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Tooth size, being the effect of interaction of genetic and prenatal factors, could be of importance in interpreting the multifactor causes of cleft lip/palate. Publications indicating decreased tooth parameters, no dental differences, or larger dimensions of teeth in cleft lip/palate patients. Researchers report mostly mesiodistal (MD) measurements of maxillary (affected) teeth. There is a lack of data for buccolingual (BL) diameters. Both MD and BL parameters have influence on the planning and performance of orthodontic treatment. The aim of this paper was to assess differences in mesiodistal and buccolingual tooth dimensions in Polish children with unilateral cleft lip and palate (UCLP) in comparison to patients without oral clefts. A total of 1883 permanent teeth, 1182 teeth of UCLP patients and 701 teeth of healthy participants were analyzed. Tooth diameters were performed using an orthodontic cast of dentition with a digital odontometer. The greatest anomalies were found in both maxillary canines and consisted of their reduced mesiodistal dimension and increased buccolingual dimension, resulting in a pathologically high crown shape index (BL/MD). Conclusion can be drawn that unilateral cleft lip and palate is a condition that causes morphological disturbances of varying severity in most mandibular and maxillary teeth both on the cleft and non-cleft sides.

To detect age-related morphological changes occurring in the median and transverse palatal sutures that could affect the outcome of rapid maxillary expansion. Determined by Cone-Beam Computed Tomography (CBCT) scans.

Purpose of Review: Migraine prevalence in females is up to 3 times higher than in males and females show higher frequency, longer duration, and increased severity of headache attacks, but the reason for that difference is not known. This narrative review presents the main aspects of sex dimorphism in migraine prevalence and discusses the role of sex-related differences in mitochondrial homeostasis in that dimorphism. The gender dimension is also shortly addressed., Recent Findings: The imbalance between energy production and demand in the brain susceptible to migraine is an important element of migraine pathogenesis. Mitochondria are the main energy source in the brain and mitochondrial impairment is reported in both migraine patients and animal models of human migraine. However, it is not known whether the observed changes are consequences of primary disturbance of mitochondrial homeostasis or are secondary to the migraine-affected hyperexcitable brain. Sex hormones regulate mitochondrial homeostasis, and several reports suggest that the female hormones may act protectively against mitochondrial impairment, contributing to more effective energy production in females, which may be utilized in the mechanisms responsible for migraine progression. Migraine is characterized by several comorbidities that are characterized by sex dimorphism in their prevalence and impairments in mitochondrial functions. Mitochondria may play a major role in sexual dimorphism in migraine through the involvement in energy production, the dependence on sex hormones, and the involvement in sex-dependent comorbidities. Studies on the role of mitochondria in sex dimorphism in migraine may contribute to precise personal therapeutic strategies., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Research has demonstrated the effectiveness of Animal-Assisted Therapy, usually involving dogs, as a way to reduce pain in inpatient and outpatient populations. Here two studies investigate the effectiveness of interacting with horses for reducing human acute pain perception., Methods: In Study 1, a blood-pressure cuff was used to administer acute ischaemic pain to 70 adult participants, who were allocated to one of three groups: Equine Assisted Psychotherapy (EAP), Horse Interaction without EAP (HI), and a Control (no horses present). All participants engaged in an activity (finding a horse treat) in a large, enclosed arena. The dependent variable was the subjective pain rating (scale 0-10) of the participant in response to moderate pain induced pre- and post-activity. In Study 2, 53 adult participants were recruited and allocated to either an Equine Assisted Learning (EAL) Group or a Control Group. The same paradigm was used. Following the activity sessions, qualitative data was elicited from the participants regarding their insights and feelings. It was hypothesized that any interaction with horses would significantly reduce an individual's perception of pain., Results: In both studies, planned paired-samples t-tests showed significant reductions in pain ratings from pre-activity to post-activity in the EAL, EAP and HI groups (large and medium effect sizes) but not the Control groups. Thematic analysis of the qualitative responses showed an overwhelmingly positive array of responses from those who interacted with the horses, for example, feeling relaxed and happy during the activity., Conclusion: Interactions with horses can reduce acute pain perception. Distraction, physiological changes, and positive emotions are discussed as possible underlying mechanisms. It remains to be seen how this could be more widely applied, for example, in relation to chronic pain., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Caiazza is Director of Cavallo Therapies where Study 1 was carried out. Cavallo Therapies were paid for providing the EAP sessions used in Study 1., (© The Author(s) 2024.)

Although the introduction of drugs targeting calcitonin gene-related peptide (CGRP) revolutionized migraine treatment, still a substantial proportion of migraine patients do not respond satisfactorily to such a treatment, and new therapeutic targets are needed. Therefore, molecular studies on migraine pathogenesis are justified. Oxidative stress is implicated in migraine pathogenesis, as many migraine triggers are related to the production of reactive oxygen and nitrogen species (RONS). Migraine has been proposed as a superior mechanism of the brain to face oxidative stress resulting from energetic imbalance. However, the precise mechanism behind the link between migraine and oxidative stress is not known. Nociceptive primary afferent nerve fiber endings express ion channel receptors that change harmful stimuli into electric pain signals. Transient receptor potential cation channel subfamily A member 1 (TRPA1) is an ion channel that can be activated by oxidative stress products and stimulate the release of CGRP from nerve endings. It is a transmembrane protein with ankyrin repeats and conserved cysteines in its N-terminus embedded in the cytosol. TRPA1 may be a central element of the signaling pathway from oxidative stress and NO production to CGRP release, which may play a critical role in headache induction. In this narrative review, we present information on the role of oxidative stress in migraine pathogenesis and provide arguments that TRPA1 may be "a missing link" between oxidative stress and migraine and therefore a druggable target in this disease.

Objective: To assess the potential of ferroptosis and ferritinophagy in migraine pathogenesis., Background: Ferroptosis and ferritinophagy are related to increased cellular iron concentration and have been associated with the pathogenesis of several neurological disorders, but their potential in migraine pathogenesis has not been explored. Increased iron deposits in some deep brain areas, mainly periaqueductal gray (PAG), are reported in migraine and they have been associated with the disease severity and chronification as well as poor response to antimigraine drugs., Results: Iron deposits may interfere with antinociceptive signaling in the neuronal network in the brain areas affected by migraine, but their mechanistic role is unclear. Independently of the location, increased iron concentration may be related to ferroptosis and ferritinophagy in the cell. Therefore, both phenomena may be related to increased iron deposits in migraine. It is unclear whether these deposits are the reason, consequence, or just a correlate of migraine. Still, due to migraine-related elevated levels of iron, which is a prerequisite of ferroptosis and ferritinophagy, the potential of both phenomena in migraine should be explored. If the iron deposits matter in migraine pathogenesis, they should be mechanically linked with the clinical picture of the disease. As iron is an exogenous essential trace element, it is provided to the human body solely with diet or supplements. Therefore, exploring the role of iron in migraine pathogenesis may help to determine the potential role of iron-rich/poor dietary products as migraine triggers or relievers., Conclusion: Ferroptosis and ferritinophagy may be related to migraine pathogenesis through iron deposits in the deep areas of the brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fila, Przyslo, Derwich, Luniewska-Bury, Pawlowska and Blasiak.)

Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1-2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA ( p < 0.01) and KYNA ( p < 0.05), but KYN and QA were enhanced, as compared with the controls ( p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios ( p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine.

Focal cortical dysplasias are abnormalities of the cerebral cortex associated with an elevated risk of neurological disturbances. Cortical spreading depolarization/depression is a correlate of migraine aura/headache and a trigger of migraine pain mechanisms. However, cortical spreading depolarization/depression is associated with cortical structural changes, which can be classified as transient focal cortical dysplasias. Migraine is reported to be associated with changes in various brain structures, including malformations and lesions in the cortex. Such malformations may be related to focal cortical dysplasias, which may play a role in migraine pathogenesis. Results obtained so far suggest that focal cortical dysplasias may belong to the causes and consequences of migraine. Certain focal cortical dysplasias may lower the threshold of cortical excitability and facilitate the action of migraine triggers. Migraine prevalence in epileptic patients is higher than in the general population, and focal cortical dysplasias are an established element of epilepsy pathogenesis. In this narrative/hypothesis review, we present mainly information on cortical structural changes in migraine, but studies on structural alterations in deep white matter and other brain regions are also presented. We develop the hypothesis that focal cortical dysplasias may be causally associated with migraine and link pathogeneses of migraine and epilepsy., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

Migraines display atypical age dependence, as the peak of their prevalence occurs between the ages of 20-40 years. With age, headache attacks occur less frequently and are characterized by a lower amplitude. However, both diagnosis and therapy of migraines in the elderly are challenging due to multiple comorbidities and polypharmacy. Dietary components and eating habits are migraine triggers; therefore, nutrition is a main target in migraine prevention. Several kinds of diets were proposed to prevent migraines, but none are commonly accepted due to inconsistent results obtained in different studies. The ketogenic diet is featured by very low-carbohydrate and high-fat contents. It may replace glucose with ketone bodies as the primary source of energy production. The ketogenic diet and the actions of ketone bodies are considered beneficial in several aspects of health, including migraine prevention, but studies on the ketogenic diet in migraines are not standardized and poorly evidenced. Apart from papers claiming beneficial effects of the ketogenic diet in migraines, several studies have reported that increased levels of ketone bodies may be associated with all-cause and incident heart failure mortality in older adults and are supported by research on mice showing that the ketogenic diets and diet supplementation with a human ketone body precursor may cause life span shortening. Therefore, despite reports showing a beneficial effect of the ketogenic diet in migraines, such a diet requires further studies, including clinical trials, to verify whether it should be recommended in older adults with migraines.

Migraine is a common neurological disease displaying an unusual dependence on age. For most patients, the peak intensity of migraine headaches occurs in 20s and lasts until 40s, but then headache attacks become less intense, occur less frequently and the disease is more responsive to therapy. This relationship is valid in both females and males, although the prevalence of migraine in the former is 2-4 times greater than the latter. Recent concepts present migraine not only as a pathological event, but rather as a part of evolutionary adaptive response to protect organism against consequences of stress-induced brain energy deficit. However, these concepts do not fully explain that unusual dependence of migraine prevalence on age. Many aspects of aging, both molecular/cellular and social/cognitive, are interwound in migraine pathogenesis, but they neither explain why only some persons are affected by migraine, nor suggest any causal relationship. In this narrative/hypothesis review we present information on associations of migraine with chronological aging, brain aging, cellular senescence, stem cell exhaustion as well as social, cognitive, epigenetic, and metabolic aging. We also underline the role of oxidative stress in these associations. We hypothesize that migraine affects only individuals who have inborn, genetic/epigenetic, or acquired (traumas, shocks or complexes) migraine predispositions. These predispositions weakly depend on age and affected individuals are more prone to migraine triggers than others. Although the triggers can be related to many aspects of aging, social aging may play a particularly important role as the prevalence of its associated stress has a similar age-dependence as the prevalence of migraine. Moreover, social aging was shown to be associated with oxidative stress, important in many aspects of aging. In perspective, molecular mechanisms underlying social aging should be further explored and related to migraine with a closer association with migraine predisposition and difference in prevalence by sex.

Persistent reprogramming of epigenetic pattern leads to changes in gene expression observed in many neurological disorders. Transient receptor potential cation channel subfamily A member 1 (TRPA1), a member of the TRP channels superfamily, is activated by many migraine triggers and expressed in trigeminal neurons and brain regions that are important in migraine pathogenesis. TRP channels change noxious stimuli into pain signals with the involvement of epigenetic regulation. The expression of the TRPA1 encoding gene, TRPA1, is modulated in pain-related syndromes by epigenetic alterations, including DNA methylation, histone modifications, and effects of non-coding RNAs: micro RNAs (miRNAs), long non-coding RNAs, and circular RNAs. TRPA1 may change epigenetic profile of many pain-related genes as it may modify enzymes responsible for epigenetic modifications and expression of non-coding RNAs. TRPA1 may induce the release of calcitonin gene related peptide (CGRP), from trigeminal neurons and dural tissue. Therefore, epigenetic regulation of TRPA1 may play a role in efficacy and safety of anti-migraine therapies targeting TRP channels and CGRP. TRPA1 is also involved in neurogenic inflammation, important in migraine pathogenesis. The fundamental role of TRPA1 in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of TRPA1 may play a role in efficacy and safety of anti-migraine therapy targeting TRP channels or CGRP and they should be further explored for efficient and safe antimigraine treatment. This narrative/perspective review presents information on the structure and functions of TRPA1 as well as role of its epigenetic connections in pain transmission and potential in migraine therapy., (© 2023. The Author(s).)

Objective: To assess the potential of autophagy in migraine pathogenesis., Background: The interplay between neurons and microglial cells is important in migraine pathogenesis. Migraine-related effects, such as cortical spreading depolarization and release of calcitonin gene-related peptide, may initiate adenosine triphosphate (ATP)-mediating pro-nociceptive signaling in the meninges causing headaches. Such signaling may be induced by the interaction of ATP with purinergic receptor P2X 7 (P2X7R) on microglial cells leading to a Ca 2+ -mediated pH increase in lysosomes and release of autolysosome-like vehicles from microglial cells indicating autophagy impairment., Methods: A search in PubMed was conducted with the use of the terms "migraine," "autophagy," "microglia," and "degradation" in different combinations., Results: Impaired autophagy in microglia may activate secretory autophagy and release of specific proteins, including brain-derived neurotrophic factor (BDNF), which can be also released through the pores induced by P2X7R activation in microglial cells. BDNF may be likewise released from microglial cells upon ATP- and Ca 2+ -mediated activation of another purinergic receptor, P2X4R. BDNF released from microglia might induce autophagy in neurons to clear cellular debris produced by oxidative stress, which is induced in the brain as the response to migraine-related energy deficit. Therefore, migraine-related signaling may impair degradative autophagy, stimulate secretory autophagy in microglia, and degradative autophagy in neurons. These effects are mediated by purinergic receptors P2X4R and P2X7R, BDNF, ATP, and Ca 2+ ., Conclusion: Different effects of migraine-related events on degradative autophagy in microglia and neurons may prevent prolonged changes in the brain related to headache attacks., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Age-related macular degeneration (AMD) is a largely incurable disease and an emerging problem in aging societies. It occurs in two forms, dry and wet (exudative, neovascular), which may cause legal blindness and sight loss. Currently, there is not any effective treatment for dry AMD. Meanwhile, repeated intravitreal injections with antibodies effective against vascular endothelial growth factor A (VEGFA) slow down wet AMD progression but are not free from complications. (-)-Epigallocatechin-3-gallate (EGCG) is an active compound of green tea, which exerts many beneficial effects in the retinal pigment epithelium and the neural retina. It has been reported to downregulate the VEGFA gene by suppressing its activators. The inhibition of mitogen-activated protein kinases 1 and 3 (MAPK1 and MAPK3) may lie behind the antiangiogenic action of EGCG mediated by VEGFA. EGCG exerts protective effects against UV-induced damage to retinal cells and improves dysfunctional autophagy. EGCG may also interact with the mechanistic target rapamycin (MTOR) and unc-51-like autophagy activating kinase (ULK1) to modulate the interplay between autophagy and apoptosis. Several other studies report beneficial effects of EGCG on the retina that may be related to wet AMD. Therefore, controlled clinical trials are needed to verify whether diet supplementation with EGCG or green tea consumption may improve the results of anti-VEGFA therapy in wet AMD.

Energy generation in the brain to ameliorate energy deficit in migraine leads to oxidative stress as it is associated with reactive oxygen species (ROS) that may damage DNA and show a pronociceptive action in meninges mediated by transient receptor potential cation channel subfamily A member 1 (TRPA1). Recent studies show high levels of single-strand breaks (SSBs) at specific sites in the genome of postmitotic neurons and point at SSB repair (SSBR) as an important element of homeostasis of the central nervous system. DNA topoisomerase 1 (TOP1) is stabilized in the DNA damage-inducing state by neuronal stimulation, including cortical spreading depression. Impairment in poly (ADP-ribose) polymerase 1 (PARP-1) and X-ray repair cross complementing 1 (XRCC1), key SSBR proteins, may be linked with migraine by transient receptor potential melastatin 2 (TRPM2). TRPM2 may also mediate the involvement of migraine-related neuroinflammation with PARP-1 activated by oxidative stress-related SSBs. In conclusion, aberrant activity of SSBR evoked by compromised PARP-1 and XRCC1 may contribute to pathological phenomena in the migraine brain. Such aberrant SSBR results in the lack of repair or misrepair of SSBs induced by ROS or resulting from impaired TOP1. Therefore, components of SSBR may be considered a prospective druggable target in migraine.

In 2018, Polish Society of Radiation Oncology formed a young section (yPTRO), dedicated to radiation oncologists under the age of 40. To evaluate their current situation, an anonymous, nationwide, online survey was carried out. Thirty-two-item-based questionnaire investigated young radiation oncologists' perception of employment, workload, education, malpractice lawsuits, scientific research, and board exam. A total of 44 physicians responded to the questionnaire, yielding a response rate of 25%. Results of the survey identified the main problematic areas. In general, young radiation oncologists in Poland are overloaded with bureaucracy. They complain on spending too much time at work and lack work-life balance. The risk of being sued for medical error is threatening two-thirds of responders in everyday work. Compensation is not satisfying for nearly half of the survey participants. Nearly all young radiation oncologists continue education and participate in national and international educational events. Forty-eight percent of responders do scientific research alongside clinical work. However, the perception of young radiation oncologists on the board exam is alarming and requires further discussion. Fifty-five percent of the survey participants think that current form of the exam is not appropriate. Hopefully, 75% of physicians feel fairly evaluated. The presented report is the first of its kind in Poland. Issues mentioned in our questionnaire will help newly formed yPTRO to develop strategic priorities for the upcoming years., (© 2021. The Author(s).)

Age-related macular degeneration (AMD) is a complex eye disease with the retina as the target tissue and aging as per definition the most serious risk factor. However, the retina contains over 60 kinds of cells that form different structures, including the neuroretina and retinal pigment epithelium (RPE) which can age at different rates. Other established or putative AMD risk factors can differentially affect the neuroretina and RPE and can differently interplay with aging of these structures. The occurrence of β-amyloid plaques and increased levels of cholesterol in AMD retinas suggest that AMD may be a syndrome of accelerated brain aging. Therefore, the question about the real meaning of age in AMD is justified. In this review we present and update information on how aging may interplay with some aspects of AMD pathogenesis, such as oxidative stress, amyloid beta formation, circadian rhythm, metabolic aging and cellular senescence. Also, we show how this interplay can be specific for photoreceptors, microglia cells and RPE cells as well as in Bruch's membrane and the choroid. Therefore, the process of aging may differentially affect different retinal structures. As an accurate quantification of biological aging is important for risk stratification and early intervention for age-related diseases, the determination how photoreceptors, microglial and RPE cells age in AMD may be helpful for a precise diagnosis and treatment of this largely untreatable disease., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background : The aim of the study was to assess the position of the hyoid bone, as well as the width of the nasopharynx and oropharynx after occlusal splint therapy combined with physiotherapy in patients diagnosed with temporomandibular disorders (TMD). Methods : This was a clinical trial study. The study group consisted of 40 patients diagnosed with TMD, who were qualified for the treatment combining physiotherapy and occlusal splint therapy. Hyoid bone position as well as the width of the nasopharynx and oropharynx were assessed in lateral cephalograms taken before and after the end of the treatment. There were 15 generally healthy participants included into the control group, who had taken lateral cephalograms twice within the period of 1 to 2 years and did not receive any occlusal treatment in the meantime. Results : The position of the hyoid bone was significantly lowered and the dimension of the lower part of the oropharynx was significantly decreased after the end of the long-term occlusal splint therapy combined with physiotherapy in patients diagnosed with TMD. Conclusions : Long-term occlusal splint therapy combined with physiotherapy affected the position of the hyoid bone and the dimension of the lower part of the oropharynx.

The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, CALCA , is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the CALCA gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the CALCA primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.

Background and Objectives: The aim of the study was to assess the craniovertebral and craniomandibular changes in patients diagnosed with temporomandibular joint disorders (TMD) after physiotherapy combined with occlusal splint therapy. Materials and Methods: There were forty patients (32 females, 80%), diagnosed with TMD, included into the study group. After the initial series of physiotherapy, patients received maxillary occlusal splints to be worn day and night. Participants continued physiotherapy simultaneously with occlusal splint therapy for 6 months. Lateral cephalograms taken in natural head position before and after the end of the therapy were used for measurements. The control group consisted of 15 healthy participants (12 females, 80%), who had taken lateral cephalograms twice, and did not receive any type of occlusal treatment nor physiotherapy in the meantime. Results: Occlusal splint therapy and physiotherapy combined together significantly affected: the vertical position of the mandible (significant increase, p < 0.0001), the sagittal position of mandible (significant decrease, p = 0.0065), as well as the width of the functional space between C1 and C2 (significant decrease, p = 0.0042). Moreover, the cervical lordosis was restored after the end of the treatment (p < 0.0001). Conclusions: Cooperation of physiotherapists with dental practitioners is necessary in the treatment of patients with TMD, including temporomandibular joint osteoarthritis.

Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro and animal studies. The exact mechanism of such action of vitamin D3 is unknown and may include several independent or partly dependent pathways. The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D, calcitriol), binds to the vitamin D receptor (VDR) and induces its translocation to the nucleus, where it transactivates a myriad of genes. Vitamin D3 is involved in the maintenance of a normal epigenetic profile whose disturbance may contribute to breast cancer. In general, the protective effect of vitamin D3 against breast cancer is underlined by inhibition of proliferation and migration, stimulation of differentiation and apoptosis, and inhibition of epithelial/mesenchymal transition in breast cells. Vitamin D3 may also inhibit the transformation of normal mammary progenitors into breast cancer stem cells that initiate and sustain the growth of breast tumors. As long noncoding RNAs (lncRNAs) play an important role in breast cancer pathogenesis, and the specific mechanisms underlying this role are poorly understood, we provided several arguments that vitamin D3/VDR may induce protective effects in breast cancer through modulation of lncRNAs that are important for breast cancer pathogenesis. The main lncRNAs candidates to mediate the protective effect of vitamin D3 in breast cancer are lncBCAS1-4&#95;1, AFAP1 antisense RNA 1 ( AFAP1-AS1 ), metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ), long intergenic non-protein-coding RNA 511 ( LINC00511 ), LINC00346 , small nucleolar RNA host gene 6 ( SNHG6 ), and SNHG16 , but there is a rationale to explore several other lncRNAs.

The research question was: do the mandibular condyles change their position within glenoid fossae after treatment combining occlusal splint therapy and physiotherapy in patients diagnosed with temporomandibular disorders (TMD)? Forty patients with TMD were included into the study. They underwent initial physiotherapy, and a six-month treatment of occlusal splint therapy with physiotherapy. Cone-beam computed tomography images of temporomandibular joints (TMJs) were taken before and after the treatment. The control group consisted of 15 asymptomatic patients, who did not receive any type of occlusal treatment. The changes in the dimension of anterior, superior, posterior, and medial joint spaces after the end of the treatment in patients with TMD were statistically insignificant. The average value of condylar ratio was significantly higher after the end of the treatment ( p = 0.025). The changes in the condylar sagittal position were statistically insignificant. Occlusal splint therapy with physiotherapy did not change significantly the dimension of joint spaces, nor placed the mandibular condyles into the centric relation. Treatment of patients with TMD should not aim at gnathological concept of placing the mandibular condyles into centric relation, because centric relation appears not to be mandatory to achieve successful results of treatment in patients with TMD.

The aim of this narrative review was to present research investigating chitosan, including its general characteristics, properties, and medical and dental applications, and finally to present the current state of knowledge regarding the efficacy of chitosan in the treatment of temporomandibular disorders (TMDs) based on the literature. The PICO approach was used for the literature search strategy. The PubMed database was analyzed with the following keywords: ("chitosan"[MeSH Terms] OR "chitosan"[All Fields] OR "chitosans"[All Fields] OR "chitosan s"[All Fields] OR "chitosane"[All Fields]) AND ("temporomandibular joint"[MeSH Terms] OR ("tem-poromandibular"[All Fields] AND "joint"[All Fields]) OR "temporomandibular joint"[All Fields] OR ("temporomandibular"[All Fields] AND "joints"[All Fields]) OR "temporo-mandibular joints"[All Fields]). After screening 8 results, 5 studies were included in this review. Chitosan presents many biological properties and therefore it can be widely used in several branches of medicine and dentistry. Chitosan promotes wound healing, helps to control bleeding, and is used in wound dressings, such as sutures and artificial skin. Apart from its antibacterial property, chitosan has many other properties, such as antifungal, mucoadhesive, anti-inflammatory, analgesic, antioxidant, antihyperglycemic, and antitumoral properties. Further clinical studies assessing the efficacy of chitosan in the treatment of TMD are required. According to only one clinical study, chitosan was effective in the treatment of TMD; however, better clinical results were obtained with platelet-rich plasma.

Background/objectives: The aim of the study was to compare the stability of orthodontic treatment in cancer survivors who had been treated with cytotoxic drugs with a generally healthy control group., Materials/methods: The study included 52 cancer survivors treated orthodontically and 52 healthy control subjects matched for age, gender, and malocclusion. The weighted Peer Assessment Rating (w-PAR) index, the Index of Complexity, Outcome and Need (ICON) were assessed before treatment, after the treatment, and at the 3-year follow-up. Patients Satisfaction Score was assessed after the treatment and at the 3-year follow-up. A repeated analysis of variance test was used to check the statistical significance between the scores., Results: Ideal occlusion was achieved in all patients. The mean w-PAR and ICON values were significantly reduced in both groups after the end of the orthodontic treatment with no significant differences between the groups regarding the obtained results. However, after the 3-year follow-up, only the cancer survivors' group presented statistically significant (P < 0.001) increase of the w-PAR and ICON values comparing to the values obtained at the end of the treatment. There was no significant change in Patients' Satisfaction Score within 3 years after treatment., Limitations: The limited size of the study sample as well as different types of oncological diagnoses could have had an impact on the final results of the study., Conclusions/implications: Previous cytotoxic drug treatment significantly decreases the stability of orthodontic treatment among the cancer survivors, particularly within first 12 months after the end of the treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Orthodontic Society.)

Replication timing (RT) is a cellular program to coordinate initiation of DNA replication in all origins within the genome. RIF1 (replication timing regulatory factor 1) is a master regulator of RT in human cells. This role of RIF1 is associated with binding G4-quadruplexes and changes in 3D chromatin that may suppress origin activation over a long distance. Many effects of RIF1 in fork reactivation and DNA double-strand (DSB) repair (DSBR) are underlined by its interaction with TP53BP1 (tumor protein p53 binding protein). In G1, RIF1 acts antagonistically to BRCA1 (BRCA1 DNA repair associated), suppressing end resection and homologous recombination repair (HRR) and promoting non-homologous end joining (NHEJ), contributing to DSBR pathway choice. RIF1 is an important element of intra-S-checkpoints to recover damaged replication fork with the involvement of HRR. High-resolution microscopic studies show that RIF1 cooperates with TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs. Apart from TP53BP1, RIF1 interact with many other proteins, including proteins involved in DNA damage response, cell cycle regulation, and chromatin remodeling. As impaired RT, DSBR and fork reactivation are associated with genomic instability, a hallmark of malignant transformation, RIF1 has a diagnostic, prognostic, and therapeutic potential in cancer. Further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by RIF1.

Platelet concentrates have been widely used in regenerative medicine, including endodontics. The aim of this manuscript was to assess critically the efficacy of PRF in the treatment of endodontic periapical lesions in adult patients on the basis of the literature. The PICO approach was used to properly develop literature search strategies. The PubMed database was analyzed with the keywords: "((PRP) OR (PRF) OR (PRGF) OR (CGF)) AND (endodontic) AND ((treatment) OR (therapy))". After screening of 155 results, 14 articles were included in this review. Different types of platelet concentrates are able to stimulate the processes of proliferation and differentiation of mesenchymal stem cells. Platelet rich fibrin (PRF) releases growth factors for at least 7 days at the application site. Growth factors and released cytokines stimulate the activity of osteoblasts. Moreover, the release of growth factors accelerates tissue regeneration by increasing the migration of fibroblasts. It was not possible to assess the efficacy of PRF supplementation in the treatment of endodontic periapical lesions in permanent, mature teeth with closed apexes, due to the lack of well-designed scientific research. Further studies are needed to analyze the effect of PRF on the healing processes in the periapical region.

Synaptic activity mediates information storage and memory consolidation in the brain and requires a fast de novo synthesis of mRNAs in the nucleus and proteins in synapses. Intracellular localization of a protein can be achieved by mRNA trafficking and localized translation. Activity-regulated cytoskeleton-associated protein (Arc) is a master regulator of synaptic plasticity and plays an important role in controlling large signaling networks implicated in learning, memory consolidation, and behavior. Transcription of the Arc gene may be induced by a short behavioral event, resulting in synaptic activation. Arc mRNA is exported into the cytoplasm and can be trafficked into the dendrite of an activated synapse where it is docked and translated. The structure of Arc is similar to the viral GAG (group-specific antigen) protein, and phylogenic analysis suggests that Arc may originate from the family of Ty3/Gypsy retrotransposons. Therefore, Arc might evolve through "domestication" of retroviruses. Arc can form a capsid-like structure that encapsulates a retrovirus-like sentence in the 3'-UTR (untranslated region) of Arc mRNA. Such complex can be loaded into extracellular vesicles and transported to other neurons or muscle cells carrying not only genetic information but also regulatory signals within neuronal networks. Therefore, Arc mRNA inter- and intramolecular trafficking is essential for the modulation of synaptic activity required for memory consolidation and cognitive functions. Recent studies with single-molecule imaging in live neurons confirmed and extended the role of Arc mRNA trafficking in synaptic plasticity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Michal Fila et al.)

Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (l-kyn) pathway (KP) is the major route for l-tryptophan (l-Trp) metabolism and transforms l-Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of l-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with poorly known pathogenesis and lack of effective treatment. Age and family history are the strongest AMD risk factors, and several loci were identified to contribute to AMD. Recently, also the epigenetic profile was associated with AMD, and some long non-coding RNAs (lncRNAs) were shown to involve in AMD pathogenesis. The Vax2os1/2 (ventral anterior homeobox 2 opposite strand isoform 1) lncRNAs may modulate the balance between pro- and anti-angiogenic factors in the eye contributing to wet AMD. The stress-induced dedifferentiation of retinal pigment epithelium cells can be inhibited by the ZNF503-AS1 (zinc finger protein 503 antisense RNA 2) and LINC00167 lncRNAs. Overexpression of the PWRN2 (Prader-Willi region non-protein-coding RNA 2) lncRNA aggravated RPE cells apoptosis and mitochondrial impairment induced by oxidative stress. Several other lncRNAs were reported to exert protective or detrimental effects in AMD. However, many studies are limited to an association between lncRNA and AMD in patients or model systems with bioinformatics. Therefore, further works on lncRNAs in AMD are rational, and they should be enriched with mechanistic and clinical studies to validate conclusions obtained in high-throughput in vitro research.

Background: One of the goals of orthodontic treatment is to obtain maximum facial harmony. The sagittal position of the lower incisors plays a significant role in the planning of orthodontic treatment. The aim of the study was to evaluate the relationship between the sagittal position of lower incisors and facial profile esthetics with reference to the skeletal vertical dimension., Methods: There were 200 patients included in the study. Patients were allocated into three groups, depending on the vertical growth pattern: normal-angle, low-angle, and high-angle cases. Tweed-Merrifield cephalometric analysis was used to assess the sagittal and vertical position of the mandible, as well as to assess the sagittal position of the lower incisors., Results: Z-angle and Frankfort mandibular incisor plane angle (FMIA) decreased significantly ( p < 0.001) with the increase of the skeletal vertical dimension. Incisor mandibular plane angle (IMPA) was significantly higher ( p < 0.001) in low-angle patients compared to the high-angle ones. Z-angle appeared to be the most accurate parameter (area under curve, AUC = 0.957) describing patients with a convex profile. The cutoff value of Z-angle 68.0° was characterized by the sensitivity of 94.1% and the specificity of 84.3%., Conclusions: The sagittal position of the lower incisors significantly affects the facial profile convexity. The Z-angle is the parameter which most accurately describes the patients with a convex profile.

Temporomandibular joint osteoarthritis (TMJ OA) is a low-inflammatory disorder with multifactorial etiology. The aim of this review was to present the current state of knowledge regarding the mechanisms of action and the efficacy of hyaluronic acid (HA), corticosteroids (CS) and platelet-rich plasma (PRP) in the treatment of TMJ OA.: The PubMed database was analyzed with the keywords: "(temporomandibular joint) AND ((osteoarthritis) OR (dysfunction) OR (disorders) OR (pain)) AND ((treatment) OR (arthrocentesis) OR (arthroscopy) OR (injection)) AND ((hyaluronic acid) OR (corticosteroid) OR (platelet rich plasma))". After screening of 363 results, 16 studies were included in this review. Arthrocentesis alone effectively reduces pain and improves jaw function in patients diagnosed with TMJ OA. Additional injections of HA, either low-molecular-weight (LMW) HA or high-molecular-weight (HMW) HA, or CS at the end of the arthrocentesis do not improve the final clinical outcomes. CS present several negative effects on the articular cartilage. Results related to additional PRP injections are not consistent and are rather questionable. Further studies should be multicenter, based on a larger group of patients and should answer the question of whether other methods of TMJ OA treatment are more beneficial for the patients than simple arthrocentesis.