas Li, the SHaRe Investigators, Caroline F. Wright, Kaitlin E. Samocha, Nicola Whiffin, and James S. Ware
- Subjects
Genetic constraint ,Missense variant interpretation ,Clinical interpretation ,Protein domains ,Developmental disorders ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.
- Published
- 2024
- Full Text
- View/download PDF
5. Fatal misdiagnosis of progressive disseminated histoplasmosis
- Author
-
Anthi Vasilopoulou, Marina Spaho, Paschalis Theotokis, Alexandra Grekou, Soultana Meditskou, and Maria Eleni Manthou
- Subjects
Disseminated histoplasmosis ,Non-endemic area ,Histoplasma capsulatum ,Misdiagnosis ,Differential diagnosis ,Erythema nodosum ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Disseminated histoplasmosis is the form of a mycosis caused by the fungus Histoplasma capsulatum that mainly occurs in immunosuppressed hosts, usually with non-specific symptoms. In non-endemic areas, where the disease is rarely involved in the differential diagnosis, a delay in treatment may lead to severe medical complications. Due to the rising prevalence of disseminated histoplasmosis in these areas, a thorough medical history is regarded as the decisive factor in prompt diagnosis of the disease.We, herein, report the case of an immunocompetent Greek farmer with disseminated histoplasmosis whose condition was initially misdiagnosed, and the consequential inadequate treatment led to his death.
- Published
- 2024
- Full Text
- View/download PDF
6. Exploring Myelin Dynamics in Demyelinating Disorders at the Molecular Level
- Author
-
Paschalis Theotokis
- Subjects
n/a ,Biology (General) ,QH301-705.5 - Abstract
Investigating the subtle molecular mechanisms underlying demyelinating disorders of the central nervous system (CNS) is pivotal in advancing therapeutic strategies and improving patient outcomes [...]
- Published
- 2024
- Full Text
- View/download PDF
7. Application of Mesenchymal Stem Cells in Female Infertility Treatment: Protocols and Preliminary Results
- Author
-
Sofia Chatzianagnosti, Iasonas Dermitzakis, Paschalis Theotokis, Eleni Kousta, George Mastorakos, and Maria Eleni Manthou
- Subjects
molecular techniques ,mesenchymal stem cells ,stem cell therapy ,signaling pathways ,reproductive system ,infertility treatment ,Science - Abstract
Infertility is a global phenomenon that impacts people of both the male and the female sex; it is related to multiple factors affecting an individual’s overall systemic health. Recently, investigators have been using mesenchymal stem cell (MSC) therapy for female-fertility-related disorders such as polycystic ovarian syndrome (PCOS), premature ovarian failure (POF), endometriosis, preeclampsia, and Asherman syndrome (AS). Studies have shown promising results, indicating that MSCs can enhance ovarian function and restore fertility for affected individuals. Due to their regenerative effects and their participation in several paracrine pathways, MSCs can improve the fertility outcome. However, their beneficial effects are dependent on the methodologies and materials used from isolation to reimplantation. In this review, we provide an overview of the protocols and methods used in applications of MSCs. Moreover, we summarize the findings of published preclinical studies on infertility treatments and discuss the multiple properties of these studies, depending on the isolation source of the MSCs used.
- Published
- 2024
- Full Text
- View/download PDF
8. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions
- Author
-
Josephs, Katherine S., Roberts, Angharad M., Theotokis, Pantazis, Walsh, Roddy, Ostrowski, Philip J., Edwards, Matthew, Fleming, Andrew, Thaxton, Courtney, Roberts, Jason D., Care, Melanie, Zareba, Wojciech, Adler, Arnon, Sturm, Amy C., Tadros, Rafik, Novelli, Valeria, Owens, Emma, Bronicki, Lucas, Jarinova, Olga, Callewaert, Bert, Peters, Stacey, Lumbers, Tom, Jordan, Elizabeth, Asatryan, Babken, Krishnan, Neesha, Hershberger, Ray E., Chahal, C. Anwar A., Landstrom, Andrew P., James, Cynthia, McNally, Elizabeth M., Judge, Daniel P., van Tintelen, Peter, Wilde, Arthur, Gollob, Michael, Ingles, Jodie, and Ware, James S.
- Published
- 2023
- Full Text
- View/download PDF
9. High-intensity interval training attenuates development of autoimmune encephalomyelitis solely by systemic immunomodulation
- Author
-
Goldberg, Yehuda, Segal, Shir, Hamdi, Liel, Nabat, Hanan, Fainstein, Nina, Mediouni, Efrat, Asis, Yarden, Theotokis, Paschalis, Salamotas, Ilias, Grigoriadis, Nikolaos, Katz, Abram, Ben-Hur, Tamir, and Einstein, Ofira
- Published
- 2023
- Full Text
- View/download PDF
10. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions
- Author
-
Katherine S. Josephs, Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D. Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C. Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey Peters, Tom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E. Hershberger, C. Anwar A. Chahal, Andrew P. Landstrom, Cynthia James, Elizabeth M. McNally, Daniel P. Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, and James S. Ware
- Subjects
Inherited cardiac conditions ,Inheritance ,Allelic requirement ,Disease mechanism ,Gene curation ,Genomic variant filtering ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.
- Published
- 2023
- Full Text
- View/download PDF
11. High-intensity interval training attenuates development of autoimmune encephalomyelitis solely by systemic immunomodulation
- Author
-
Yehuda Goldberg, Shir Segal, Liel Hamdi, Hanan Nabat, Nina Fainstein, Efrat Mediouni, Yarden Asis, Paschalis Theotokis, Ilias Salamotas, Nikolaos Grigoriadis, Abram Katz, Tamir Ben-Hur, and Ofira Einstein
- Subjects
Medicine ,Science - Abstract
Abstract The impact of high-intensity interval training (HIIT) on the central nervous system (CNS) in autoimmune neuroinflammation is not known. The aim of this study was to determine the direct effects of HIIT on the CNS and development of experimental autoimmune encephalomyelitis (EAE). Healthy mice were subjected to HIIT by treadmill running and the proteolipid protein (PLP) transfer EAE model was utilized. To examine neuroprotection, PLP-reactive lymph-node cells (LNCs) were transferred to HIIT and sedentary (SED) mice. To examine immunomodulation, PLP-reactive LNCs from HIIT and SED donor mice were transferred to naïve recipients and analyzed in vitro. HIIT in recipient mice did not affect the development of EAE following exposure to PLP-reactive LNCs. HIIT mice exhibited enhanced migration of systemic autoimmune cells into the CNS and increased demyelination. In contrast, EAE severity in recipient mice injected with PLP-reactive LNCs from HIIT donor mice was significantly diminished. The latter positive effect was associated with decreased migration of autoimmune cells into the CNS and inhibition of very late antigen (VLA)-4 expression in LNCs. Thus, the beneficial effect of HIIT on EAE development is attributed solely to systemic immunomodulatory effects, likely because of systemic inhibition of autoreactive cell migration and reduced VLA-4 integrin expression.
- Published
- 2023
- Full Text
- View/download PDF
12. Genetic Identity of Neural Crest Cell Differentiation in Tissue and Organ Development
- Author
-
Stella Aikaterini Kyriakoudi, Despoina Chatzi, Iasonas Dermitzakis, Sofia Gargani, Maria Eleni Manthou, Soultana Meditskou, and Paschalis Theotokis
- Subjects
neural crest cells ,genes ,epithelial-mesenchymal transition ,animal models ,model organisms ,congenital anomalies ,Biochemistry ,QD415-436 ,Biology (General) ,QH301-705.5 - Abstract
The neural crest (NC), also known as the “fourth germ layer”, is an embryonic structure with important contributions to multiple tissue and organ systems. Neural crest cells (NCCs) are subjected to epithelial to mesenchymal transition and migrate throughout the embryo until they reach their destinations, where they differentiate into discrete cell types. Specific gene expression enables this precise NCCs delamination and colonization potency in distinct and diverse locations therein. This review aims to summarize the current experimental evidence from multiple species into the NCCs specifier genes that drive this embryo body axes segmentation. Additionally, it attempts to filter further into the genetic background that produces these individual cell subpopulations. Understanding the multifaceted genetic makeup that shapes NC-related embryonic structures will offer valuable insights to researchers studying organogenesis and disease phenotypes arising from dysmorphogenesis.
- Published
- 2024
- Full Text
- View/download PDF
13. The Impact of Lifestyle on the Secondary Sex Ratio: A Review
- Author
-
Iasonas Dermitzakis, Paschalis Theotokis, Evangelos Axarloglou, Efthymia Delilampou, Dimosthenis Miliaras, Soultana Meditskou, and Maria Eleni Manthou
- Subjects
lifestyle ,secondary sex ratio ,diet ,psychological distress ,socioeconomics ,occupation ,Science - Abstract
The secondary sex ratio (SSR), indicating the ratio of male to female live births, has garnered considerable attention within the realms of reproductive biology and public health. Numerous factors have been posited as potential trendsetters of the SSR. Given the extensive research on the impact of daily behaviors and habits on individuals’ reproductive health, there is a plausible suggestion that lifestyle choices may also influence the SSR. By synthesizing the existing literature on the current research field, this comprehensive review indicates that an elevated SSR has been associated with an increased intake of fatty acids and monosaccharides, proper nutrition, higher educational levels, financial prosperity, and favorable housing conditions. On the other hand, a decreased SSR may be linked to undernutrition, socioeconomic disparities, and psychological distress, aligning with the Trivers–Willard hypothesis. Occupational factors, smoking habits, and cultural beliefs could also contribute to trends in the SSR. Our review underscores the significance of considering the aforementioned factors in studies examining the SSR and emphasizes the necessity for further research to unravel the mechanisms underpinning these connections. A more profound comprehension of SSR alterations due to lifestyle holds the potential to adequately develop public health interventions and healthcare strategies to enhance reproductive health and overall well-being.
- Published
- 2024
- Full Text
- View/download PDF
14. Systemic LPS Administration Stimulates the Activation of Non-Neuronal Cells in an Experimental Model of Spinal Muscular Atrophy
- Author
-
Eleni Karafoulidou, Evangelia Kesidou, Paschalis Theotokis, Chrystalla Konstantinou, Maria-Konstantina Nella, Iliana Michailidou, Olga Touloumi, Eleni Polyzoidou, Ilias Salamotas, Ofira Einstein, Athanasios Chatzisotiriou, Marina-Kleopatra Boziki, and Nikolaos Grigoriadis
- Subjects
spinal muscular atrophy ,SMNΔ7 ,microglia ,astrocytes ,gut–brain axis ,gut–skeletal muscle axis ,Cytology ,QH573-671 - Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells’ reactive phenotype.
- Published
- 2024
- Full Text
- View/download PDF
15. CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease
- Author
-
Iasonas Dermitzakis, Paschalis Theotokis, Paschalis Evangelidis, Efthymia Delilampou, Nikolaos Evangelidis, Anastasia Chatzisavvidou, Eleni Avramidou, and Maria Eleni Manthou
- Subjects
CNS border-associated macrophages ,tissue-resident macrophages ,origin ,yolk sac ,molecular cues ,development ,Biology (General) ,QH301-705.5 - Abstract
Being immune privileged, the central nervous system (CNS) is constituted by unique parenchymal and non-parenchymal tissue-resident macrophages, namely, microglia and border-associated macrophages (BAMs), respectively. BAMs are found in the choroid plexus, meningeal and perivascular spaces, playing critical roles in maintaining CNS homeostasis while being phenotypically and functionally distinct from microglial cells. Although the ontogeny of microglia has been largely determined, BAMs need comparable scrutiny as they have been recently discovered and have not been thoroughly explored. Newly developed techniques have transformed our understanding of BAMs, revealing their cellular heterogeneity and diversity. Recent data showed that BAMs also originate from yolk sac progenitors instead of bone marrow-derived monocytes, highlighting the absolute need to further investigate their repopulation pattern in adult CNS. Shedding light on the molecular cues and drivers orchestrating BAM generation is essential for delineating their cellular identity. BAMs are receiving more attention since they are gradually incorporated into neurodegenerative and neuroinflammatory disease evaluations. The present review provides insights towards the current understanding regarding the ontogeny of BAMs and their involvement in CNS diseases, paving their way into targeted therapeutic strategies and precision medicine.
- Published
- 2023
- Full Text
- View/download PDF
16. A Genotype-phenotype Taxonomy of Hypertrophic Cardiomyopathy
- Author
-
Lara Curran, BSc, Antonio De Marvao, PhD, Paolo Inglese, PhD, Kathryn McGurk, PhD, Adam Clement, PhD, Sean Zheng, Surui Li, PhD, Chee Jian Pua, BSc, Mit Shah, Mina Jafari, PhD, Pantazis Theotokis, PhD, Rachel Buchan, Sean Jurgens, Claire Raphael, PhD, John Baksi, PhD, Antonis Pantazis, PhD, Brian Halliday, PhD, Dudley Pennell, MD, PhD, Wenjia Bai, PhD, Calvin Chin, MD, PhD, Rafik Tadros, PhD, Connie Bezzina, PhD, Hugh Watkins, PhD, Stuart Cook, PhD, Sanjay Prasad, James Ware, PhD, and Declan O'Regan, PhD
- Subjects
Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2024
- Full Text
- View/download PDF
17. Editorial: Molecular and cellular interactions of myelin in neurodevelopmental & neurodegenerative disorders
- Author
-
Paschalis Theotokis, Lida Zoupi, Marie-Ève Tremblay, and Jing-Wei Zhao
- Subjects
myelin ,neurodevelopment ,neurodegenerative disorders ,multiple sclerosis ,caloric mimetics ,peripheral nerve alterations ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
- Full Text
- View/download PDF
18. Effects of Whole-Body Vibration and Manually Assisted Locomotor Therapy on Neurotrophin-3 Expression and Microglia/Macrophage Mobilization Following Thoracic Spinal Cord Injury in Rats
- Author
-
Diana Schaufler, Maria Eleni Manthou, Paschalis Theotokis, Svenja Rink-Notzon, and Doychin N. Angelov
- Subjects
microglia ,Iba1 ,neurotrophin-3 ,spinal cord injury ,vibration therapy ,functional recovery ,Biology (General) ,QH301-705.5 - Abstract
Microglial cells play an important role in neuroinflammation and secondary damages after spinal cord injury (SCI). Progressive microglia/macrophage inflammation along the entire spinal axis follows SCI, and various factors may determine the microglial activation profile. Neurotrophin-3 (NT-3) is known to control the survival of neurons, the function of synapses, and the release of neurotransmitters, while also stimulating axon plasticity and growth. We examined the effects of whole-body vibration (WBV) and forms of assisted locomotor therapy, such as passive flexion–extension (PFE) therapy, at the neuronal level after SCI, with a focus on changes in NT-3 expression and on microglia/macrophage reaction, as they play a major role in the reconstitution of CNS integrity after injury and they may critically account for the observed structural and functional benefits of physical therapy. More specifically, the WBV therapy resulted in the best overall functional recovery when initiated at day 14, while inducing a decrease in Iba1 and the highest increase in NT-3. Therefore, the WBV therapy at the 14th day appeared to be superior to the PFE therapy in terms of recovery. Functional deficits and subsequent rehabilitation depend heavily upon the inflammatory processes occurring caudally to the injury site; thus, we propose that increased expression of NT-3, especially in the dorsal horn, could potentially be the mediator of this favorable outcome.
- Published
- 2023
- Full Text
- View/download PDF
19. Origin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell
- Author
-
Iasonas Dermitzakis, Maria Eleni Manthou, Soultana Meditskou, Marie-Ève Tremblay, Steven Petratos, Lida Zoupi, Marina Boziki, Evangelia Kesidou, Constantina Simeonidou, and Paschalis Theotokis
- Subjects
microglia ,origin ,yolk sac ,progeny ,molecular cues ,development ,Biology (General) ,QH301-705.5 - Abstract
Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the late embryonic to adult brain. Its unique identity that distinguishes its “glial” features from tissue-resident macrophages resides in the fact that once entering the CNS, it is perennially exposed to a unique environment following the formation of the blood–brain barrier. Additionally, tissue-resident macrophage progenies derive from various peripheral sites that exhibit hematopoietic potential, and this has resulted in interpretation issues surrounding their origin. Intensive research endeavors have intended to track microglial progenitors during development and disease. The current review provides a corpus of recent evidence in an attempt to disentangle the birthplace of microglia from the progenitor state and underlies the molecular elements that drive microgliogenesis. Furthermore, it caters towards tracking the lineage spatiotemporally during embryonic development and outlining microglial repopulation in the mature CNS. This collection of data can potentially shed light on the therapeutic potential of microglia for CNS perturbations across various levels of severity.
- Published
- 2023
- Full Text
- View/download PDF
20. Morphosyntactic Abilities and Cognitive Performance in Multiple Sclerosis
- Author
-
Panagiotis Grigoriadis, Christos Bakirtzis, Elli Nteli, Marina-Kleopatra Boziki, Maria Kotoumpa, Paschalis Theotokis, Evangelia Kesidou, and Stavroula Stavrakaki
- Subjects
multiple sclerosis ,language ,cognition ,morphology ,syntax ,memory ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
While cognitive abilities in people with multiple sclerosis (PwMS) have been studied in detail, little is known about linguistic abilities in PwMS and their relation to cognitive impairment. In this cross-sectional explorative study, we aim to investigate the morphosyntactic abilities of PwMS alongside their cognitive performance. Furthermore, we explore the effect of clinical factors, namely, the disease duration and MS type, on the linguistic and cognitive performance of PwMS. By so doing, we aim to shed light on neurocognitive and clinical correlates of linguistic performance in PwMS. We included 78 patients and 78 age-, sex- and education-matched healthy individuals. All participants were additionally administered the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, a verbal short-term memory task (non-word repetition) and questionnaires about mood, fatigue and quality of life. In addition, they underwent examinations with morphology and syntax tasks. PwMS were found to be impaired in morphology (past tense) and selectively impaired in syntax alongside cognitive impairments. Disease duration had the main impact on cognitive abilities. The MS type selectively impacted linguistic abilities, as shown by the remarkably deficient performance of the MS individuals with the progressive disease subtype. Linguistic impairments were predicted by only one measure of the BICAM test, namely, the Symbol Digit Modalities Test (SDMT), a measure of cognitive processing speed. Overall, this study contributes to the better understanding of the linguistic profile of PwMS by reporting selective deficits in their morphological and syntactical abilities. Furthermore, it provides insights into the clinical and cognitive correlates of linguistic performance. By so doing, it suggests clinical implications for the development of intervention programs for PwMS.
- Published
- 2024
- Full Text
- View/download PDF
21. ENVIRONMENTAL ENRICHMENT PROTECTS AGAINST DECREASED EXPRESSION OF HIPPOCAMPAL SYNAPTOPHYSIN AND GFAP IN RATS EXPOSED TO CHRONIC UNPREDICTABLE STRESS: THE ROLE OF SEX
- Author
-
Evgenia Dandi, Paschalis Theotokis, Evangelia Spandou, and Despina Tata
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2023
- Full Text
- View/download PDF
22. How does Nogo receptor influence demyelination and remyelination in the context of multiple sclerosis?
- Author
-
Zahra Rashidbenam, Ezgi Ozturk, Maurice Pagnin, Paschalis Theotokis, Nikolaos Grigoriadis, and Steven Petratos
- Subjects
myelin debris ,Nogo-A ,Nogo receptor 1 ,Nogo receptor 1-dependent axonopathy ,oligodendrocyte ,progressive multiple sclerosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Multiple sclerosis (MS) can progress with neurodegeneration as a consequence of chronic inflammatory mechanisms that drive neural cell loss and/or neuroaxonal dystrophy in the central nervous system. Immune-mediated mechanisms can accumulate myelin debris in the disease extracellular milieu during chronic-active demyelination that can limit neurorepair/plasticity and experimental evidence suggests that potentiated removal of myelin debris can promote neurorepair in models of MS. The myelin-associated inhibitory factors (MAIFs) are integral contributors to neurodegenerative processes in models of trauma and experimental MS-like disease that can be targeted to promote neurorepair. This review highlights the molecular and cellular mechanisms that drive neurodegeneration as a consequence of chronic-active inflammation and outlines plausible therapeutic approaches to antagonize the MAIFs during the evolution of neuroinflammatory lesions. Moreover, investigative lines for translation of targeted therapies against these myelin inhibitors are defined with an emphasis on the chief MAIF, Nogo-A, that may demonstrate clinical efficacy of neurorepair during progressive MS.
- Published
- 2023
- Full Text
- View/download PDF
23. Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin
- Author
-
Iasonas Dermitzakis, Maria Eleni Manthou, Soultana Meditskou, Dimosthenis Miliaras, Evangelia Kesidou, Marina Boziki, Steven Petratos, Nikolaos Grigoriadis, and Paschalis Theotokis
- Subjects
oligodendrogenesis ,myelinogenesis ,myelin formation ,embryology ,CNS development ,neural tube development ,Biology (General) ,QH301-705.5 - Abstract
The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.
- Published
- 2022
- Full Text
- View/download PDF
24. Skin Development and Disease: A Molecular Perspective.
- Author
-
Dermitzakis, Iasonas, Chatzi, Despoina, Kyriakoudi, Stella Aikaterini, Evangelidis, Nikolaos, Vakirlis, Efstratios, Meditskou, Soultana, Theotokis, Paschalis, and Manthou, Maria Eleni
- Published
- 2024
- Full Text
- View/download PDF
25. Ontogeny of Skin Stem Cells and Molecular Underpinnings.
- Author
-
Dermitzakis, Iasonas, Kampitsi, Despoina Dimitria, Manthou, Maria Eleni, Evangelidis, Paschalis, Vakirlis, Efstratios, Meditskou, Soultana, and Theotokis, Paschalis
- Published
- 2024
- Full Text
- View/download PDF
26. Histological Alterations in Hashimoto’s Disease: A Case-Series Ultrastructural Study
- Author
-
Eleni Avramidou, Antonios Gkantaras, Iasonas Dermitzakis, Konstantinos Sapalidis, Maria Eleni Manthou, and Paschalis Theotokis
- Subjects
Hashimoto’s thyroiditis ,electron microscopy ,ultrastructure ,blood vessels ,angiogenesis ,Medicine - Abstract
Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease exhibiting stromal fibrosis and follicular cell destruction due to lymphoplasmacytic infiltration. Besides deprecated analyses, histopathological approaches have not employed the use of electron microscopy adequately toward delineating subcellular-level interactions. Methods: Biopsies for ultrastructural investigations were obtained from the thyroids of five patients with HT after a thyroidectomy. Transmission electron microscopy (TEM) was utilized to study representative tissue specimens. Results: Examination indicated interstitial extravasated blood cells and a plethora of plasma cells, based on their subcellular identity landmarks. These antibody-secreting cells were profoundly spotted near follicular cells, fibroblasts, and cell debris entrenched in collagenous areas. Pathological changes persistently affected subcellular components of the thyrocytes, including the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and other intracellular vesicles. Interestingly, significant endothelial destruction was observed, specifically in the larger blood vessels, while the smaller vessels appeared comparatively unaffected. Conclusions: Our TEM findings highlight the immune-related alterations occurring within the thyroid stroma. The impaired vasculature component and remodeling have not been described ultrastructurally before; thus, further exploration is needed with regards to angiogenesis in HT in order to achieve successful prognostic, diagnostic, and treatment-monitoring strategies.
- Published
- 2023
- Full Text
- View/download PDF
27. Sex, aging and immunity in multiple sclerosis and experimental autoimmune encephalomyelitis: An intriguing interaction
- Author
-
Marina Boziki, Paschalis Theotokis, Evangelia Kesidou, Eleni Karafoulidou, Chrystalla Konstantinou, Iliana Michailidou, Yasemin Bahar, Ayse Altintas, and Nikolaos Grigoriadis
- Subjects
sex ,relapsing-remitting multiple sclerosis ,progressive multiple sclerosis ,experimental autoimmune encephalomyelitis ,aging ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with a profound neurodegenerative component early in the disease pathogenesis. Age is a factor with a well-described effect on the primary disease phenotype, namely, the relapsing-remitting vs. the primary progressive disease. Moreover, aging is a prominent factor contributing to the transition from relapsing-remitting MS (RRMS) to secondary progressive disease. However, sex also seems to, at least in part, dictate disease phenotype and evolution, as evidenced in humans and in animal models of the disease. Sex-specific gene expression profiles have recently elucidated an association with differential immunological signatures in the context of experimental disease. This review aims to summarize current knowledge stemming from experimental autoimmune encephalomyelitis (EAE) models regarding the effects of sex, either independently or as a factor combined with aging, on disease phenotype, with relevance to the immune system and the CNS.
- Published
- 2023
- Full Text
- View/download PDF
28. The Campaign and Battle of Manzikert, 1071
- Author
-
THEOTOKIS, GEORGIOS and THEOTOKIS, GEORGIOS
- Published
- 2024
29. Thyroid hormone-dependent oligodendroglial cell lineage genomic and non-genomic signaling through integrin receptors
- Author
-
Rahimeh Emamnejad, Mary Dass, Michael Mahlis, Salome Bozkurt, Sining Ye, Maurice Pagnin, Paschalis Theotokis, Nikolaos Grigoriadis, and Steven Petratos
- Subjects
integrin ,thyroid hormone ,oligodendrocyte (OL) ,Akt ,mTOR-mammalian target of rapamycin ,monocarboxylate transporter 8 (MCT8) ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Multiple sclerosis (MS) is a heterogeneous autoimmune disease whereby the pathological sequelae evolve from oligodendrocytes (OLs) within the central nervous system and are targeted by the immune system, which causes widespread white matter pathology and results in neuronal dysfunction and neurological impairment. The progression of this disease is facilitated by a failure in remyelination following chronic demyelination. One mediator of remyelination is thyroid hormone (TH), whose reliance on monocarboxylate transporter 8 (MCT8) was recently defined. MCT8 facilitates the entry of THs into oligodendrocyte progenitor cell (OPC) and pre-myelinating oligodendrocytes (pre-OLs). Patients with MS may exhibit downregulated MCT8 near inflammatory lesions, which emphasizes an inhibition of TH signaling and subsequent downstream targeted pathways such as phosphoinositide 3-kinase (PI3K)-Akt. However, the role of the closely related mammalian target of rapamycin (mTOR) in pre-OLs during neuroinflammation may also be central to the remyelination process and is governed by various growth promoting signals. Recent research indicates that this may be reliant on TH-dependent signaling through β1-integrins. This review identifies genomic and non-genomic signaling that is regulated through mTOR in TH-responsive pre-OLs and mature OLs in mouse models of MS. This review critiques data that implicates non-genomic Akt and mTOR signaling in response to TH-dependent integrin receptor activation in pre-OLs. We have also examined whether this can drive remyelination in the context of neuroinflammation and associated sequelae. Importantly, we outline how novel therapeutic small molecules are being designed to target integrin receptors on oligodendroglial lineage cells and whether these are viable therapeutic options for future use in clinical trials for MS.
- Published
- 2022
- Full Text
- View/download PDF
30. Secondary Central Nervous System Demyelinating Disorders in the Elderly: A Narrative Review
- Author
-
Christos Bakirtzis, Maria Lima, Sotiria Stavropoulou De Lorenzo, Artemios Artemiadis, Paschalis Theotokis, Evangelia Kesidou, Natalia Konstantinidou, Styliani-Aggeliki Sintila, Marina-Kleopatra Boziki, Dimitrios Parissis, Panagiotis Ioannidis, Theodoros Karapanayiotides, Georgios Hadjigeorgiou, and Nikolaos Grigoriadis
- Subjects
demyelination ,postinfectious ,metabolic ,nutritional ,radiation-induced ,drug-induced ,Medicine - Abstract
Secondary demyelinating diseases comprise a wide spectrum group of pathological conditions and may either be attributed to a disorder primarily affecting the neurons or axons, followed by demyelination, or to an underlying condition leading to secondary damage of the myelin sheath. In the elderly, primary demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis, are relatively uncommon. However, secondary causes of CNS demyelination may often occur and in this case, extensive diagnostic workup is usually needed. Infectious, postinfectious, or postvaccinal demyelination may be observed, attributed to age-related alterations of the immune system in this population. Osmotic disturbances and nutritional deficiencies, more commonly observed in the elderly, may lead to conditions such as pontine/extrapontine myelinolysis, Wernicke encephalopathy, and demyelination of the posterior columns of the spinal cord. The prevalence of malignancies is higher in the elderly, sometimes leading to radiation-induced, immunotherapy-related, or paraneoplastic CNS demyelination. This review intends to aid clinical neurologists in broadening their diagnostic approach to secondary CNS demyelinating diseases in the elderly. Common clinical conditions leading to secondary demyelination and their clinical manifestations are summarized here, while the current knowledge of the underlying pathophysiological mechanisms is additionally presented.
- Published
- 2023
- Full Text
- View/download PDF
31. The Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?
- Author
-
Olivia Ellen, Sining Ye, Danica Nheu, Mary Dass, Maurice Pagnin, Ezgi Ozturk, Paschalis Theotokis, Nikolaos Grigoriadis, and Steven Petratos
- Subjects
multiple sclerosis ,oligodendrocyte ,myelination ,inflammation ,microglia ,macrophage ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified as cooperating with and/or contributing to neurodegeneration that characterizes individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that can demonstrate the efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque.
- Published
- 2023
- Full Text
- View/download PDF
32. The Diversity of Astrocyte Activation during Multiple Sclerosis: Potential Cellular Targets for Novel Disease Modifying Therapeutics
- Author
-
Konstantinos Barmpagiannos, Paschalis Theotokis, Steven Petratos, Maurice Pagnin, Ofira Einstein, Evangelia Kesidou, Marina Boziki, Artemios Artemiadis, Christos Bakirtzis, and Nikolaos Grigoriadis
- Subjects
astrocytes ,reactivity ,reactive astrocytes ,transcriptional subsets ,functional subsets ,myelination ,Medicine - Abstract
Neuroglial cells, and especially astrocytes, constitute the most varied group of central nervous system (CNS) cells, displaying substantial diversity and plasticity during development and in disease states. The morphological changes exhibited by astrocytes during the acute and chronic stages following CNS injury can be characterized more precisely as a dynamic continuum of astrocytic reactivity. Different subpopulations of reactive astrocytes may be ascribed to stages of degenerative progression through their direct pathogenic influence upon neurons, neuroglia, the blood-brain barrier, and infiltrating immune cells. Multiple sclerosis (MS) constitutes an autoimmune demyelinating disease of the CNS. Despite the previously held notion that reactive astrocytes purely form the structured glial scar in MS plaques, their continued multifaceted participation in neuroinflammatory outcomes and oligodendrocyte and neuronal function during chronicity, suggest that they may be an integral cell type that can govern the pathophysiology of MS. From a therapeutic-oriented perspective, astrocytes could serve as key players to limit MS progression, once the integral astrocyte–MS relationship is accurately identified. This review aims toward delineating the current knowledge, which is mainly focused on immunomodulatory therapies of the relapsing–remitting form, while shedding light on uncharted approaches of astrocyte-specific therapies that could constitute novel, innovative applications once the role of specific subgroups in disease pathogenesis is clarified.
- Published
- 2023
- Full Text
- View/download PDF
33. B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF
- Author
-
Maha M. Bakhuraysah, Paschalis Theotokis, Jae Young Lee, Amani A. Alrehaili, Pei-Mun Aui, William A. Figgett, Michael F. Azari, John-Paul Abou-Afech, Fabienne Mackay, Christopher Siatskas, Frank Alderuccio, Stephen M. Strittmatter, Nikolaos Grigoriadis, and Steven Petratos
- Subjects
Medicine ,Science - Abstract
Abstract We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1 +/+ EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells of ngr1 +/+ EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.
- Published
- 2021
- Full Text
- View/download PDF
34. Addressing Spaceflight Biology through the Lens of a Histologist–Embryologist
- Author
-
Paschalis Theotokis, Maria Eleni Manthou, Theodora-Eleftheria Deftereou, Dimosthenis Miliaras, and Soultana Meditskou
- Subjects
microgravity ,radiation ,organogenesis ,vestibular system ,brain plasticity ,gut microbiome ,Science - Abstract
Embryogenesis and fetal development are highly delicate and error-prone processes in their core physiology, let alone if stress-associated factors and conditions are involved. Space radiation and altered gravity are factors that could radically affect fertility and pregnancy and compromise a physiological organogenesis. Unfortunately, there is a dearth of information examining the effects of cosmic exposures on reproductive and proliferating outcomes with regard to mammalian embryonic development. However, explicit attention has been given to investigations exploring discrete structures and neural networks such as the vestibular system, an entity that is viewed as the sixth sense and organically controls gravity beginning with the prenatal period. The role of the gut microbiome, a newly acknowledged field of research in the space community, is also being challenged to be added in forthcoming experimental protocols. This review discusses the data that have surfaced from simulations or actual space expeditions and addresses developmental adaptations at the histological level induced by an extraterrestrial milieu.
- Published
- 2023
- Full Text
- View/download PDF
35. Shared and distinguishing phenotypic characteristics of filamin c and desmoplakin cardiomyopathy
- Author
-
Yazdani, M F, primary, Morris-Rosendahl, D, additional, Lota, A, additional, Mach, L, additional, Hammersley, D, additional, Halliday, B, additional, Tayal, U, additional, Theotokis, P, additional, Noseda, M, additional, Ware, J S, additional, and Prasad, S, additional
- Published
- 2023
- Full Text
- View/download PDF
36. Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis
- Author
-
Nickoleta Delivanoglou, Marina Boziki, Paschalis Theotokis, Evangelia Kesidou, Olga Touloumi, Nikolina Dafi, Evangelia Nousiopoulou, Roza Lagoudaki, Nikolaos Grigoriadis, Ioannis Charalampopoulos, and Constantina Simeonidou
- Subjects
NGF ,TrkA ,p75NTR ,EAE ,Neuroinflammation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Nerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and pan-neurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system. There are only few studies with inconclusive results concerning the expression pattern and role of NGF, TrkA, and p75NTR (NGF system) under the neuroinflammatory conditions in multiple sclerosis (MS) and its mouse model, the experimental autoimmune encephalomyelitis (EAE). The aim of this study is to investigate the temporal expression in different cell types of NGF system in the central nervous system (CNS) during the EAE course. Methods EAE was induced in C57BL/6 mice 6–8 weeks old. CNS tissue samples were collected on specific time points: day 10 (D10), days 20–22 (acute phase), and day 50 (chronic phase), compared to controls. Real-time PCR, Western Blot, histochemistry, and immunofluorescence were performed throughout the disease course for the detection of the spatio-temporal expression of the NGF system. Results Our findings suggest that both NGF and its receptors, TrkA and p75NTR, are upregulated during acute and chronic phase of the EAE model in the inflammatory lesions in the spinal cord. NGF and its receptors were co-localized with NeuN+ cells, GAP-43+ axons, GFAP+ cells, Arginase1+ cells, and Mac3+ cells. Furthermore, TrkA and p75NTR were sparsely detected on CNPase+ cells within the inflammatory lesion. Of high importance is our observation that despite EAE being a T-mediated disease, only NGF and p75NTR were shown to be expressed by B lymphocytes (B220+ cells) and no expression on T lymphocytes was noticed. Conclusion Our results indicate that the components of the NGF system are subjected to differential regulation during the EAE disease course. The expression pattern of NGF, TrkA, and p75NTR is described in detail, suggesting possible functional roles in neuroprotection, neuroregeneration, and remyelination by direct and indirect effects on the components of the immune system.
- Published
- 2020
- Full Text
- View/download PDF
37. The Experience of a Tertiary Reference Hospital in the Study of Rare Neurological Diseases
- Author
-
Styliani-Aggeliki Sintila, Marina Boziki, Christos Bakirtzis, Thomai Stardeli, Nikoletta Smyrni, Ioannis Nikolaidis, Dimitrios Parissis, Theodora Afrantou, Theodore Karapanayiotides, Ioanna Koutroulou, Virginia Giantzi, Paschalis Theotokis, Evangelia Kesidou, Georgia Xiromerisiou, Efthimios Dardiotis, Panagiotis Ioannidis, and Nikolaos Grigoriadis
- Subjects
rare neurological diseases ,reference center ,orphan disease ,neurodegenerative disease ,clinical genetics ,Medicine (General) ,R5-920 - Abstract
Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world’s population. RDs are often called ‘orphan’ diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.
- Published
- 2023
- Full Text
- View/download PDF
38. B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF
- Author
-
Bakhuraysah, Maha M., Theotokis, Paschalis, Lee, Jae Young, Alrehaili, Amani A., Aui, Pei-Mun, Figgett, William A., Azari, Michael F., Abou-Afech, John-Paul, Mackay, Fabienne, Siatskas, Christopher, Alderuccio, Frank, Strittmatter, Stephen M., Grigoriadis, Nikolaos, and Petratos, Steven
- Published
- 2021
- Full Text
- View/download PDF
39. N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats
- Author
-
Evangelia Kesidou, Christina Bitsina, Athanasios Chatzisotiriou, Paschalis Theotokis, Evgenia Dandi, Despina A. Tata, and Evangelia Spandou
- Subjects
hypoxia ,ischemia ,brain injury ,N-acetylcysteine (NAC) ,inducible nitric oxide synthase (iNOS) ,sensorimotor tests ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hypoxic ischemic (HI) brain injury that occurs during neonatal period has been correlated with severe neuronal damage, behavioral deficits and infant mortality. Previous evidence indicates that N-acetylcysteine (NAC), a compound with antioxidant action, exerts a potential neuroprotective effect in various neurological disorders including injury induced by brain ischemia. The aim of the present study was to investigate the role of NAC as a potential therapeutic agent in a rat model of neonatal HI brain injury and explore its long-term behavioral effects. To this end, NAC (50 mg/kg/dose, i.p.) was administered prior to and instantly after HI, in order to evaluate hippocampal and cerebral cortex damage as well as long-term functional outcome. Immunohistochemistry was used to detect inducible nitric oxide synthase (iNOS) expression. The results revealed that NAC significantly alleviated sensorimotor deficits and this effect was maintained up to adulthood. These improvements in functional outcome were associated with a significant decrease in the severity of brain damage. Moreover, NAC decreased the short-term expression of iNOS, a finding implying that iNOS activity may be suppressed and that through this action NAC may exert its therapeutic action against neonatal HI brain injury.
- Published
- 2022
- Full Text
- View/download PDF
40. Blood Metabolomics May Discriminate a Sub-Group of Patients with First Demyelinating Episode in the Context of RRMS with Increased Disability and MRI Characteristics Indicative of Poor Prognosis
- Author
-
Marina Boziki, Alexandros Pechlivanis, Christina Virgiliou, Christos Bakirtzis, Styliani Aggeliki Sintila, Eleni Karafoulidou, Evangelia Kesidou, Paschalis Theotokis, Ioannis Nikolaidis, Georgios Theodoridis, Helen Gika, and Nikolaos Grigoriadis
- Subjects
metabolomics ,first demyelinating episode ,Relapsing-Remitting Multiple Sclerosis ,Clinically Isolated Syndrome ,biomarkers ,disability ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Biomarker research across the health-to-disease continuum is being increasingly applied. We applied blood-based metabolomics in order to identify patient clusters with a first demyelinating episode, and explored the prognostic potential of the method by thoroughly characterizing each cluster in terms of clinical, laboratory and MRI markers of established prognostic potential for Multiple Sclerosis (MS). Recruitment consisted of 11 patients with Clinically Isolated Syndrome (CIS), 37 patients with a first demyelinating episode in the context of Relapsing-Remitting MS (RRMS) and 11 control participants. Blood-based metabolomics and hierarchical clustering analysis (HCL) were applied. Constructed OPLS-DA models illustrated a discrimination between patients with CIS and the controls (p = 0.0014), as well as between patients with RRMS and the controls (p = 1 × 10−5). Hierarchical clustering analysis (HCL) for patients with RRMS identified three clusters. RRMS-patients-cluster-3 exhibited higher mean cell numbers in the Cerebro-spinal Fluid (CSF) compared to patients with CIS (18.17 ± 6.3 vs. 1.09 ± 0.41, p = 0.004). Mean glucose CSF/serum ratio and infratentorial lesion burden significantly differed across CIS- and HCL-derived RRMS-patient clusters (F = 14.95, p < 0.001 and F = 6.087, p = 0.002, respectively), mainly due to increased mean values for patients with RRMS-cluster-3. HCL discriminated a cluster of patients with a first demyelinating episode in the context of RRMS with increased disability, laboratory findings linked with increased pathology burden and MRI markers of poor prognosis.
- Published
- 2022
- Full Text
- View/download PDF
41. Modulation of the Microglial Nogo-A/NgR Signaling Pathway as a Therapeutic Target for Multiple Sclerosis
- Author
-
Danica Nheu, Olivia Ellen, Sining Ye, Ezgi Ozturk, Maurice Pagnin, Stephen Kertadjaja, Paschalis Theotokis, Nikolaos Grigoriadis, Catriona McLean, and Steven Petratos
- Subjects
multiple sclerosis ,microglia ,microglial polarization ,classically activated microglia ,alternatively activated microglia ,Nogo-A ,Cytology ,QH573-671 - Abstract
Current therapeutics targeting chronic phases of multiple sclerosis (MS) are considerably limited in reversing the neural damage resulting from repeated inflammation and demyelination insults in the multi-focal lesions. This inflammation is propagated by the activation of microglia, the endogenous immune cell aiding in the central nervous system homeostasis. Activated microglia may transition into polarized phenotypes; namely, the classically activated proinflammatory phenotype (previously categorized as M1) and the alternatively activated anti-inflammatory phenotype (previously, M2). These transitional microglial phenotypes are dynamic states, existing as a continuum. Shifting microglial polarization to an anti-inflammatory status may be a potential therapeutic strategy that can be harnessed to limit neuroinflammation and further neurodegeneration in MS. Our research has observed that the obstruction of signaling by inhibitory myelin proteins such as myelin-associated inhibitory factor, Nogo-A, with its receptor (NgR), can regulate microglial cell function and activity in pre-clinical animal studies. Our review explores the microglial role and polarization in MS pathology. Additionally, the potential therapeutics of targeting Nogo-A/NgR cellular mechanisms on microglia migration, polarization and phagocytosis for neurorepair in MS and other demyelination diseases will be discussed.
- Published
- 2022
- Full Text
- View/download PDF
42. RNA Editing Alterations Define Disease Manifestations in the Progression of Experimental Autoimmune Encephalomyelitis (EAE)
- Author
-
Dimitra Dafou, Eirini Kanata, Spyros Pettas, Nikolaos Bekas, Athanasios Dimitriadis, Garyfalia Kempapidou, Roza Lagoudaki, Paschalis Theotokis, Olga Touloumi, Nikoleta Delivanoglou, Evangelia Kesidou, Konstantinos Xanthopoulos, Nikolaos Grigoriadis, Fotini Nina Papavasiliou, and Theodoros Sklaviadis
- Subjects
RNA editing ,multiple sclerosis ,experimental autoimmune encephalomyelitis ,RNA-sequencing ,gene expression ,microglia ,Cytology ,QH573-671 - Abstract
RNA editing is an epitranscriptomic modification, leading to targeted changes in RNA transcripts. It is mediated by the action of ADAR (adenosine deaminases acting on double-stranded (ds) RNA and APOBEC (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like) deaminases and appears to play a major role in the pathogenesis of many diseases. Here, we assessed its role in experimental autoimmune encephalomyelitis (EAE), a widely used non-clinical model of autoimmune inflammatory diseases of the central nervous system (CNS), which resembles many aspects of human multiple sclerosis (MS). We have analyzed in silico data from microglia isolated at different timepoints through disease progression to identify the global editing events and validated the selected targets in murine tissue samples. To further evaluate the functional role of RNA editing, we induced EAE in transgenic animals lacking expression of APOBEC-1. We found that RNA-editing events, mediated by the APOBEC and ADAR deaminases, are significantly reduced throughout the course of disease, possibly affecting the protein expression necessary for normal neurological function. Moreover, the severity of the EAE model was significantly higher in APOBEC-1 knock-out mice, compared to wild-type controls. Our results implicate regulatory epitranscriptomic mechanisms in EAE pathogenesis that could be extrapolated to MS and other neurodegenerative disorders (NDs) with common clinical and molecular features.
- Published
- 2022
- Full Text
- View/download PDF
43. Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response
- Author
-
Marina Boziki, Christos Bakirtzis, Styliani-Aggeliki Sintila, Evangelia Kesidou, Evdoxia Gounari, Aliki Ioakimidou, Vasiliki Tsavdaridou, Lemonia Skoura, Asimina Fylaktou, Vasiliki Nikolaidou, Maria Stangou, Ioannis Nikolaidis, Virginia Giantzi, Eleni Karafoulidou, Paschalis Theotokis, and Nikolaos Grigoriadis
- Subjects
primary progressive multiple sclerosis ,disease activity ,ocrelizumab ,disease-modifying treatment ,depletion treatment ,treatment response ,Cytology ,QH573-671 - Abstract
Ocrelizumab is a B-cell-depleting monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and active primary progressive MS (aPPMS). This prospective, uncontrolled, open-label, observational study aimed to assess the efficacy of ocrelizumab in patients with aPPMS and to dissect the clinical, radiological and laboratory attributes of treatment response. In total, 22 patients with aPPMS followed for 24 months were included. The primary efficacy outcome was the proportion of patients with optimal response at 24 months, defined as patients free of relapses, free of confirmed disability accumulation (CDA) and free of T1 Gd-enhancing lesions and new/enlarging T2 lesions on the brain and cervical MRI. In total, 14 (63.6%) patients and 13 patients (59.1%) were classified as responders at 12 and 24 months, respectively. Time exhibited a significant effect on mean absolute and normalized gray matter cerebellar volume (F = 4.342, p = 0.23 and F = 4.279, p = 0.024, respectively). Responders at 24 months exhibited reduced peripheral blood ((%) of CD19+ cells) plasmablasts compared to non-responders at the 6-month point estimate (7.69 ± 4.4 vs. 22.66 ± 7.19, respectively, p = 0.043). Response to ocrelizumab was linked to lower total and gray matter cerebellar volume loss over time. Reduced plasmablast depletion was linked for the first time to sub-optimal response to ocrelizumab in aPPMS.
- Published
- 2022
- Full Text
- View/download PDF
44. That’s a Wrap! Molecular Drivers Governing Neuronal Nogo Receptor-Dependent Myelin Plasticity and Integrity
- Author
-
Steven Petratos, Paschalis Theotokis, Min Jung Kim, Michael F. Azari, and Jae Young Lee
- Subjects
nogo receptor ,Nogo-A ,Caspr ,paranode ,myelin ,PrPc ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Myelin is a dynamic membrane that is important for coordinating the fast propagation of action potentials along small or large caliber axons (0.1–10 μm) some of which extend the entire length of the spinal cord. Due to the heterogeneity of electrical and energy demands of the variable neuronal populations, the axo-myelinic and axo-glial interactions that regulate the biophysical properties of myelinated axons also vary in terms of molecular interactions at the membrane interfaces. An important topic of debate in neuroscience is how myelin is maintained and modified under neuronal control and how disruption of this control (due to disease or injury) can initiate and/or propagate neurodegeneration. One of the key molecular signaling cascades that have been investigated in the context of neural injury over the past two decades involves the myelin-associated inhibitory factors (MAIFs) that interact with Nogo receptor 1 (NgR1). Chief among the MAIF superfamily of molecules is a reticulon family protein, Nogo-A, that is established as a potent inhibitor of neurite sprouting and axon regeneration. However, an understated role for NgR1 is its ability to control axo-myelin interactions and Nogo-A specific ligand binding. These interactions may occur at axo-dendritic and axo-glial synapses regulating their functional and dynamic membrane domains. The current review provides a comprehensive analysis of how neuronal NgR1 can regulate myelin thickness and plasticity under normal and disease conditions. Specifically, we discuss how NgR1 plays an important role in regulating paranodal and juxtaparanodal domains through specific signal transduction cascades that are important for microdomain molecular architecture and action potential propagation. Potential therapeutics designed to target NgR1-dependent signaling during disease are being developed in animal models since interference with the involvement of the receptor may facilitate neurological recovery. Hence, the regulatory role played by NgR1 in the axo-myelinic interface is an important research field of clinical significance that requires comprehensive investigation.
- Published
- 2020
- Full Text
- View/download PDF
45. Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs
- Author
-
Pantazis I. Theotokis, Louise Usher, Christopher K. Kortschak, Ed Schwalbe, and Sterghios A. Moschos
- Subjects
siRNA ,SNP susceptibility ,RACE-SEQ ,personalized medicine ,oligonucleotides ,RNAi ,pharmacology ,mechanism of action ,shRNA ,bioinformatics ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Low allelic and clonal variability among endogenous RNAi targets has focused mismatch tolerance studies to RNAi-active guide strands. However, the inherent genomic instability of RNA viruses such as hepatitis C virus (HCV) gives rise to quasi-species mutants within discrete clones: this facilitates mismatch tolerance studies from a target perspective. We recently quantified the slicing imprecision of Argonaute 2 using small interfering RNA (siRNA) analogs of the DNA-directed RNAi drug TT-034 and next-generation sequencing of 5′ RNA ligase-mediated rapid amplification of cDNA ends (RACE-SEQ). Here, we present an open-source, customizable, and computationally light RACE-SEQ bioinformatic pipeline, describing adaptations that semiquantitatively report the impact of RNAi hybridization site mismatches from the target perspective. The analysis shows that Argonaute 2 has a substitution-specific, 3- to 5-log activity window between fully complementary targets and targets with mismatches across positions 10–11. It further focuses the endonucleotic Slicer imprecision around positions 13–17, demonstrating its dependence on guide strand central region complementarity, and potentiation by even a single mismatch. We further propose pharmacogenomics value in testing endogenous targets using recombinant replicon systems and RACE-SEQ to report the pharmacodynamics of sequence-specific oligonucleotide therapeutics against all possible polymorphisms in a population, in a minimally biased, patient-free manner.
- Published
- 2017
- Full Text
- View/download PDF
46. Humoral response in experimental autoimmune encephalomyelitis targets neural precursor cells in the central nervous system of naive rodents
- Author
-
Evangelia Kesidou, Olga Touloumi, Roza Lagoudaki, Evangelia Nousiopoulou, Paschalis Theotokis, Kyriaki-Nepheli Poulatsidou, Marina Boziki, Evangelia Kofidou, Nickoleta Delivanoglou, Fani Minti, Georgios Hadjigeorgiou, Nikolaos Grigoriadis, and Constantina Simeonidou
- Subjects
Experimental autoimmune encephalomyelitis ,Neural precursor cells ,Autoantibody ,Subventricular zone ,Remyelination ,Apoptosis ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Neural precursor cells (NPCs) located in the subventricular zone (SVZ), a well-defined NPC niche, play a crucial role in central nervous system (CNS) homeostasis. Moreover, NPCs are involved in the endogenous reparative process both in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the possibility that NPCs may be vulnerable to immune-related components may not be ruled out. Therefore, we investigated the potential affinity of myelin oligodendrocyte glycoprotein (MOG)-induced humoral response(s) to NPCs. Methods MOG35–55-EAE was induced in C57BL/6 mice; blood-sampling was performed on days 17–21 (acute phase) along with a naive group and corresponding antisera (AS) were collected (EAE-AS, NAIVE-AS). The presence of anti-CNS autoantibodies was examined with western blotting. Furthermore, using the collected antisera and anti-MOG antibody (as positive control), immunohistochemistry and double immunofluorescence were implemented on normal neonatal, postnatal, and adult mouse brain sections. Targeted NPCs were identified with confocal microscopy. In vitro immunoreactivity assessment on NPCs challenged with autoantibodies was evaluated for apoptotic/autophagic activity. Results Western blotting verified the existence of autoantibodies in EAE mice and demonstrated bands corresponding to yet unidentified NPC surface epitopes. A dominant selective binding of EAE-AS in the subventricular zone in all age groups compared to NAIVE-AS (p
- Published
- 2017
- Full Text
- View/download PDF
47. The Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project: defining a healthy volunteer cohort
- Author
-
Aguib, Yasmine, Allouba, Mona, Afify, Alaa, Halawa, Sarah, El-Khatib, Mohamed, Sous, Marina, Galal, Aya, Abdelrahman, Eslam, Shehata, Nairouz, El Sawy, Amr, Elmaghawry, Mohamed, Anwer, Shehab, Kamel, Omnia, El Mozy, Wesam, Khedr, Hadir, Kharabish, Ahmed, Thabet, Nagwa, Theotokis, Pantazis I., Buchan, Rachel, Govind, Risha, Whiffin, Nicola, Walsh, Roddy, Aguib, Heba, Elguindy, Ahmed, O’Regan, Declan P., Cook, Stuart A., Barton, Paul J., Ware, James S., and Yacoub, Magdi
- Published
- 2020
- Full Text
- View/download PDF
48. Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis
- Author
-
Delivanoglou, Nickoleta, Boziki, Marina, Theotokis, Paschalis, Kesidou, Evangelia, Touloumi, Olga, Dafi, Nikolina, Nousiopoulou, Evangelia, Lagoudaki, Roza, Grigoriadis, Nikolaos, Charalampopoulos, Ioannis, and Simeonidou, Constantina
- Published
- 2020
- Full Text
- View/download PDF
49. p75NTR and TROY: Uncharted Roles of Nogo Receptor Complex in Experimental Autoimmune Encephalomyelitis
- Author
-
Theotokis, Paschalis and Grigoriadis, Nikolaos
- Published
- 2018
- Full Text
- View/download PDF
50. Validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in Greek population with multiple sclerosis
- Author
-
Polychroniadou, E., Bakirtzis, C., Langdon, D., Lagoudaki, R., Kesidou, E., Theotokis, P., Tsalikakis, D., Poulatsidou, K., Kyriazis, O., Boziki, M., Papadopoulos, G., Boura, E., Sintila, L., Hatzigeorgiou, S., Ziamos, C., Ioannidis, P., Karacostas, D., and Grigoriadis, N.
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.