Synovial tissue is a key structure in diarthrodial joints and is the primary target of inflammation in autoimmune arthritis. The study of synovial tissue has developed significantly in the last two decades as arthroscopic and ultrasonographic techniques have allowed visualization and access to synovial biopsy. Further progress in synovial tissue processing and analysis has improved studies of disease pathogenesis, biomarker discovery, and molecular therapeutic targeting with increasingly specialized analytical and technological approaches. In September 2018 the first course on Synovial Tissue Biopsies was convened in Brussels, in this Mini Review these approaches will be described and I will summarize how synovial tissue research advanced. In the last two decades, considerable advances have been made in the diagnosis and therapy of RA . Howeverin vivo  interspersed with macrophages . In RA tin vivo .The analysis of synovial tissue biopsies has advanced our understanding of RA pathogenesis, yielded potential therapeutic targets, and allows detailed evaluation of new therapies , 10.Synovial tissue biopsies have been obtained by blind needle biopsy, arthroplasty, arthroscopy, and more recently using ultrasound- . ArthrosImmunohistochemical analysis of synovial tissue has a clinical role in the differential diagnosis of arthritis , the benefit in studies of personalized medicine have yet to provide a substantial advance . InteresIn the last 15 years, synovial tissue analysis has impacted the treatment of early RA using clinical, pathological, and -omic data analysis. A link between circulating ACPAs and the development of RA in subjects with arthralgia, and bone damage has been described in patients with early arthritis , 18. TheInflammatory genes overexpressed in pre-treatment biopsies might predict those RA patients most likely to responded to TNF inhibitor therapy. Another study of synovial tissue RNA suggested that transcripts associated with lymphocyte aggregates predicted response to infliximab therapy . The rolRecent advances in -omic techniques are allowing deeper molecular analysis of synovial tissue, however several challenges remain. The new technologies have become faster, better value and provide a more detailed analyses of genes, proteins, and epigenetic modifications. However, a number of commonly used microarray platforms have yielded poor reproducibility causing some problems with interpretation of data. In addition, the results of initial whole tissue transcriptional profiling await more detailed analysis. Therefore, in the last 2 years, we have developed laboratory techniques to dissociate the synovial biopsies into viable single cell subsets allowing specific analysis of the genes, proteins, and functions of the cell subsets that comprise the population in the actively inflamed synovial joint tissue .RA is characterized by inflammation of the synovial tissue, which therefore represents the target tissue of autoimmune arthritis. Various methods of sampling synovial tissue have now been validated as safe, well-tolerated by patients and minimally invasive thus they have become more widely practiced. In this Mini review I have focused on the development of synovial tissue biopsy studies including the current technological advances in analysis that allow detailed cellular and molecular experiments that define the functions of immune cells in the RA synovial tissue. These studies might allow greater understanding of the pathogenesis of RA and development of a “precision medicine” approach with improved therapy, patient stratification, development of new therapeutic targets, and development of specific biomarkers of response.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Today, pre-implantation genetic diagnosis/screening (PGD/PGS) tests are a key part of reproductive medicine in most countries. These techniques have been designed for a variety of purposes, including identification of embryos affected or carriers of monogenic diseases, identification of aneuploid embryos or selection of embryos with specific gender. Technical updates and improvements of PGD/PGS were done over time. According to CDC statistics, about 4–6% of ART cycles are candidates for PGS annually and there is evidence on the increase in request . InsomucBut in cases where couples inevitably request the transfer of mosaic embryos, the importance of post PGS consultation is more critical. The data discussed at this level should be different from pre-PGS counseling. The couples should be aware of the potential risks encountered with implantation of mosaic embryos, their lower implantation rate and higher abortion rate, the risk of fetal demise or uniparental disomy, the emotional and financial risk and also the couples should be informed that most of associated risks following mosaic embryos transfer are still unknown. Therefore, pregnancies following transfer of mosaic embryos should be referred for prenatal screening to detect any aneuploidy in the fetus . RecentlIn addition to the challenge of mosaic in PGS, there is a similar and even more important challenge for PGD in which due to economic, ethical, religious issues or couples' request, physcians are forced to transfer carrier embryos or the ones affected with single-gene disorders. There are several considerations on the request for transfer of genetically defective embryos; the couple’s reproductive autonomy and liberty, physician’s professional conscience, professional norms, laws, and practices, health of born children and psychological and medical consequences for pregnant spouse are the typical issues. Therefore, making decisions on transfer of probably defective embryos is not so simple and straightforward and consequently before the final decision, all the above considerations should be taken into consideration . In addiSince transfer of defective embryos is associated with numerous medical, psychological, and socio-economic consequences, until obtaining further information in this area, it is recommended the couples try another cycle to find healthy euploid embryos instead of tranfer of mosaic or genetically defective embryos.


It has been just over 20 years since the effects of height-induced threat on human postural control were first investigated. Raising the height of the support surface on which individuals stood increased the perceived consequences of instability and generated postural control changes. Since this initial work, converging evidence has accumulated supporting the efficacy of using height-induced threat to study the effects of emotions on postural control and confirming a direct influence of threat-related changes in arousal, anxiety, and fear of falling on all aspects of postural control, including standing, anticipatory, and reactive balance. In general, threat-related postural changes promote a greater physical safety margin while maintaining upright stance. We use the static balance literature to critically examine the current state of knowledge regarding: (1) the extent to which threat-related changes in postural control are sensitive to threat-related changes in emotions; (2) the underlying neurophysiological and cognitive mechanisms that may contribute to explaining the relationship between emotions and postural control; and (3) the generalizability of threat-related changes across different populations and types of threat. These findings have important implications for understanding the neuromechanisms that control healthy balance, and highlight the need to recognize the potential contributions of psychological and physiological factors to balance deficits associated with age or pathology. We conclude with a discussion of the practical significance of this research, its impact on improving diagnosis and treatment of postural control deficits, and potential directions for future research. Fear of falling is frequently reported in older adults , 2 and pBrown and Frank  were theSince these initial studies, physically raising the height of the support surface on which individuals stand has been used extensively to: (1) confirm the effects on standing balance control in young and older healthy adults –36, and Given the breadth of research on this topic over the past 20 years, we chose to focus on height-induced postural threat effects on standing balance control, as this represents the majority of studies conducted to date, and has the potential to influence anticipatory and reactive postural adjustments. In order to critically evaluate and allow for a direct comparison between the studies, we controlled for key factors known to influence standing balance control. A search of PubMed, PsychINFO, EMBASE, CINAHL , and hand searches, identified 89 original research articles (non-duplicate). Manual screening removed 51 articles that did not include a manipulation of postural threat/anxiety or a standing task in the study design. The remaining 38 studies were examined, and a subset of studies was selected based on the following five criteria: (1) young or older healthy adults; (2) height threat; (3) quiet standing task; (4) sample duration (≥60 s); and (5) psychological or physiological measure to confirm the efficacy of the threat manipulation. Stance duration was considered a critical factor because it has been shown to significantly affect COP summary measures , 69, 70 A consistent postural strategy emerged from the collective results of the eight studies that met our criteria. All studies revealed that young and older healthy adults leaned significantly away from the edge of the platform and significantly increased their COP sway frequency , 35, 39.Studies have utilized other methods to manipulate threat or emotions, to confirm if the effects of height are generalizable to other threat sources, and to avoid some of the context-specific limitations associated with standing on an elevated surface. One common alternative is to manipulate the threat of an impending perturbation, during which individuals are required to stand with or without the threat of experiencing a sudden, unpredictable balance disturbance, such as a push or pull to the upper trunk  or a supInitial comparisons between reported effects of height and perturbation-related threat reveal a common effect of increased frequency of COP displacements during quiet stance Figure . In contThe mechanisms that may contribute to, or explain threat-related changes in postural control remain poorly understood. In general, theories can be divided along the lines of emotionally-evoked neurophysiological changes, and/or changes in attention.Neurophysiological theories are based on the existence of highly-integrated neural networks responsible for processing emotional information, such as fear and anxiety, and sensori-motor control of upright stance  and gaitAlternatively, changes in attention may mediate threat-related postural changes , 84. It It is most likely that the effects of threat on balance control rely on a complex interaction between neurophysiological changes and changes in attentional processes. With repeated exposure to height, emotional and attentional changes are attenuated, and correspond to reduced changes in high frequency COP displacements and co-contraction of lower leg muscles. In contrast, initial height-induced posterior leaning and decreases in COP amplitude do not appear to attenuate with repeated exposure and thus may be influenced by other mechanisms  not accounted for in the study  areAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Altered metabolism in cancer cells is critical for tumor growth. One of the most notable aspects of this metabolic reprogramming lies in one-carbon metabolism. Cells require one-carbon units for nucleotide synthesis, methylation reactions, and for the generation of reducing cofactors. Therefore, the ability to rewire and fine-tune one-carbon metabolism is essential for the maintenance of cellular homeostasis. In this review, we describe how the major nutrient, energy, and redox sensors of the cell play a significant role in the regulation of flux through one-carbon metabolism to enable cell fate decisions. We will also discuss how dysregulated oncogenic signaling hijacks these regulatory mechanisms to support and sustain high rates of proliferation and cell survival essential for tumor growth. One-carbon metabolism encompasses a broad range of biosynthetic reactions that occur in the cytoplasm and the mitochondria which are essential for maintaining cellular homeostasis. These pathways catabolize different carbon sources to derive one-carbon (methyl) units to be utilized in fundamental cellular functions  into serine   is a critical rheostat for the maintenance of metabolic balance and tightly regulates many aspects of metabolism . AMPK is the energy sensor of the cell; when ATP levels are high, AMPK is inhibited allowing anabolic reactions to transpire. When ATP levels are low and AMP levels rise, AMPK is activated, inhibiting anabolism and promoting catabolic reactions to restore ATP levels  maintains the proper function of redox sensitive pathways. When redox homeostasis is disturbed, oxidative stress contributes to disease development and can also lead to aberrant cell death. Therefore, eukaryotic cells have evolved systems to tightly regulate redox balance  coordinates an evolutionarily conserved transcriptional activation pathway that mediates antioxidant and detoxification responses, which is activated in response to oxidative stress. NRF2 has been shown to lead to the upregulation of the SSP and SHMT enzymes, through induction of ATF4 H production, one-carbon flux induced by these oxygen and redox sensing pathways also contributes to the maintenance of the oxidative balance through generation of glutathione , breast cancer, and melanoma (Locasale et al., More recently, it has been established that the repression of tumor suppressor genes by methylation, which is dependent on SAM levels, is a key-initiating event for many cancers (Kulis and Esteller, Glycine metabolism has also been shown to be important in cancer development and growth. The main enzyme in the glycine cleavage pathway, GLDC, is upregulated in lung-tumor initiating cells as well as glioblastomas, and sustained GLDC hyperactivity has been shown to be critical for tumorigenesis (Zhang et al., In many cancer types, proto-oncogenes have their function altered, thus contributing to hijacking of the regulatory mechanisms that preserve homeostasis in healthy cells (Gomes and Blenis, In support of this idea, the oncogene MYC has been shown to hijack regulatory pathways to increase flux through one-carbon metabolism in different cancers. For example, C-MYC induces SSP activity under nutrient deficient conditions in liver carcinomas (Sun et al., Oncogenic mutations promoting constitutive KRAS activation, one of the most common occurrences in cancer, correlates with increased expression of folate cycle enzymes (Moran et al., The tumor suppressor p53 is also known to play a key role in one-carbon metabolism regulation. p53 is responsible for halting the cell cycle in conditions of stress, preventing uncontrolled proliferation (Maddocks et al., de novo serine synthesis. Upregulation of the SSP allows for flexibility to fuel various downstream pathways. Additionally, this phenomenon can be explained by the Warburg effect, where glucose consumption and oxidation become dysregulated to allow for rapid growth and proliferation (Liberti and Locasale, de novo serine synthesis, 3PG. By upregulating the SSP and other enzymes necessary for one-carbon metabolism, glucose-derived carbon can be shunted to a process capable of producing a variety of biomolecules and redox species (Lunt and Vander Heiden, It is notable that the majority of evidence regarding oncogenic regulation of one-carbon metabolism lies in the upregulation of These examples demonstrate that activation and/or loss of oncogenes and tumor suppressors override the control of sensing mechanisms and drive flux through one-carbon metabolism, allowing tumors to thrive Figure .As a growing body of evidence supports the key role of one-carbon metabolism in cancer, it becomes of interest to expand our knowledge on how one-carbon metabolism is regulated. Here, we propose that one-carbon metabolism integrates the nutrient, energetic, and redox statuses of cells, and that flux through associated pathways is fine-tuned to reflect said status and to ensure cellular homeostasis. Taking into consideration the critical role of one-carbon metabolism as a producer of reducing power and building blocks, as well as its part in regulating substrates for epigenetic and post-translational modifications, an important line of questioning emerges. What determines preferential utilization of the mitochondrial vs. the cytosolic folate cycle? Can we take advantage of one-carbon metabolism for the development of more efficacious cancer therapies? Additionally, can we use one-carbon metabolism as a predictor of responsiveness to chemotherapies such as methotrexate and 5-FU? Is one-carbon metabolism and its remarkable flexibility responsible for the development of drug resistance? The answers to these questions are still largely unknown but may prove vital for advances in precision medicine and the treatment of cancer.APG conceived, wrote and edited the manuscript. AR wrote and JB edited the manuscript.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.


Biomechanical modelsof stress study during exercise demonstrate that the tibia is the bone subjected to thegreatest compressive load during running, as well as that thigh muscle fatigue and theaddition of load during exercise significantly increase the risk of developing fracturesof stress.Stress fractures are a common clinical problem, especially among soldiers and athletes.At the 2016 Olympics in Rio de Janeiro, stress fractures were detected in 36% of theathletes with abnormal imaging tests, the most common location being thetibia. Planar X-ray and ultrasound, despite their low cost, show limitedsensitivity in this context. An abnormal X-ray has a high diagnostic capacity, althoughit is often a late finding and is uncommon. Computed tomography (CT) can add useful anatomical information,but it is not part of the routine investigation of suspected cases of stress fractures.A study conducted by Groves et al. demonstrated that the sensitivity of CT is lower thanis that of bone scintigraphy, and that CT can be a better option when scintigraphyproduces inconclusive results.Recently, the American College of Radiology published the appropriateness criteria forthe investigation of patients with suspected stress fractures and recommended the use ofmagnetic resonance imaging (MRI) as the method of choice for the identification ofstress fractures that were not readily diagnosed by conventional radiology. MRI offers excellent spatialresolution and superior ability to assess bone marrow involvement. Three-phase bonescintigraphy is considered a useful, effective method for evaluating patients withsuspected stress fractures, especially those with lower limb injuries, having theadvantages of high sensitivity, wide availability, and low cost. However, scintigraphy has limitationsdue to the possibility of false-positive results in cases of focal infections or smalltumors. Novel techniques of bone scintigraphy optimization, such as single-photonemission CT/CT (SPECT/CT), significantly increase the specificity of this method for thedetection of stress fractures.However, there are no direct studies comparing its accuracy with that of MRI in thiscontext. Therefore, the use of imaging techniques for the diagnostic evaluation offractures presents an array of evidence that guides clinical use. In contrast, there isa relative scarcity of data in the literature regarding the use of imaging in monitoringthe recovery of stress fractures. Classifications of the degree of impairment seen onMRI, such as that proposed Fredericson et al., are widely used but have not been objectively studied fortheir correlation with patient recovery time. Although quite relevant, defining theoptimal recovery time for a given stress fracture continues to pose a challenge forspecialists in the area.The clinical diagnosis of stress fracture can represent a clinical challenge and meritsadequate evaluation by imaging methodsRadiologia Brasileira, whichevaluated the potential of scintigraphy to facilitate the clinical management ofpatients diagnosed with stress fractures. Using the score devised by Chisin et al. as the basis for quantification of thefindings, the authors demonstrated an objective correlation to estimate the appropriaterecovery time after a tibial stress fracture. Castropil et al. found a statistically significantlinear relationship between the quantification of uptake and the time required foradequate recovery. These encouraging results, because of the potential impact on themore assertive behavior of patients recovering from stress fractures, open space for newclinical studies. A validation of the relationship found in the study in question, withlarger cohorts and stress fractures from other locations, is highly desirable. Otherpromising analyses could be related to the increase in improvements already available inthree-phase bone scintigraphy, such as lateral projections or SPECT of the balanceimages and quantifications using the SPECT and SPECT/CT images. It is known that CTfindings, such as characterization of the periosteal reaction and absence of thefracture line, can be quite useful in evaluating the healing of stress fractures.Therefore, the addition of these anatomical aspects to the greater sensitivity of themetabolic information provided by bone scintigraphy with SPECT/CT could enhance theability of the method to estimate the time needed for adequate recovery of patients withstress fractures. In conclusion, the authors have provided us with relevant informationabout the prognostic capacity of bone scintigraphy and have laid the groundwork forsubsequent clinical applications.In view of the difficulties discussed above, we congratulate Castropil et al. on theirstudy, published in the previous issue of the


Twenty-two states have turned to managed care organizations to finance and deliver long-term services and supports (LTSS) as a way to control costs, improve quality and shift the locus of care away from institutional settings. These programs, referred to as Managed Long-Term Services and Supports (MLTSS) have been undertaken under several CMS authorities, and vary in terms of the program design and populations covered. Some programs such as the financial alignment demonstration, have integrated Medicaid and Medicare financing, while others have used waiver authority and three-party agreements to achieve coordination. However, all efforts share the same goal of improving the linkage between LTSS and both physical and behavioral health care. This presentation will provide conceptual framework for understanding and assessing program impact using the example of the multi-method evaluation of the $4 billion Pennsylvania Community HealthChoices program, one of the largest transitions in Medicaid policy to date.


Bisphosphonates are drugs indicated for the treatment of bone metabolic diseases or malignant hypercalcemia. They are generally well-tolerated drugs, however, recent reports have described osteonecrosis of the jaw bones as a potentially serious complication related to the long-term use of these drugs. We report a case of severe osteonecrosis in a 52-years-old white woman that was taking bisphosphonates  for the management of osteoporosis. Following a long exposure to these drugs and after being subjected to multiples exodontias, developed bisphosphonate-related osteonecrosis of the jaw compromising the whole maxilla and that extended toward the base of skull. Due to the extent of osteonecrosis, total maxillectomy and removal of all adjacent necrotic bone were planned guided by ultraviolet light. fluorescence. This case illustrates that if not treated correctly, bisphosphonate-related osteonecrosis of the jaw may cause significant morbidity, affect the quality of life and can eventually produce significant morbidity with the dissemination to noble structures and potentially causing life-threatening complications. Key words:Osteonecrosis, bisphosphonate, bisphosphonate-associated osteonecrosis of the jaw, maxilla, osteoporosis.  Bisphosphonates are medications indicated for the treatment of bones metabolic diseases, including osteoporosis, osteogenesis imperfecta, Paget disease or for management of malignant hypercalcemia, such as those associated with multiple myeloma; cervical, lung or mammary cancer. They are generally a well-tolerated drugs, causing few side effects, such as gastrointestinal symptoms, transient low grade fever, arthralgias and increased bone pain for the injectable drugs. In addition, elevated serum levels of creatinine have been observed in some cases. However, recent reports have described osteonecrosis of the jaw bones as a potentially serious complication associated with the long-term use of these drugs .This complication is more frequent in women than in men and the mean age is 66 years. The incidence of BRONJ is higher in the mandible than in the maxilla, with a 2:1 ratio . The staThe aim of the present study is to present an atypical case of BRONJ that, due to its severity it was necessary to perform total maxilectomy.A was 52-years-old white woman with history of hypertension, diabetes, rheumatoid arthritis treated with corticoid (prednisone 10mg/day) was evaluated in our department with complains of recurrent infections and maxillary bone exposure. The patient reported that from 2007 started treatment for osteoporosis with zoledronic acid (5mg/month) that was replaced after five years by oral alendronate sodium (70mg / week). In 2013 underwent multiple exodontias and after 10 months developed persistent pain, recurrent infections and bone exposure at the sites of extractions. The patient was treated with multiple antibiotics and curettage by her general dental practitioner. In 2016, after worsening of the condition, she was referred to the Department of Oral and Maxillofacial Surgery of Universitary Hospital .The clinical examination revealed edema and erythema in the third middle of the face, total maxillary edentulism, presence of necrotic bone exposure involving an extensive area of the maxilla associated with dehiscence in the alveolar and palatine mucosa on the left side and minor points on the right side Fig. A,B whichThe initial management included treatment for infection and the acute pain. The patient was given Amoxicillin 500mg plus Clavulanic Acid 125mg and Paracetamol 500mg as well as mouthwash (chlorhexidine digluconate 0.12%). Subsequently, due to the extent of osteonecrosis, total maxillectomy and removal of all adjacent necrotic bone were planned. Bone resection was guided by ultraviolet light fluorescence through the use of 100mg doxycycline twice daily for 10 days prior to surgery (Fig. After a period of Six-months, complete tissue healing was observed Fig. D,E PostoBRONJ most commonly affects women, due to cases involving treatments for breast cancer and osteoporosis and the mean age is 68 years ,8. The rBRONJ can be misdiagnosed as alveolar osteitis, sinusitis, gingivitis / periodontitis, periapical pathologies, fibro-osseous lesion, sarcoma and chronic sclerosing osteomyelitis . In thisThere are rare cases of spontaneous development BRONJ, most cases affect patients who underwent dentoalveolar surgeries. Therefore, patients and practitioners should be advised about the relation of treatment with bisphosphonates and the risk of developing BRONJ. Patients who will start bisphosphonate treatment, if medical conditions allow it, should delay the treatment until oral health is optimized to minimize the risks of developing BRONJ, this decision must be made together with the patient´s physician .The incidence of BRONJ depends on the type of medication used, duration of administration, and medical conditions such as the presence of systemic diseases, associated medication and local lesions. The patient in this report had multiple systemic diseases such as diabetes mellitus, rheumatoid arthritis and was also using corticosteroids and various studies have reported that the use of corticosteroids, immunosuppressive therapies and diabetes mellitus are considered important risk factors for the development of this complication .The extent of bone resection, in most cases, is subjective and depends on the transoperative parameters. Characteristics that do not correlate with bone vitality, such as coloration, bone bleeding and others, are observed. As a way to allow surgical standardization, fluorescence-guided bone resection has emerged and is a technique that allows the surgeon to distinguish between viable and necrotic bone, so there is no other technique that allows visualization of residual necrotic bone . The fluIn the case presented here, due to dehiscence caused by osteonecrosis and cicatricial retraction, the patient develops oro-antral communications. A treatment plan was established with the use of three layers: 1 - Surrounding oral mucosa; 2 - Buccal fat pad as pedicled graft and 3 - Myomucosal tunneling flap from the buccinator muscle. The buccal fat pad has been proved to be a low risk approach and is associated with high success rate, including for the closing of large oral communications like this one . FurtherPentoxifylline and Tocopherol were used in this case in order to improve vascularization, accelerate healing and to avoid fibrosis of adjacent soft tissues. Pentoxifylline is used in the management of vascular diseases, such as ischemic heart disease and intermittent claudication, improves peripheral blood flow, increasing flexibility and vasodilation of erythrocytes. It also inhibits tumor necrosis factor alpha and may decrease inflammatory reactions and fibrosis. It is also very likely to have an effect on the decrease of pain and the acceleration of scarring of radiation-induced soft tissue necrosis. Tocopherol reduces oxygen free radicals, its antioxidant properties occur through the inhibition of platelet aggregation and also reduces tissue fibrosis. The combination of these two medications is well tolerated and has shown efficacy in the treatment of BRONJ .We report an atypical case of BRONJ extending across the maxilla and getting close to skull base. If not treated correctly, this pathology can evolve severely to affect the quality of life and can eventually produce significant morbidity with the dissemination to noble structures and potentially causing life-threatening complications.


Ostracoderms (fossil armoured jawless fishes) shed light on early vertebrate evolution by revealing the step-wise acquisition of jawed vertebrate characters, and were important constituents of Middle Palaeozoic vertebrate faunas. A wide variety of head shield shapes are observed within and between the ostracoderm groups, but the timing of these diversifications and the consistency between different measures of their morphospace are unclear. Here, we present the first disparity (explored morphospace) versus diversity (number of taxa) analysis of Pteraspidiformes heterostracans using continuous and discrete characters. Patterns of taxic diversity and morphological disparity are in accordance: they both show a rise to a peak in the Lochkovian followed by a gradual decline in the Middle-Late Devonian. Patterns are largely consistent for disparity measures using sum of ranges or total variance, and when using continuous or discrete characters. Pteraspidiformes heterostracans can be classified as a “bottom-heavy clade”, i.e., a group where a high initial disparity decreasing over time is detected. In fact, the group explored morphospace early in its evolutionary history, with much of the subsequent variation in dermal armour occurring as variation in the proportions of already evolved anatomical features. This Early Devonian radiation is also in agreement with the paleobiogeographic distribution of the group, with a maximum of dispersal and explored morphospace during the Lochkovian and Pragian time bins. Protopteraspis are stratigraphically the oldest Pteraspidiformes first occurring in the Pridoli  are a paraphyletic assemblage comprising the jawed vertebrate stem group, which dominated the early vertebrate assemblages, first appearing with high levels of diversity in the Silurian . Seen wi Pridoli . The Ancd rostra . The Ancd rostra . Other fd rostra , which cdorostum . Randle dorostum  . According to several authors  disparitc = 2 Transformation Exponent), preferable to the simple Euclidean distance (see Helaspis and Psephaspis has been replaced by a question mark being polymorphic in the two taxa (two states of the character present). The PCO scores were used to calculate disparity, both as total variance and as sum of ranges, for the discrete character dataset  with fairly low levels of diversity , and theDisparity for the discrete characters  follow aSimilarly to the discrete characters the trend of disparity as sum of ranges for the continuous characters , closelyMorphospace occupation for the discrete characters and continuous characters through time can be seen in Psammosteus occurring completely within the morphospace of the Doryaspidae. Many Pteraspidoidei incertae sedis fall within the convex hull identified by the families recognized by Eucyclaspis, Parapteraspis, and Podolaspis.Other patterns seen in the continuous character plot  includesAlthaspis occurring in the shared morphospace. A second overlap in morphospace occupation is observed in the ranges of Protaspididae and Protopteraspididae, with Tuberculaspis and Lampraspis falling well inside the morphospace of Protopteraspididae. Among the Pteraspidoidei incertae sedis, the taxa Djurinaspis, Dnestraspis, Europrotaspis, Lamiaspis, Larnovaspis, Oreaspis, Pteraspis Semipodolaspis and Unarkaspis are not included in any convex hull identified by the PCA; Mylopteraspis, Eucyclaspis fall within the Protaspididae; Alaeckaspis, Blieckaspis, Eucyclaspis, Mylopteraspidella, and Protaspis fall within the morphospace of Protopteraspididae; Parapteraspis and Pirumaspis fall within the convex hull identified by the Rhinopteraspididae. Compared to the result obtained with the continuous characters , a greater and substantial separation is evident among the families of Pteraspidiformes in morphospace.The scatter plot of the PCA conducted on discrete characters is shown in Diversity-disparity curves show that the disparity as sum of the ranges and total variance provide completely compatible and mostly superimposable macroevolution trends for classical discrete characters , whereasan important and broadly applicable tool for quantitative paleobiological analyses” . It follows that part of the original biological variation, expressed as disparity, will be missing from the cladistics dataset analyses. However, in addition to encompassing the gain and loss of structures, they readily allow all aspects of organismal biology to be captured, as opposed to morphometrics which, for entirely practical reasons, is invariably only ever applied to proxy components of anatomy” , with much of the subsequent variation in their dermal armour occurring as variation in the proportions of already evolved anatomical features  and 3. CExtending the classic diversity categories identified by The discrete and continuous characters display differing patterns of overall morphospace occupation for the different taxonomic groups . The conIn this paper we present the first disparity (explored morphospace) versus diversity (number of taxa) analysis of Pteraspidiformes heterostracans using continuous and discrete characters. Patterns of morphological disparity and taxic diversity are in accordance, both showing a rise to a peak in the Lochkovian followed by a gradual decline in the Middle-Late Devonian.The Pteraspidiformes, unlike other groups of heterostracans  arose later in the evolutionary history of the Heterostraci (the first heterostracans are from the Wenlock) . Therefo10.7717/peerj.5249/supp-1Appendix S1Click here for additional data file.10.7717/peerj.5249/supp-2Appendix S2Click here for additional data file.


Children with “metabolically healthy obesity” (MHO) are a distinct subgroup of youth with obesity, who are less prone to the clustering of cardiometabolic risk factors. Although this phenotype, frequently defined by the absence of metabolic syndrome components or insulin resistance, was first described during the early 1980s, a consensus-based definition of pediatric MHO was introduced only recently, in 2018. The purpose of this review was to concisely summarize current knowledge regarding the MHO phenomenon in youth. The prevalence of MHO in children varies from 3 to 87%, depending on the definition used and the parameters evaluated, as well as the ethnicity and the pubertal status of the sample. The most consistent predictors of MHO in youth include younger age, lower body mass index, lower waist circumference, and lower body fat measurements. Various hypotheses have been proposed to elucidate the underlying factors maintaining the favorable MHO phenotype. While preserved insulin sensitivity and lack of inflammation were previously considered to be the main etiological factors, the most recent findings have implicated adipokine levels, the number of inflammatory immune cells in the adipose tissue, and the reduction of visceral adiposity due to adipose tissue expandability. Physical activity and genetic factors also contribute to the MHO phenotype. Obesity constitutes a continuum-increased risk for cardiometabolic complications, which is less evident in children with MHO. However, some findings have highlighted the emergence of hepatic steatosis, increased carotid intima-media thickness and inflammatory biomarkers in the MHO group compared to peers without obesity. Screening should be directed at those more likely to develop clustering of cardiometabolic risk factors. Lifestyle modifications should include behavioral changes focusing on sleep duration, screen time, diet, physical activity, and tobacco smoke exposure. Weight loss has also been associated with the improvement of insulin sensitivity and inflammation. Further investigative efforts are needed in order to elucidate the mechanisms which protect against the clustering of cardiometabolic risk factors in pediatric obesity, to provide more efficient, targeted treatment approaches for children with obesity, and to identify the protective factors preserving the MHO profile, avoiding the crossover of MHO to the phenotype with metabolically unhealthy obesity. The global epidemic of childhood obesity, with the accompanying rise in the prevalence of endocrine, metabolic, and cardiovascular comorbidities in youth, represents one of the most important public health issues of the modern world –4. The eIn the context of the childhood obesity pandemic, a distinct subgroup of youth with obesity less prone to the development of metabolic disturbances, called “metabolically healthy obese” (MHO), has come into focus , 8. DespAlthough MHO status might not necessarily translate into lower mortality, and can crossover to “metabolically unhealthy obese” (MUO) phenotype during puberty, defining the MHO subpopulation within the youth with obesity is of high importance in order to elucidate the mechanisms protecting against the clustering of cardiometabolic risk factors, and for its clinical, preventive, and therapeutic decision-making implications , 13–17. Although MHO phenotype was first described during the early 1980s, and is frequently defined  by the absence of MS components and/or preserved insulin sensitivity, a consensus-based definition of pediatric MHO was introduced only recently, in 2018 , 19, 20.sine qua non for youth with MHO. The cutoff values for obesity have differed amongst studies from the 85th to 97th percentile of body mass index (BMI) according to the Centers for Disease Control and Prevention (CDC) growth charts, while other researchers have used the World Health Organization (WHO) criteria, waist circumference (WC) or waist-to-height-ratio  preht-ratio , (d) othht-ratio , 30, 31.ht-ratio . Furtherht-ratio , 32–36.Finally, in 2018, Damanhoury et al. proposed the first international consensus-based definition of MHO [One of the advantages of using the consensus-based definition proposed by Damanhoury et al. is the fact that most of the cutoff values are based on cutoffs provided by the International Diabetes Federation (IDF) definition of MS in youth, and are therefore widely used and known by clinicians and researchers dealing with pediatric obesity. The use of IDF MS cutoff values should facilitate comparison with future studies, and these fasting measures have also been shown to be reliable and valid for use in the population of youth with obesity , 13, 31.It should be noted, that the consensus-based MHO definition lacks important indicators of “metabolic health,” such as indicators of hepatic steatosis, immune, and inflammation markers. In addition, insulin resistance, a component considered to have a central role in the development of the obesity related cardiometabolic risk factors, is not included in this definition , 13. TheThe ideal definition of MHO should include (in addition to the MS components) the degree of visceral adiposity, insulin sensitivity, markers of hepatic steatosis, inflammatory, and immune parameters, although as yet, no consensus has been reached on the use of these parameters  in defining MHO . Thus, tThe estimated prevalence of children with MHO has differed significantly in previous studies, in large part due to the various definitions used. As already stated, until 2018 there was no consensus regarding the definition of MHO in pediatrics and the criteria used for defining both the obesity and MHO/MUO status varied widely. Moreover, the groups studied were significantly distinct from one another . Bearing all this in mind, the overall estimated prevalence of metabolically healthy phenotype in children of all weight status varied from 7 to 21%, whereas the prevalence of MHO among overweight and obese children varied from 3 to 87% , 38–56.Even though the protecting factors keeping the children with MHO on the healthy side of the metabolic phenotype, despite the increase in adiposity, have not yet been fully elucidated, many authors have tried to identify the predictors of MHO status. The adiposity rebound, the early increase in BMI-SDS occurring in some children between the ages of 3 and 7 years, is known to be a significant risk factor for later obesity . A recenPubertal status also plays a significant role in the development of both MHO and MUO phenotypes in youth with obesity. Puberty is a period of dynamic physiological changes, including a well-described physiological decrease in insulin sensitivity . A longiIn an attempt to address the predictors of the MHO phenotype in youth, a recent large-scale, cross-sectional Chinese study of 7,926 children and adolescents aged 7–16 years in all weight ranges found that those with the metabolically healthy obesity phenotype were younger, and had lower BMI-SDS, WC, and body fat measurements . AnotherAmong children and adolescents with overweight and obesity, the most consistent predictors for being metabolically healthy, as described in the previous studies were lower WC measurements , 61, 62,Acanthosis nigricans , may contribute to the metabolically healthy or unhealthy status , 97–99. The liver plays a major role in both carbohydrate and lipid metabolism through several metabolic pathways, with the ectopic accumulation of lipids in the liver causing NAFLD and having the strongest effect on the metabolic profile , 113. GeGenetic factors also play a role in the development of MHO and MUO phenotypes in youth with obesity. Recently published genome wide association studies have shown the relationship between some genetic loci and BMI , 123, adIf not diagnosed early, prevented and treated, obesity in children and adolescents leads to the development of T2D, hypertension, dyslipidemia, atherosclerosis, and consequently a higher incidence of cardiovascular premature death in adulthood , 129. AlAlthough children with MHO are usually defined as being without traditional cardiometabolic risk factors within the MS definition, several studies have detected the presence of other features among this population, such as: hepatic steatosis, increased carotid intima-media thickness, and inflammatory biomarkers, as well as higher degree of visceral fat accumulation, higher birth weight, adipose cell size, and different gene expression-encoding markers in adipose tissue , 130–134The development or deterioration of cardiometabolic risk factors in children with MHO could potentially be prevented using specific measures such as low-intensity exercise. It is plausible that metabolic deterioration and crossover to MUO could be avoided in youth with MHO if a modest weight reduction is achieved or weight gain prevented . AlthougThe management of children with MHO should not differ from the management of any child with obesity and therefore should emphasize preventive strategies, such as the promotion of a healthy lifestyle, especially targeting those with early onset obesity or rapid weight gain . In geneMore studies are required to clarify the effects of different therapeutic approaches for the MHO profile in childhood. Most of the current data available is derived from studies performed in adults, and results from longitudinal studies of youth with obesity (both MHO and MUO) will hopefully help to identify appropriate intervention strategies for children with obesity, according to their metabolic health status. Promising research linking MHO patients and additional cardiometabolic risk factors such as NAFLD, inflammatory biomarkers and carotid intima-media thickness, although not currently included in either MS or MHO consensus criteria, will be useful to identify and manage both MHO and MUO alike.In conclusion, the use of a single/universal definition of MHO in childhood is highly beneficial for advancement in the field. We recommend use of the international consensus-based definition proposed by Damanhoury et al. to define the MHO phenotype in youth with obesity. When accessible, additional measures of “metabolic health” can also be included. This is crucial in order to have comparable results and further our understanding of the MHO phenomenon in children and adolescents. More data is needed in order to indentify the parameters which have the highest ability to predict clinically significant outcomes.Future studies will improve our understanding of the prevalence, predictors and protective factors in MHO, as well as the underlying mechanisms leading to the crossover from MHO to MUO during puberty. The MHO status should be defined and controlled for during longitudinal interventional studies, in order to account for possible differences in treatment outcomes compared to the rest of the population with obesity. This could influence the development of targeted preventive and treatment strategies for youth with obesity with or without cardiometabolic risk factors in the future. Until then, the same therapeutic approaches and weight goals should be used in children with MHO, with the emphasis on the prevention and promotion of healthy lifestyle habits.RV conceptualized the manuscript, drafted the sections regarding background, and definitions of MHO. MY drafted the section regarding prevalence and predictors. MA drafted the section regarding mechanisms. TD drafted the section regarding the treatment and outcomes. All authors reviewed and revised the manuscript and approved the final version.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.


Structural and functional specializations of neurons and glial cells, and the dynamical nature of their connections, allow the precise modulation of homeostatic variables and the ongoing behavioral display. Synaptic transmission and plasticity are key cellular processes that enable the nervous system to process information, respond and adapt to a changing environment and internal milieu. In the last few years, the field of synaptic plasticity/modulation has undergone dramatic advances, in particular in the study of the mammalian central nervous system.This Research Topic provides a state-of-the-art and comprehensive collection of studies focusing on the various mechanisms for modulation of synaptic formation and transmission. Articles depict relevant data about the molecular and structural basis of neuronal cell signaling, plasticity of dendritic spines, synaptic and extrasynaptic transmission, neuronal-glial interactions, modulation of chemical transmitters release, and their functional role, receptor types, and signal transduction up to the level of neural network properties under physiological conditions or related to brain disorders.Petralia et al. reviewed the structural features to classify invaginating structures at chemical synapses into three categories in the central and peripheral nervous system. Ultrastructural data demonstrate the existence of these elements in presynaptic axonal terminals, postsynaptic spines or dendrites, and glial processes. Spinules and related structures compose the first type of protrusions, which do not present synaptic active zones, whereas the other two categories show active zones within the invagination. Postsynaptic spines that protrude directly into the presynaptic terminal exemplify the second type. Presynaptic terminals that protrude directly into the postsynaptic structure, such as at the neuromuscular junction, represent the third type. Evidence indicate that these specialized invaginating structures have to be carefully considered when further evaluating the mechanisms for neuronal cell signaling.Mederos et al. reviewed the existing data supporting the crucial roles of astrocytes in synaptic function. These authors described the correlation between structurally- and functionally- different astrocyte populations, by highlighting the current data regarding the heterogeneity of anatomical, molecular, and functional properties of astrocyte–neuron communication. This article critically demonstrates the specialized role of these glial cells in the synaptic transmission and plasticity in different brain areas.Del-Bel and De-Miguel reviewed the mechanisms of extrasynaptic release of transmitters, by exocytosis or diffusion, from the soma, axon, and dendrites in the absence of postsynaptic counterparts. These authors compared the mechanisms of classic transmitters release, peptides, nitric oxide, and cannabinoids and explored how extrasynaptic transmission interacts to modulate visual sensitivity and blood flow. It is commented on the importance of considering extrasynaptic communication as an important component to understand the function of different neural circuits.Repetto et al. provided original data into specific roles of individual domains of the multidomain protein Neurobeachin (Nbea) in spine formation, postsynaptic neurotransmitter receptor targeting, and actin distribution. By using live cell imaging and patch-clamp electrophysiology, these authors monitored the structure and function of spinous synapses in primary hippocampal neurons of wild type and Nbea KO mutant mice. They showed the function of specific domains of Nbea in restoring normal dendritic spine density and surface targeting of AMPAR subunits, and in regulating filopodia extension. Interestingly, as the heterozygous mutations in Nbea occur in autistic patients, these findings provides new understanding of the mechanism underlying neuropsychiatric disorders associated with impairments of spine function.Aubrey and Supplisson provided original data on the heterogeneous signaling at GABA and glycine co-releasing terminals. Using cultured spinal neurons and a combination of loose-patch and whole-cell electrophysiology, these authors have demonstrated that miniature inhibitory postsynaptic currents (mIPSC) originated from terminals containing both GABA and glycine. Their modeling approach predicts that, when glycine gradually replaces GABA in synaptic vesicles, “the redistribution between the peak amplitude and charge transfer of mIPSCs acts to maintain the strength of inhibition while increasing the temporal precision of signaling.” These new data add considerably to the interpretation of changes in synaptic signaling, the strength and plasticity of inhibitory transmission, and the functional role for the corelease of GABA and glycine at central synapses.Cheng et al. used genetic, electrophysiological, and pharmacological approaches in cultured hippocampal neurons to determine the role of protein kinases and synapsins in two forms of activity dependent, short-term synaptic plasticity that enhance neurotransmitter release. In this original research article, authors provided novel evidence that PKA and synapsins, apparently the main substrates of PKA, are important for augmentation of spontaneous glutamate release at excitatory synapses. These results elucidate important signaling pathways involved in these two forms of short-term plasticity.Fontes-Dutra et al. showed original results on altered localization of parvalbumin expressing neurons and reduced level of gephyrin in primary sensory cortex in the valproic acid animal model of autism spectrum disorder (ASD). Their results highlighted the importance of changes in GABAergic transmission during brain development. In addition, they demonstrated that resveratrol could have an important effect in rescuing the gephyrin expression in the studied rats.Rajamani et al. reviewed the role of the neuropeptide oxytocin (OXT) as modulator of synaptic plasticity and neural activity in circuits that regulate social behavior in neurodevelopmental disorders, including ASD. This work highlights studies that report specific alterations in the OXT system in rodent models and explored the potential convergence between the OXT system and genes associated with brain disorders, focusing on the SHANK3 gene. These authors showed evidence supporting the hypothesis that failure of the OXT system during early development could affect social behavior by altering synaptic activity and plasticity.Rigas et al. report original findings on the impact of early life seizures (ELS) on the network dynamics of the mouse neocortex. Single or multiple seizures were induced using pentylenetetrazole at two different brain developmental stages , and cortical electrophysiology was assessed by comparing spontaneous network activity (in the form of recurring Up states) in slices of the primary motor and the somatosensory areas of animals at adulthood. Interestingly, results showed that long lasting changes induced by seizures depend on their severity, are region-specific, and are related to the brain maturation period at which the seizures are induced. For example, “single intermittent ELS at P19–23 had no effect on Up state activity, but multiple seizures induced during the same period caused a significant change in the spectral content of spontaneous Up states.”Quillfeldt provides a Hypothesis and Theory article, discussing a series of findings in which systems consolidation temporal framework changes according to the nature of the behavioral task interposed between the training and the remote test. He proposes a hypothetical “reset” mechanism acting upon a fixed/limited pool of plastic synapses in the CA1 hippocampal area, according to their level of occupancy, to explain the observed temporal flexibility of systems consolidation. The occupancy/reset theory conceives putative CA1 synapse populations with different levels of ability to reset, providing not only a common basis for both synaptic and systems consolidation, but also explaining the different dynamics of episodic and semantic memories.These current articles highlighted relevant mechanisms of synaptic activity with physiological and/or pathological implications. Indeed, the spatiotemporal modulation of synaptic function is crucial for emergent properties of neural cells, networks, and behaviors. This is a broad and vivid research area. We foresee new approaches and working hypotheses from the data of this Research Topic to the endeavor of understanding the functional organization of the central nervous system.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Objective: Infertility causes psychological and social problems in many infertile women, men, and couples, and the most common of which is anxiety. Also, assisted reproductive treatments (ART) increase anxiety. Numerous medical and community associations have strongly recommended psychosocial interventions and counselling to help infertile couples.Method: A review was done on studies published from 1982 to 2018 that were indexed in Medline, ISI Web of Knowledge, and Scopus. The references of each article were used for more resources and references.Results: Most psychosocial interventions were effective on infertile women, men, and couples. These articles showed a significant decrease in anxiety with CBT interventions, body-mind interventions, and other interventions.Conclusion: All interventions based on CBT, most interventions based on body-mind, and some other interventions are effective in treating anxiety in infertile women and men. Infertility means not having children after one year of regular sexual life without using contraception techniques . AccordiMen and women undergoing ART experience high stresses related to both the experience of infertility and participation in associated medical treatments . The proAn updated review is needed to determine what psychosocial interventions may affect infertility-related anxiety. In addition, it is important to review the outcomes of studies that conducted psychosocial intervention to treat anxiety in infertile men and women. This systematic review was performed in 2018 to review all studies published from 1982 to 2018. Because of different tools and types of interventions, contradictory results, and high heterogeneity of the studies, no meta-analysis was done. These articles were indexed in Medline, ISI Web of Knowledge, and Scopus. Also, abstract books on this subject, regardless of type of study, its publication status, language, sex of individuals, or treatment protocols, were included in this review. We also corresponded with the authors of cited references for more resources and references. The research strategy involved general and specific terms related to infertile women, including "psychology", "psycological", "intervention", "method", "methodological", "procedure", "hypervigilance", "nervousness", "social anxiety”, ”anxiety” "infertility" and "sterility". The main inclusion criteria were as follow: assessment of psychosocial interventions multidimensionally using general or specific interventions on anxiety; use of standard interventions assessing psychosocial interventions on anxiety in infertile men and women. All procedures were performed by two independent researchers and any disagreement between them was evaluated by interviewing them and then by feed-back from a third person. The abstracts and full-texts of the papers were primarily reviewed for rejection or acceptance. Then, the full-texts of the accepted papers were critically evaluated and the needed data were extracted. Because the tools and types of interventions were different, contradictory results were observed, and heterogeneity of the studies was high, no meta-analysis has been used. The authors' names and those of the journals and the results were concealed from the researchers. To identify interventions on anxiety in infertile men and women, Medical Outcomes Trust  was usedAmong 2945 studies obtained from physical and electronic resources, some studies were repetitive and some found to be irrelavant after reviewing their abstracts or full-texts, and thus were excluded. In total, 52 studies were reviewed and analyzed .After initial assessment and comparison of the results, the papers were categorized based on the following criteria: (a) design of interventions; (b) quantitative assessment of psychological interventions in different cultures; (c) assessment of anxiety in patients under treatment and evaluation of the effects of therapeutic interventions on improving quality of life; and (d) assessment of the impact of psychological interventions on anxiety in infertile couples. Psychological interventions that are frequently used for anxiety in infertile men and women are as follow:(A) CBT interventions; (B) Body-Mind Interventions; and (C) Other InterventionsCBT interventionsCognitive-behavioral therapy (CBT) has been used successfully to resolve or reduce anxiety in infertile women . SeveralDomar used cognitive-behavioral therapy for infertile women. Participants in the CB group met for 2 hours on a weekly basis for 10 weeks on a weekday evening and they were introduced to a wide variety of techniques, including relaxation-response training, cognitive restructuring, emotional expression, and nutrition, and exercise information relevant to infertility . In the study of Heydari conducted on infertile women undergoing IUI, cognitive behavioral therapy was applied in the experimental group individually and face-to-face for 10 minutes and included information about the anatomy of the reproductive system, sperm and ovum, physiology of the fetus, how to perform IUI steps, anxiety symptoms and its effect on fertility, physiological changes during anxiety, and relaxation. Also, focus technique training and breathing were taught for 10 minutes. Then, each participant practiced the technique and persisted to acquire the skills. Participants have to do the breathing practice 3 times a day for 10 minutes at home and note them on the sheet .In another research that was performed on infertile women, the therapist considered social, sexual, and relationship concerns of the infertile women for restructuring and eliminating in CBT sessions. The first 3 sessions provided patients with a general orientation to cognitive therapy and the causes of infertility. A gynecologist participated in these sessions for 30 minutes and explained the cause of infertility for each patient. Fourth and fifth sessions included the identification and challenges of core dysfunctional or irrational beliefs that underlie automatic negative thoughts about infertility. Finally, in sessions 7–10 participants were taught various techniques  to change their dysfunctional beliefs about infertility. In addition to the above program, in sessions 5–10 participants were taught progressive muscle relaxation in a group setting .In a study performed on infertile couples by Noorbala, cognitive-behavioral therapy included recognizing negative thinking to help the participants distinguish phobia from reality and thereby change their cognitive structure. The behavioral techniques used included physical activity , muscle relaxation exercises, imagination exercises, expressing feelings, keeping a balanced diet, and engaging in leisure activities .A study was conducted by Hamzehpour on infertile women, in which he focused on cognitive behavioral education, including emphasis on attitude, identification and rehabilitation of cognitive distortions, correct thinking techniques, and recognizing judgments and negative thoughts that have an important effect on mental health of infertile women and help reduce anxiety levels and other psychological problems in these women . CBT buiBody-Mind InterventionsChan conducted a study on anxiety of infertile women. In their study, Eastern Body-Mind-Spirit was used. Group intervention took place at the Centre on Behavioral Health, University of Hong Kong and consisted of 4 weekly sessions that were held on Saturday or Sunday evenings.Under the EBMS framework, physical, psychosocial, and spiritual well-being are believed to be interconnected and all play a major role in the face of stressful life events. . In a study, Anna Galhardo used Mindfulness-Based Program (MBPI) method on infertile women with psychological problems. The MBPI is based on Mindfulness-Based Program for stress reduction, the Mind/Body Program for Infertility, and basic principles of acceptance and commitment therapy (ACT). It is a structured group intervention targeting infertile women that aims to cultivate mindfulness and acceptance, helping them to move towards a chosen and valued life direction. One of the main goals of MBPI is to promote psychological flexibility/acceptance. After the first half hour, a formal mindfulness practice is held, followed by sharing how participants felt, what they have noticed, and how the experience was for them. The set of formal practices selected for the MBPI is commonly used in mindfulness programs. Informal mindfulness practice is also presented as early as the second session through mindful eating. Metaphors and experiential exercises are included in most of the sessions, which include an experiential exercise of listening to others, introduction of values clarification through imagery exercise, and a psychoeducational section on healthy lifestyle .A trained yoga teacher conducts this practice following a sequence of yoga postures recommended by Kabat-Zinn in the Mindfulness-Based Stress Reduction Program. Before lunch, participants watch the video ‘The Joy of Stress by Loretta LaRoche’. In the afternoon, creativity is encouraged through the ‘‘map of life” exercise. Although this exercise resembles that of the Mind/Body Program for Infertility, its aim is to highlight the importance of values as the chosen life directions and to commit to building patterns of effective action towards a meaningful life. After this, each couple is invited to accomplish a communication exercise intended to provide an opportunity for each partner to share her/his feelings about the relationship .Hoveyda conducted mind-body-based interventions on infertile women with mindfulness-based stress reduction (MBSR) and conscious yoga. MBSR was presented by Kabat-Zinn in Medical Centre of Massachusetts University in 1979. It is an 8-week program and each session lasts 120 to 180 minutes. Mindfulness skills are taught to coping with life stresses and raise awareness about the present moment and include thought-related meditation, relaxation, and Hatha yoga. The sessions introduced the following strategies: automatic guidance system, learning how to use the present moment, awareness of bodily sensation, thoughts and emotions in reducing stress, practicing eating raisins, giving feedback and discussion about the practice, 3-minute breathing, practicing breathing mindfulness meditation, yoga stretching exercise, having conscious sitting with awareness of breathing , 5-minute practicing of “seeing or hearing”, re-practicing conscious session with awareness of breathing and body, re-practicing conscious session , explaining stress and identifying participants’ reactions to stress, examining awareness of pleasant and unpleasant events on feelings, thoughts, and bodily sensations, mindfulness of sounds and thoughts, practicing mountain meditation, sleep hygiene, making a list of enjoyable activities, examining and discussing programs, practicing stone, and beads and marbles meditation .Other interventionsThe third category of articles are related to psychosocial interventions that have been called “other” interventions in Debra used emotion-focused and problem-focused group therapies for women with fertilityProblems. Problem-focused coping demands include the necessity for seeking information regarding diagnostic and treatment options, actively pursuing treatments designed to improve fertility, and assertively communicating with partners and medical personnel to increase the probability of successful treatment. Emotion-focused treatment had 3 primary goals: (1) to encourage emotional expression surrounding fertility concerns, (2) to promote pleasurable activities and relaxation to counteract the experience of negative infertility-related emotions, and (3) to reduce negative affect associated with dysfunctional beliefs surrounding infertility. Primary aims of problem-focused techniques were to increase perceived control and mastery over infertility through interacting assertively about infertility issues with medical personnel and others, increasing sources of infertility-relevant information, and promoting problem-solving strategies on infertility concerns. Potentially useful emotion-focused strategies include expression and processing of feelings surrounding the experience, implementation of strategies designed to ameliorate negative emotions, and enhancement of communication skills to facilitate emotional expression and emotional support-seeking .Another type of intervention was support group for infertile women in Domar study. Support groups are the most common psychological intervention offered to infertile women .The aim of the Emery study was to evaluate the RMU's model of routine pre-IVF counselling, which focuses on the narrative capacities of couples. However, this model of counselling focusing on narrative is clearly focused on psychological support. The hypotheses were that routine pre-IVF is acceptable to most couples, and that it can contribute to decreasing anxiety and depressive symptoms during and after the first cycle of IVF, and that couples feel they are helped through this form of psychological assistance .In Yektatalab study, infertile women were trained with group psychotherapy in the experimental group. The intervention took 12 two-hour sessions, with 5-day intervals. Subjects of psychotherapy included discussion and education on the causes and diagnostic and treatment methods used in infertility, psychological aspects of infertility, the impact of anxiety on the reproductive system, and the process of crisis. .In Klerk study, the intervention consisted of 3 sessions, with a social worker trained in experiential psychosocial therapy: one before, one during, and one after the first IVF cycle. The objective of Klerk study was to evaluate a psychosocial counselling intervention for first time IVF couples. The main goal of experiential psychosocial therapy is teaching clients new skills by forming not only a professional but also a personal relationship with them. Instead of being an objective observer, the counsellor expresses his/her own feelings and ideas about the client to create new interpersonal experiences for that client. It is assumed that through these personal experiences with the therapist clients learn how to cope with interpersonal problems .Two articles of Nilforooshan were about cognitive-behavioral counseling based on interacting cognitive subsystems (ICS). ICS proposes that implicational meaning plays a crucial role in the production of emotion. ICS approach emphasizes the close relationship between implicational level and states of bodily arousal. Issues about infertility, anxiety, feelings and thoughts, schemas and how they are designated and recognizing them, and creating substituted schemes with control schemas were discussed. Relaxation and concentration on breathing and mindfulness techniques were practiced. At the first session of ICS, the participants were informed about goals, definition of infertility, anxiety generation and its symptoms, and the relationship between anxiety and infertility. In addition, relaxation practice along with mental imagery was done. The second session was allocated to the identification of thoughts and feelings, and the focus was on working on feelings directly and their acceptance without judgment, and concentration on breathing.The third session focused on thoughts. The fourth session started with mindfulness, followed by identifying schematic models and developing new schematic models to replace the former ones. Concentration on breathing was practiced. The fifth session was allocated to developing the control schema, and the main focus was on how they can take care of themselves. At the sixth session, they were taught to cope with their mood status in future using their instructions , 27.In the study of Noorbala, supportive psychotherapy intervention has been evaluated (A) the suitability of the psychological treatment, the cause of infertility, and the most suitable infertility treatment for each couple; (B) the depressed participants' psychological and emotional responses to family, friends, and others; and (C) the depressed participants' selfesteem in their relation to partner, friends, colleagues, and others .Cousineau used online psychoeducational support for infertile women to form of Solomon-four group design. This assessment serves as the tailoring mechanism of the online program, resulting in targeted feedback based on a high, medium, or low confidence level in the areas of taking care of oneself, managing feelings, and relationship with partner; managing treatment, and relationship with health care provider .In Mori study, supporting stress management was performed for women undergoing the early stages of fertility treatment. Stress management education is stress-related health education with the intention of allowing healthy people to avoid becoming unhealthy and to improve their health. It helps people to recognize stress and to learn how to control stressors and stress responses. Stress management education is stress-related health education with the intention of allowing healthy people to avoid becoming unhealthy and to improve their health. It helps people to recognize stress and to learn how to control stressors and stress responses. The participants used notebooks as a stress diary, a relaxation diary, a social support network, and a stress calendar . In the Hakim study, psychological readiness has been used for women who use assisted reproductive techniques. The broad purpose of the session was to discuss the implications of pursuing IUI treatment and specific topics addressed included the role and availability of counselling services, the psychosocial and infertility history, potential concerns about IUI treatment, the experience of infertility-related stress on both individuals and the relationship, the utilization of coping strategies, availability and use of social support, and any other stressors of concern. Counsellors addressed all topics to some extent but tailored the session to each couples’ expressed concerns. The counselling session typically lasted 60–90 minutes .Nekavand study was about the effect of relaxation on infertile women undergoing IVF treatment. Technique of progressive muscle relaxation is used to reduce muscle tension or muscle contraction. Progressive muscle relaxation technique is a practice with a series of systematic steps that helps the patients to contract a group of muscles regularly and then relax them. This method neutralize muscle tension. Progressive muscle relaxation increases activity of the parasympathetic cycle and neutralizes muscle tension. This method is done through traction contrasting modes and relaxing muscles . In Domar research, in vitro fertilization (IVF) patients in group of cognitive coping and relaxation intervention (CCRI) were compared for emotions, quality of life, discontinuation, and pregnancy rates with routine care (RC). The CCRI comprised a cognitive and a relaxation component adapted for the study from 2 existing support interventions to help women cope with the stimulation and waiting phases of ART. The relaxation component of the CCRI consisted of relaxation techniques taken from the Mind/Body Program (MBP) for infertility. The cognitive component of the CCRI was positive reappraisal coping intervention. The PRCI intervention consists of an explanatory leaflet and a set of 10 statements designed to facilitate the use of positive reappraisal coping, a form of coping that helps people think more about the positive aspects of a difficult situation and dwell less on its negative aspects. . Seyedi Asl worked on positive psychotherapy in infertile woman. It is one of the new approaches in psychology, which is innovated for treating psychological disorders and enhancing positive emotions. The aim of that study was to investigate the effectiveness of group positive psychotherapy on increasing life satisfaction and quality of life in infertile women. The treatment of the control group was delayed by 6 weeks, but the intervention group participated in a 6-week group positive psychotherapy. Each session lasted 90 minutes and was held in a group therapy format. In each meeting, tasks were completed by the participants for the next meeting. The meetings included the following 6 positive exercises: (i) using strengths; (ii) gratitude visit; (iii) active-constructive response; (iv) counting blessings; (v) savoring; and (vi) biography. The subjects of sessions were as follow: opening and positive introductions; using strengths; gratitude letter; active-constructive responses; blessings; write a short essay; biography and savoring .Soltanzadeh Mezreji study examined the efficacy of group reality therapy on infertile women undergoing treatment with assisted reproductive techniques (IUI). Group reality therapy in the experimental group was administered over 10-90-minute sessions. Tools of reality therapy include intense emotional relationship of the individual, facing the facts, abandoning irresponsible behaviors, and training to adapt a better behavior. The sessions covered the following issues: implementation of the pretest and diagnostic interview; familiarity of members with the concept of reality therapy and emotional interaction with group members; members’ familiarization with their own identity; types of identity and characteristics of a successful and unsuccessful identity; how to take responsibility for one’s behavior; and importance and necessity of responsibility in life. Moreover, the sessions focused on the following topics: introduction to anxiety from the perspective of reality therapy and anxiety management skills training; familiarization with basic and effective needs in real life; familiarization with how to plan problem-solving; planning for life and for the treatment assisted reproductive method IUI; familiarization with the commitment to implement medical programs; and familiarization with denying excuses on implementing selected projects and programs .The objective of Moeenizadeh study was to examine the effectiveness of well-being therapy (WBT) on anxiety of infertile women. WBT is based on an educational model; it is structured, directive, and problem-oriented and presents problems and situations. WBT includes technique of self-observation along with the use of a structured diary and interaction between patients and therapists. The therapy sessions are divided into 3 phases: initial, intermediate and final. These sessions identify incidences of well-being and apply the rules into situational context regardless of its short period . The patThis study reviewed the effectiveness of psychosocial interventions on anxiety and depressive symptoms of couples. In all studies of category A (CBT method), the samples were women, with the exception of a study, which was conducted on couples. Also, all studies showed reduction in anxiety in this category. There was a study in category B with different results. Some studies used mindfulness (mind-body method) as an intervention. In category C, counselling , experiential psychosocial therapy, group positive psychotherapy, and supporting stress management methods did not have any effects on reducing anxiety, but they were effective in other studies , 29, 33.Most psychosocial interventions used cognitive-behavioral therapy mothod and the least interventions were in category. In the present study, we found that the majority of psychosocial interventions are effective in reducing anxiety in infertile women, men, or couples. These studies used several methods: cognitive-behavioral therapy -19; EastIn this study, only articles in English were used. Also, unpublished and gray literatures were not used in the study.Based on the results of this study, psychological interventions for anxiety are necessary for infertile couples undergoing fertility treatment. There are several interventions for treating anxiety in this group, such as CBT interventions and body-mind interventions.


The aim of this report is to present a clinical case of oral lichenoid lesions associated with amalgam restorations with the presence of desquamative gingivitis for a nine months follow up period.The histopathologic characteristics and direct immunofluorescence were compatible with Oral Lichenoid Lesion (LLO). Diagnosis was based on a synthesis of all available information, including medical history, clinical examination, histopathology and the results of specific tests, such as the patch test, which confirmed allergy to thimerosal, an organic compound of mercury.The replacement of amalgam restorations has brought improvements to the instrument, as evidenced by the disappearance of desquamative gingivitis, aspect erythematosus and erosive lesions. The fading does not complete the same, however, indicates the need to continue has been under continuous observation, the patient, having in view the possibility of the existence of an underlying lichen planus. Lichenoid lesions have also been associated with Dental Amalgam (OLL-DA), representing type IV hypersensitivity reaction, often referred to as delayed hypersensitivity, since it generally develops after a relatively long-time period, in this case, from months to years. OLLs generally show heterogeneous clinical manifestations ranging from white asymptomatic plaque lesions to atrophic, symptomatic reticular lesions, erosive lesions , 2 or evWhen the clinical aspect described occurs in marginal and/or inserted gingiva, the clinical term Desquamative Gingivitis (DG) is used. The latter is not considered a definite pathology, but rather a common sign of several pathologies, encompassing a broad clinical spectrum of mucocutaneous diseases ranging from vesiculobullous immune disorders to allergic reactions to a number of chemical products or allergens , 5.via immunological mechanisms from innate and adaptive immunities, an immune response which activates inflammatory mediators such as cytosines and Metalloproteinases (MMPs) [The possible correlation between the presence of DG associated with autoimmune diseases and the worsening of periodontal parameters has been discussed in the literature, since both conditions can share immuno-inflammatory mechanisms in their pathogenesis. DG may indirectly worsen the accumulation of plaque in the affected sites, since pain and bleeding may inhibit the patient’s oral hygiene. Microorganisms from the oral biofilm trigger, s (MMPs) , 7. Theis (MMPs) , commonls (MMPs) -11.Diagnosis must be based on a synthesis of all available information, including medical history, clinical examination and histopathology as well as the results of specific tests, such as the patch test -18 The rThere have been few reports associating desquamative gingivitis and OLL-DA available in the current literature. Therefore, the aim of this study is to report a clinical case of idiopathic OLL caused by an allergic reaction to thimerosal associated with desquamative gingivitis in a patient with periodontal disease.21A-D) and desquamative gingivitis located in the inserted gingiva. The asymptomatic lesions showed an atrophic leuco-erythroblastic reticular aspect, with an ulcerated surface. Teeth 17, 15, 14 and 48 had extensive amalgam restorations two years prior, in close contact with the injured areas.A 33-year-old woman sought dental assistance and presented multiple unilateral lesions distributed throughout the oral mucosa, retro commissural region, inserted gingiva lateral borders of the tongue on the right side  and the measure of probing depth was registered, as well as the presence of bleeding during the probing step  and the plaque index . The gingival depth ranged from 1 to 7 mm; however, in the region affected by the gingival desquamation, the depths ranged from 2 to 6 mm. The bleeding index during probing was 91.3%, and the plaque index was 74%. With such results, the patient was diagnosed with generalized periodontitis. The patient’s medical history did not reveal any systemic alterations, such as hypertension, diabetes or any autoimmune diseases, nor did she mention the use of any medication. Blood analysis did not reveal any alterations.2A-C). The histological section of the gingiva also revealed chronically inflamed connective tissue and subepithelial cleft  A provisional diagnosis of OLL-DA was initially taken. The patch test reading confirmed allergy to thimerosal, a compound of mercury metal. Therefore, all the metallic restorations were removed in one single appointment. Afterwards, basic periodontal therapy was accomplished in four consecutive weekly appointments, with scaling and root debridement, structured plaque control, dental brushing and interdental cleaning instructions.A perilesional biopsy was then carried out using hematoxylin-eosin staining. The oral mucosa fragment was covered by focal acantholytic, atrophic and parakeratinized squamous epithelium. The connective tissue showed chronic subepithelial and deep inflammatory infiltrate, predominantly composed of lymphocytes and plasmocytes, with the formation of lymphoid follicles and subepithelial cleft, compatible with oral lichenoid reaction  to six  months, during which time the desquamative gingivitis was reduced. However, the leucoplast lesions located on the retro commissural area and tongue were unchanged. A new perilesional biopsy for the direct immunofluorescence test was conducted in order to exclude other diagnostic hypotheses. The results in question showed non-specific focal granular deposits of IgM 2+  in the basement membrane zone of the epidermis . The findings were compatible with Lichenoid Stomatitis. After clinical-pathological correlation, the diagnosis of idiopathic oral lichenoid lesion was finally established. Nine months after the removal of all the amalgam restorations, remission of the desquamative gingivitis  and disappearance of reddish-white plaques, as well as the ulcerated surface of the oral mucosa were observed. Nevertheless, the reticular leucoplast and retro commissural region lesions persisted .The follow-up period ranged from three  represent a late hypersensitivity response to some components of metal alloys, particularly mercury . ClinicaOLLs caused by hypersensitivity to amalgam or its constituents typically have a clear anatomical relationship with dental restorations, and are usually unilateral and non-symmetric . OLLs aret al., [There is a difficulty in establishing the differential diagnosis between OLP and OLL-DA due to similarities between them, which often makes them clinically and histologically indistinguishable . Mravak-et al., , in a stet al., , 20.et al., [Histopathological examination revealed interstitial lymphohistiocytic inflammatory infiltrate in the subepithelial band, with fibrosis in some points and presence of lymphoid follicles. These characteristics are in agreement with those described in literature studies  concerniet al., , all of et al., [Essentially, OLL-DA is the equivalent, in the oral environment, to allergic contact dermatitis. In most cases, the allergen is mercury, but occasionally some other alloy components may trigger a reaction . In the et al.,  showed aet al.,  similar Histopathological examination performed after the removal of the amalgam restorations showed the disappearance of the lymphoid follicle. Ribeiro and Larsson , 27 dist3A) of the buccal mucosa and tongue. However, there was still the persistence of leucoplast plaque in the retro commissural area  and a residual erythematous area  related to tooth 15, whose provisional filling had failed. Montebugnoli et al., and Pawar et al., [Three months following the replacement of the restorations, there was an improvement of the clinical aspect .In the six month clinical examination, clinical improvement and disappearance of desquamative gingivitis were observed. However, there were persistent reticular white lesions coincident with the occlusion line in the buccal mucosa and ulceration in the center of an erythematous area adjacent to the retro commissural area and leucoplast plaques on the lateral side of the tongue and retro commissural area  or ulcerations, smoothed reticular lines in the buccal mucosa were observed . It is speculated that in this case, the persistence of lesions in the other sites was due either to exclusively unilateral mastication, which promoted trauma and subsequent development of hyperkeratosis, or to scarification in the region of the oral lichenoid lesion, or to the persistence of an underlying lichen planus.After nine months, although there were no indications of desquamative gingivitis (Fig. The complete healing of the desquamative gingivitis, after this period, however, reinforced that it was related to the development of lichenoid lesions associated with dental amalgam, as a hypersensitive response to thimerosal. Although basic periodontal therapy may have contributed to the resolution of the DG, it was not sufficient, since the complete removal of dental amalgam restorations was necessary for the complete disappearance of the erythematous areas of the gingiva.