The last few decades have witnessed an outstanding advancement in our understanding of the hallmarks of endocrine cancers. This includes the epithelial to mesenchymal transition (EMT), a process that alters the morphology and functional characteristics of carcinoma cells. The mesenchymal stem cell like phenotype produced by EMT allows the dislocation of cancer cells from the primary tumor site with inheritance of motility, metastatic and invasive properties. A fundamental driver thought to initiate and propagate EMT is metabolic reprogramming that occur during these transitions. Though there remains a paucity of data regarding the alterations that occur during EMT in endocrine cancers, the contribution of deregulated metabolism is a prominent feature. This mini review focuses on metabolic reprogramming events that occur in cancer cells and in particular those of endocrine origin. It highlights the main metabolic reprogramming outcomes of EMT, encompassing glycolysis, mitochondria oxidative phosphorylation and function, glutamine and lipid metabolism. Comprehending the metabolic changes that occur during EMT will help formulate potential bioenergetic targets as therapies for endocrine cancer metastasis. The preceding few decades have witnessed an outstanding advancement in our understanding of the hallmarks of cancer including the rare endocrine tumors. These include the signals that sustain their proliferative capacity, prevent apoptosis, enable replicative immortality, and induce angiogenesis . AnotherEMT occurs when tumorigenic epithelial cells acquire a mesenchymal stem cell like phenotype by undergoing transcriptional, epigenetic, and metabolic changes. This causes loss of cell to cell adherence, imparting motility to the cells which are free to migrate and invade tissues, a process known as metastasis. Normally EMT is a physiological process necessary for organogenesis during embryonic development and for wound healing . HoweverTICs derived from EMT share similar characteristics with CSCs such as metastatic potential, chemo resistivity, anti-apoptotic function, gene expression signature, and metabolic profile . To sustHow the metabolic network is reprogrammed to influence EMT remains unclear. The shift from epithelial to the mesenchymal morphology and loss of cell-cell adhesion is orchestrated by various transcription factor families (EMT-TFs) such as Snail, Twist and Zeb . EMT-TFsUnlike normal cells, cancer cells rely more on aerobic glycolysis, also known as the Warburg effect, to meet their elevated demand for energy during proliferation . In thisIt is not clear how aerobic glycolysis favors EMT. One hypothesis is it provides a survival benefit against anoikis, which is a type of cell death that occurs when insufficient matrix attachment generates high levels of reactive oxygen species (ROS) to kill the cell . NormallDespite the prominence of deregulated glycolysis in endocrine cancers there are few data available regarding its role in EMT. Proteomic analysis of endocrine pancreatic cells showed predominance of the Warburg effect and enhanced expression of factors involved in glucose metabolism . The potDysregulation of glycolytic enzymes are evident in some endocrine cancers, but their role in EMT is unknown. For example, in pancreatic cancer cells, there is upregulation of the key enzymes of glycolytic metabolism and glucose transporters . MoreoveAlso, some cancer cells can facilitate a metabolic shift toward aerobic glycolysis by upregulating glucose metabolism by impeding gluconeogenesis. For example, in several cancers including endocrine pancreatic cancer cells, loss of fructose-1,6-bisphosphatase (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate, is associated with increased cancer stem cell like phenotype and metastasis –42. FBP1In addition to the glycolytic enzymes, EMT induction occurs through enhanced activity and expression of glucose transporters, Glut1 and Glut3. They are important proteins that regulate glucose uptake, enabling rapidly dividing cells to sustain aerobic glycolysis . High lein-vivo and in-vitro (in vivo (Another important factor that is positively regulated with cancer invasiveness and EMT is lactate dehydrogensase a (LDHa), a rate limiting enzyme converting pyruvate to lactate during aerobic glycolysis. Invasive pituitary adenomas exhibit high levels of LDHa both in-vitro . In intein-vitro . Also, iin-vitro  and sile . ImportaThe EMT-TF Snail has been shown to reduce ETC complex formation by targeting cytochrome c oxidase (Cox), a Complex IV enzyme responsible for transferring electrons for mitochondrial respiration. Snail binds to the mtDNA promoter and downregulates the expression of three Cox subunits, COX6c, COX7a and COX7c, reducing the formation of Complex IV, thereby suppressing oxygen consumption and mitochondrial respiration .A master regulator of mitochondrial biogenesis and enhancer of Oxphos, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α), has been shown to either suppress or activate EMT and metastasis depending on cancer types and metabolic cues of the tumor microenvironment . In endoOne of the important metabolic pathways in mitochondria is the tri-carboxylic acid cycle (TCA) that provides reducing agents for Oxphos and metabolites for various biosynthetic pathways. Evident in endocrine cancers are mutations of TCA cycle operational enzymes, which are linked to EMT . The neuMutation of another important enzyme of the TCA cycle, fumarate hydratase (FH), which converts fumarate to malate, is also implicated in metastasis of pheochromocytoma and paraganglioma. This is due to accumulation of high levels of fumarate and succinate that act as oncometabolites by enhancing epigenetic modification of DNA hypermethylation, ROS production and changes in the mitochondrial structure , 73–76. In the TCA cycle, isocitrate dehydrogenase that converts isocitrate to α-ketoglutarate by decarboxylation, is also associated with many cancers . An oncoin vitro and in vivo   . FASN ise (FASN) . High FAe (FASN) , 96.Overexpression of acyl-CoA synthetases (ACSs), which convert long chain fatty acids into acyl CoA and stearoyl CoA desaturase-1 (SCD), induced EMT and increased cellular migration and invasion in colorectal cancer . Their dThe plasma membrane (PM) integrity also has a crucial role in mediating EMT. This is evident by marked differences in the lipid composition of PM between normal epithelial cells and the cells that have undergone EMT . Cancer EMT causes dissociation of cancer cells from primary carcinomas, which migrate and disseminate to distant sites. In this review, we have summarized how cancer cell metabolic reprogramming reflected by changes in glycolysis, mitochondrial Oxphos, glutamine and lipid metabolism are involved in EMT. For many cancer types it is not known if one or more metabolic pathways are necessary for EMT and metastasis, nor if they operate independently or together within a metabolic framework. Moreover, it has not been resolved if the same metabolic reprogramming in different cancer types have opposite effects on EMT and metastasis. Although, endocrine cancers are one of the most aggressive cancers types, there is a gap in research connecting its metabolic deregulations and EMT. Elucidation of the compromised metabolic targets will help in identifying potential therapeutic targets.Finally, recent advancement in the understanding of EMT, has unveiled that metastatic cascade is multifaceted, where EMT is required for tumor initiation and invasiveness, but mesenchymal to epithelial transition (MET) is crucial for the later stages of metastasis, particularly during metastatic colonization. Despite considerable understanding in metabolic regulation of EMT, there is not much known about metabolic control of MET. As MET occurs at a distant site from primary tumors and are functionally different than cells that have undergone EMT, it is likely that these cancer cells have a completely different metabolic reprogramming.AS and DB both conceived and designed the idea and wrote the paper. DB and AS collected the information for 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.


Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease that commonly affects older adults and is associated with the histopathological and/or radiological patterns of usual interstitial pneumonia (UIP). Despite significant advances in our understanding of disease pathobiology and natural history, what causes IPF remains unknown. A potential role for infection in the disease’s pathogenesis and progression or as a trigger of acute exacerbation has long been postulated, but initial studies based on traditional culture methods have yielded inconsistent results. The recent application to IPF of culture-independent techniques for microbiological analysis has revealed previously unappreciated alterations of the lung microbiome, as well as an increased bacterial burden in the bronchoalveolar lavage (BAL) of IPF patients, although correlation does not necessarily entail causation. In addition, the lung microbiome remains only partially characterized and further research should investigate organisms other than bacteria and viruses, including fungi. The clarification of the role of the microbiome in the pathogenesis and progression of IPF may potentially allow its manipulation, providing an opportunity for targeted therapeutic intervention. The term “microbiome” refers to the “ecological community of commensal, symbiotic and pathogenic organisms that share our body space,”  as well MUC5B gene, which encodes a mucin required for normal macrophage function and effective muco-ciliary clearance of bacteria in mice  0.21) . The autA phase III double blind, randomised, placebo-controlled, multi-centre clinical trial of oral co-trimoxazole versus placebo in 330 patients with moderate and severe IPF is currently underway  . The prin = 38) than in those treated with fluoroquinolones . Multivariate analysis confirmed that azithromycin use was independently correlated with 60-day mortality. More recently, in a retrospective observational study, Macaluso and co-workers looked at 108 IPF patients receiving prophylactic azithromycin (250 mg three times weekly) to evaluate its long-term effect on the rate of hospitalization. To this end, they compared the number of all-cause non-elective hospitalizations and antibiotic courses in the 12 months preceding and following treatment initiation, and found that both hospital admissions (seven versus 31) and antibiotic courses (40 versus 176) were significantly lower in the year after institution of prophylactic azithromycin [The potential benefit of macrolides has also been evaluated in IPF patients, although only in retrospective, relatively small cohorts. In a single-centre study, Kawamura and colleagues compared the efficacy of azithromycin 500 mg/day for five days with that of a fluoroquinolone-based regimen from a historical control group in 85 patients with idiopathic AE-IPF [hromycin . OverallA balanced intestinal microbial community is essential for the development and maintenance of immune function and health. The respiratory microbiome develops in tandem with that of the gut . There iSeveral studies have suggested that altered microbiome burden, diversity and composition may contribute to disease pathogenesis, progression, acute exacerbation and mortality in IPF. Should a mechanistic link between a deranged lung microbiome and IPF development and progression be established, microbiome manipulation, with the aim of restoring a “healthy” microbiome community, will soon represent a potential therapeutic intervention for IPF, although a holistic approach to account for the many factors driving disease development, progression and acute worsening is more likely to be truly efficacious. Whether the lung microbiome should be manipulated by using antibiotics, probiotics  or prebiotics  is unknown. Regardless, microbiome manipulation should target pathogenic microbes without altering the residential members of the microbial community . That wo


The human antibody response to influenza virus infection or vaccination is as complicated as it is essential for protection against flu. The constant antigenic changes of the virus to escape human herd immunity hinder the yearly selection of vaccine strains since it is hard to predict which virus strains will circulate for the coming flu season. A “universal” influenza vaccine that could induce broad cross-influenza subtype protection would help to address this issue. However, the human antibody response is intricate and often obscure, with factors such as antigenic seniority or original antigenic sin (OAS), and back-boosting ensuring that each person mounts a unique immune response to infection or vaccination with any new influenza virus strain. Notably, the effects of existing antibodies on cross-protective immunity after repeated vaccinations are unclear. More research is needed to characterize the mechanisms at play, but traditional assays such as hemagglutinin inhibition (HAI) and microneutralization (MN) are excessively limited in scope and too resource-intensive to effectively meet this challenge. In the past ten years, new multiple dimensional assays (MDAs) have been developed to help overcome these problems by simultaneously measuring antibodies against a large panel of influenza hemagglutinin (HA) proteins with a minimal amount of sample in a high throughput way. MDAs will likely be a powerful tool for accelerating the study of the humoral immune response to influenza vaccination and the development of a universal influenza vaccine. Influenza is a global public health problem, causing approximately 300,000–650,000 global deaths each year . InfluenTo date, seasonal influenza vaccines composed of three or four inactivated virus strains are the only licensed vaccines to elicit or boost protective immunity against influenza viruses in the United States. However, both antigenic drift and shift necessitate that the flu vaccine be reformulated and re-administered annually . It is aAntibody mediated immune responses against influenza HA are multi-dimensional, targeting multiple antigenic determinants (epitopes) within the HA molecule. Antibody mediated responses are also incredibly complicated, as they are influenced and altered by an individual’s prior influenza exposure history. This includes factors such as “original antigenic sin” (OAS)   ,14, micrHere, we review the genetic foundations of shared epitopes leading to IgG cross-reactivity between antigenically similar influenza virus strains, and the contributions of these cross-reactivities to OAS and subsequent host immune responses to influenza infection and vaccination. The remainder of the review discusses the technology of MDA, and highlights the application of MDA as a powerful tool for future influenza immunity studies and universal vaccine development.Orthomyxoviridae family, a group of negative-sense single strain RNA viruses [Influenza viruses, the pathogens that cause flu, belong to the  viruses . Influen viruses . Influen viruses . The maj viruses . HA is t viruses .Protective antibody-mediated immunity against HA is the first line of defense in preventing influenza virus infection. Such immunity is elicited by prior influenza exposure: infection or vaccination ,23. AntiThe goal of universal vaccines is to elicit protective broad cross-reactive antibodies (bcAbs), especially broad neutralizing antibodies (bnAbs). Most head-reactive antibodies are not bcAbs or bnAbs but rather strain-specific. However, more and more head domain recognizing bnAbs have been identified, such as KBm2, 5J8 and CH65, which neutralize a broad spectrum of H1 strain viruses in the MN assay ,32,33, aRecently, an increasing number of bnAbs have been isolated and identified from the B cell repertoire after influenza virus infection and vaccination ,39, targOne major issue with the evaluation of bnAb activities by traditional HAI and MN assays is that they can only measure the magnitude of bnAb against specific virus strains, and cannot determine the breadth of bnAbs against a large panel of influenza strains. In addition, during antibody screening, these assays most likely omit bcAbs, such as the human mAb FluA-20 , as we dThe complexity of the human immune response to repeated influenza virus exposure is another major obstacle to the development of a universal vaccine. Because of the frequent antigenic drift in circulating influenza strains, humans have more complicated immune responses than can be modeled in naive animals. Each person has a unique history of influenza virus exposure, leading to pre-existing immune repertoires that are activated in the event of an immune challenge with an antigenically similar flu strain.new epitopes. This suggests that preexisting antibodies could play a role in the MBC response, such as accelerating the clearance of influenza antigens or sterically blocking MBCs from accessing specific epitopes [In 1960, Thomas Francis Jr. reported that antibodies against the first H1N1 flu strain encountered in life would be produced at high levels throughout a person’s lifespan, to the detriment of future specific responses to new strains ,53,54. Iepitopes ,56. Meanepitopes . OAS [58epitopes  and HA iepitopes  try to dThe gold standard and most widely used assays to evaluate antibody activity against HA and protection in clinical trials are HAI ,14 and MTo overcome the limitations of single dimensional assays, novel multidimensional assays (MDAs) have been developed over the last decade. MDAs are high throughput assays that use protein array technology to simultaneously measure antibodies against a panel of the HA proteins and peptides of multiple influenza virus strains in a single test with minimum amount of sample. They can measure the magnitude and breadth of antibody response against HAs of influenza virus. In general, the purified HA proteins are immobilized on a solid surface such as microchips, membranes or beads, to keep the native structure and provide their maximal binding properties. Then, the reactive antibodies are characterized by binding to the protein, followed by a fluorescent probed secondary antibody that is read by an array chips reader as median fluorescent intensity (MFI). The HA protein or peptide array offers the advantage of multiplex capabilities to generate statistically powerful data while conserving time, money, and requiring minimal sample compared to the traditional assays. While not a functional assay, multiple studies have confirmed that MDA results correlate well with HAI titers ,62,63,64Based on the immobilizing materials, there are two major types of array-based assays currently used for evaluation of HA antibodies: protein microarray and Luminex assays. The first method involves printing HA protein on chips to estimate the binding antibodies. The first report of HA protein array assay was published in 2010 , and sinIn contrast to peptide arrays, the Luminex-based MDA method, which involves coupling HA protein to color coded Luminex beads, allows the user increased flexibility to customize the panel by easily combining multiple strain-specific beads without reprinting the entire panel ,67. In aThe first Luminex-based MDA, mPLEX-Flu, was developed to characterize the breadth and magnitude of the IgA, IgM and IgG antibodies against a large panel of whole HA proteins of multiple influenza virus types and subtypes in 2015 . Our recBased on the above characteristics of MDA, we use the example of a Luminex-based MDA, the mPLEX-Flu assay , to discAntigenic cartography was first presented by Smith et al. in 2004  as a wayIsolation and analysis of human monoclonal antibodies from the B cell repertoire of infected or vaccinated individuals is an important method to measure the B cell response against influenza virus ,39,89,90The major goal in developing the mPlex-Flu assay is to quantitatively evaluate the cross-reactivity of influenza virus antibodies, including IgG, IgA and IgM isotypes. After we established and verified the mPlex-Flu assay, we applied it for detection of a breadth of cross-reactive Abs elicited by infection of influenza virus or vaccination with recombinant HA proteins  in mice The high sensitivity and minimal sample size requirement enable MDA to quantitatively detect multiple influenza virus antibodies in samples other than serum  pdm virus in 13 countries from five continents by screening bloodspots . Similarsampling . Combinisampling . This stsampling . In addiThe mPLEX-Flu assay can also be used to monitor the development of HA-specific antibodies against the influenza virus in infants. Tracking developing infant immunity to not only infection and vaccination strains but also other revolutionary strains would allow us to learn more about how OAS-type responses are first established. It would provide essential data for universal vaccine study and for understanding the mechanism of OAS.Right now, as discussed above, the broad neutralizing antibody (bnAb) activities still are the most important profiles of monoclonal antibodies to be considered. However, after the FluA-20 antibody was isolated, the broad cross-reactive antibodies (bcAbs) showed the protection against influenza virus that would likely be disregarded by traditional assays . By contBesides HA, neuraminidase (NA) also is an important target for inducing protective antibody- mediated responses . SimilarAt the same time, other internal proteins, such as nucleoprotein (NP) and the matrix protein 1 (M1), which are highly conserved between human seasonal and zoonotic influenza viruses , induce Applying an expanded MDA panel that includes NA, NP and M1 protein-coupled beads in future influenza population surveys and clinical infection studies will allow us to evaluate antibodies against all these highly conserved proteins and HAs simultaneously. It would provide highly comprehensive data to help us to understand the T and B cell response to influenza virus infection, and also be beneficial for developing a “universal” influenza vaccine. While this review focuses on influenza, the underlying principles of MDA analysis apply equally to the study of immunity against other viruses that have multiple, antigenically similar strains.As a novel technique, mPLEX-Flu and other MDAs also face some challenges and limitations. First, because MDAs detect the binding between the antibodies and HAs of influenza viruses, they are not able to directly reflect antibody protective function. By contrast, MN assays can estimate titers of neutralizing antibodies that inhibit influenza virus infection. However, our studies showed that data generated from mPLEX-Flu assay are highly correlated to HAI and MN data ,63,64,76Other limitations of MDAs are caused by the HA antigen coupled on the Luminex beads or microchips. First, most HA proteins used in the MDAs are expressed and purified by an insect cell baculovirus system that has to be glycosylated during post-translational modifications in infected insect cells. However, the insect cell glycosylation pathway is far simpler than those of human cells , even whThe constantly changing HA antigenicity of influenza virus, along with the complexity of serological responses induced by the viruses in the human immune system, muddies efforts to interpret serology testing results. It had been commonly accepted that assessing the antibody response against only vaccine strain viral HAs is too restricted for understanding this complexity. Understanding the effects of pre-existing antibodies and cross-reactive antibodies against multiple strains’ HAs is becoming increasingly enticing in the influenza B cell immunity research field. MDAs and systems serology, the novel technologies combined with multidimensional data, computer modeling, and bioinformatics, are groundbreaking new tools for influenza vaccine study. They will open a novel comprehensive view to investigate the B cell response to influenza virus and be a powerful tool for universal vaccine development.


Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues  and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications. Severe obesity is associated with elevated risks of adverse health consequences. The prevalence of obesity is rising worldwide, and if the trend continues, global prevalence will reach 18% in men and 21% in women by 2025 ,4,5,6,7.Obesity is a critical risk factor for the development of type 2 diabetes (T2D). By 2025, more than 300 million people are expected to have T2D as a complication of obesity . The priInsulin reduces blood glucose by inducing glucose uptake in insulin-sensitive tissues  and by inhibiting glucose production in liver. IR occurs when the insulin-sensitive tissues lose insulin response. In this scenario, insulin-mediated glucose uptake is impaired in the insulin target tissues. This failure is a result of the insulin signaling pathway inhibition . NonetheWAT is a complex organ and has primary roles in energy homeostasis control. Adipocytes not only act as a reservoir for energy storage and utilization, but also sense energy demands and secrete paracrine factors to regulate other metabolic tissues. In a high energy state, for example, leptin is secreted from adipocytes to reduce food intake centrally and increase energy expenditure ,18. HoweIn obesity, “healthy” WAT expansion is achieved by recruiting and differentiating adipose precursor cells rather than infiltrating fat into mature adipocytes. Alterations in the precursor cell commitment and subcutaneous adipose tissue (SAT) adipogenesis are associated with the metabolic complications of obesity. When the storage capacity of SAT, the largest adipose tissue depot, is exceeded, further caloric overload leads to the fat accumulation in ectopic tissues  as well as in the visceral depots. It has been largely demonstrated that excessive lipid accumulation in ectopic tissues leads to local inflammation and IR . The ectAlthough IR has, by definition, different potential pathogenic mechanisms, we believe that, given the relevance of its association with obesity, it is likely that adipose tissue dysfunction becomes the major contributor to subsequent associated complications in a high percentage of obese patients. This review outlines the current knowledge on WAT expansion in obesity and highlights the mechanisms that make it dysfunctional and associated with metabolic alterations, including inflammation, impaired adipogenesis, and ectopic lipid deposition.The adipose tissue has a crucial role in the regulation of systemic energy homeostasis acting as a “safe” depot to store excess fat. In overnutrition, mature adipocytes accumulate more fat and undergo cellular hypertrophy , whereasTo review the adipose tissue remodeling in obesity and associated metabolic comorbidities, it is essential to examine how the morphology can change depending on the adipose tissue location. The adipose tissue is classified, according to the regional distribution, as SAT (located under the skin) and visceral adipose tissue , and it is diffused throughout the entire human body . The sitDifferent studies report that fat distribution is strongly associated with IR, the main risk factor for T2D and cardiovascular disease (CVD) . A systeIn response to a positive energy balance, dynamic mechanisms reorganize the adipose tissue by changing the number and size of mature adipocytes. In the meantime, the precursor cells of the stromal vascular fraction begin to be recruited and committed towards the adipocyte lineage. Hypertrophic adipocytes secrete paracrine factors (hormones and cytokines), which facilitate preadipocytes recruitment and promote their differentiation into mature adipocytes . These eIn addition to the regional distribution of fat, the adipocyte morphology (hypertrophy vs. hyperplasia) contributes to the obesity-associated metabolic abnormalities. In a chronic state of positive energy balance, the adipocyte size reaches a critical threshold before recruiting precursor cells to increase the adipocytes number. Spalding et al. demonstrated that the adipocyte number is tightly regulated and determined during childhood, suggesting that the increase in cell size is the main plasticity mechanism in response to an energy imbalance . AdiposeHIF) 1α, increases the local inflammation and accelerates adipose tissue fibrosis   ,121. Acc (RAGE)] ,123. Bot (RAGE)] . In obes (RAGE)] ,126.Besides affecting insulin action, chronic low-grade inflammation alters preadipocytes differentiation into mature adipocytes. An in vitro study has shown that the exposure of pre-adipocytes to pro-inflammatory cytokines compromises adipocyte differentiation . The mecIn conclusion, chronic low-grade inflammation leads to adipose tissue dysfunction, impairing adipogenesis and insulin sensitivity. Inflammation is a finely regulated mechanism, and defects in its balance cause adipose tissue dysfunction.Ectopic fat deposition is defined as the accumulation of triglycerides in tissues not associated with adipose tissue storage, containing only small amounts of fat . These aMultiple genetic, environmental and behavioral factors contribute to subcutaneous versus ectopic fat deposition . Recent SAT angiogenic capacity is another factor contributing to ectopic fat deposition. Impaired angiogenesis of the adipose tissue could potentially limit adipogenesis and thus contribute to metabolic dysfunction by promoting ectopic lipid accumulation. Additionally, human SAT has a considerable capillary density and angiogenic growth capacity, but this ability has been reduced by morbid obesity and adversely correlated with insulin sensitivity .Ectopic fat depots can be classified according to their local and systemic potential implications. We can speculate that there are two major subtypes of ectopic fat depots, locally acting fat depots such as pericardial, perivascular, and epicardial fat, and systematically acting fat depots consisting of intrahepatic and intramuscular fat .Liver plays a key role in maintaining hepatic fat homeostasis and energy balance through multiple metabolic pathways . An imbalance between these processes could result in abnormal hepatic lipid accumulation ,141, comLipids accumulate as lipid droplets in the cytoplasm, but glycerols themselves do not damage the cells, but rather the imbalance between the above-described metabolic pathways that leads to intermediate toxic lipid synthesis  ,145. ConDGAT2) in the liver, an integral membrane protein essential for triglyceride biosynthesis, can shed light on the mechanisms [A study conducted in mice overexpressing acyl-CoA diacylglycerol acyltransferase 2 , pericardial , and perivascular adipose tissue  ,170. PVAFor a long time, the role of adipose tissue has been underestimated, and it has been considered a merely storage organ. The obesity pandemic has put a spotlight on adipocyte function, and we now recognize it as an endocrine organ essential in regulating systemic energy homeostasis. Obesity and the associated metabolic diseases are rapidly increasing and, in our opinion, the dysfunction of adipose tissue is the central mechanism for the development of these complications. A deep understanding of the molecular mechanisms responsible for adipose tissue dysfunction is needed. Impaired adipose tissue plasticity also synergizes with age-related metabolic defects to exacerbate metabolic disorders. Understanding the molecular alterations that regulate defective adipose tissue plasticity may identify therapeutic targets to enhance the expandability and function of adipose tissue. Lifestyle interventions as exercise and diet are effective in promoting a healthy adipose tissue expansion, although these approaches are difficult to maintain in the long term. Recently, adipogenesis has emerged as a possible therapeutic target to enhance adipose tissue health. Increasing adipogenesis during weight gain can counteract the negative metabolic consequences of obesity. However, a remaining issue is to address these mechanisms in human.In the era of personalized and precision medicine, increasing our knowledge of adipose tissue biology might enable us to overcome the limitations of the traditional anthropometric indices of obesity. Obesity-related metabolic complications do not correlate with BMI, and additional clinical parameters are necessary for risk evaluation. There is the need to move closer to an individualized understanding of adipose tissue health and its contribution on regulating systemic energy homeostasis.


Lately, the number of people using marijuana in the USA has dramatically increased. In 2018, many states have legalized marijuana use for both medical and recreational purposes, thus exploring the evidence behind medical marijuana use became essential. Muslim majority countries enforce rigorous rules as marijuana has been a long-debated issue due to the stigma associated with its use as a treatment. Marijuana has a high beneficial effect in managing chronic pain in adults and relieving spasticity symptoms in multiple sclerosis, obstructive sleep apnea syndrome, and fibromyalgia. As well as, used as pain management, and as anti-emetic in treatment of chemotherapy-induced vomiting and nausea. Marijuana is requested from more than one-third of posttraumatic stress disorder patients due to its significant clinical improvement in nightmares and subsidence disorder symptoms.Marijuana adversely affects the body’s resistance to many infections, compromising their immune response. Its recreational use has led to an increasing trend in the occurrence of major acute cardiovascular events as stroke, epilepsy, acute myocardial infarction, congestive heart failure, and arrhythmia.Many countries started to allow medicinal use of marijuana due to its beneficial effect in managing chronic pain, spasticity symptoms in multiple sclerosis, obstructive sleep apnea syndrome, fibromyalgia, and posttraumatic stress disorder. But literature lacks benefit-harm analysis for marijuana usage in medicine. Therefore, evidence-based report of short- and long-term health effects of marijuana use—both harmful and beneficial effects—is crucial for further marijuana prescription in healthcare settings. Medicinal marijuana is legally used in the USA in 33 states and the District of Columbia, while other 10 states allow consuming it for both recreational and medical proposes . About 4Currently, Muslim majority countries enforce rigorous rules as marijuana has been a long debated issue, but there are countries such as the Islamic Republic of Iran where reformation is under consideration. Experience of medical marijuana with counterintuitive religious interpretations has led policymakers to review legal decisions in countries as Iran, yet to implement on national perspective . NoteworMedicinal marijuana has been approved for the treatment of diseases like HIV/AIDS, cancer, glaucoma, and posttraumatic stress disorder. In 2016, it was reported that the usage of medicinal marijuana helped head and neck cancer patients with long-term side effects of radiotherapy [However, there is an alarming rise in cardiovascular and respiratory problems after its consumption. A CARDIA meta-analysis study reported that 38% of its 3500 participants used marijuana with a positive correlation between its usage, hypertension, and dyslipidemia, which may lead to coronary artery disease . Impact Contradictory findings are reported in literature regarding recommending or prohibiting the use of marijuana for various medical conditions.In addition to Marijuana’s mentioned medical benefits, it is linked to various adverse effects regarding short-term use and long-term use. For short-term use, it may lead to disturbance in the short-term memory and cognitive functions; not only that but also psychosis in high doses . AddictiDespite the lack of a thorough benefit-harm analysis, marijuana has proven effective for pain management, and as anti-emetic in the treatment of chemotherapy-induced vomiting and nausea. Synthetic marijuana analog such as nabilole, levonantradol, and tetrahydrocannabinol reported mildly effective in cancer chemotherapy emesis palliation . IronicaSixteen states legalized posttraumatic stress disorder (PTSD) as an implication and primary reason for marijuana usage; therefore, marijuana is requested from more than one-third of PTSD patients –26. A syThere is a stigma associated with marijuana use as a treatment, and several patients waited months or years before deciding that marijuana could be a beneficial treatment. Since the last decade till now, Middle East Muslim predominant countries are amidst regional violence and myriad sectarian conflicts contributing to rising in various mental health issues especially PTSD among war veterans . PrimaryLiterature supports the proposition that marijuana and cannabinoids have substantial adverse effects on the human body’s resistance to various infections through altering immune cell function and cytokines production to invading micro-organisms . MoreoveTherefore, an objective and evidence-based report of the short- and long-term health effects of marijuana use , which fully investigates the impacts of regulatory barriers to cannabis research and that proposes strategies for supporting the development of the resources and infrastructure necessary to conduct a comprehensive cannabis research agenda, is warranted.


The epicardial surface of the heart is readily accessible during cardiac surgery and presents an opportunity for therapeutic intervention for cardiac repair and regeneration. As an important anatomic niche for endogenous mechanisms of repair, targeting the epicardium using decellularized extracellular matrix (ECM) bioscaffold therapy may provide the necessary environmental cues to promote functional recovery. Following ischemic injury to the heart caused by myocardial infarction (MI), epicardium derived progenitor cells (EPDCs) become activated and migrate to the site of injury. EPDC differentiation has been shown to contribute to endothelial cell, cardiac fibroblast, cardiomyocyte, and vascular smooth muscle cell populations. Post-MI, it is largely the activation of cardiac fibroblasts and the resultant dysregulation of ECM turnover which leads to maladaptive structural cardiac remodeling and loss of cardiac function. Decellularized ECM bioscaffolds not only provide structural support, but have also been shown to act as a bioactive reservoir for growth factors, cytokines, and matricellular proteins capable of attenuating maladaptive cardiac remodeling. Targeting the epicardium post-MI using decellularized ECM bioscaffold therapy may provide the necessary bioinductive cues to promote differentiation toward a pro-regenerative phenotype and attenuate cardiac fibroblast activation. There is an opportunity to leverage the clinical benefits of this innovative technology with an aim to improve the prognosis of patients suffering from progressive heart failure. An enhanced understanding of the utility of decellularized ECM bioscaffolds in epicardial repair will facilitate their growth and transition into clinical practice. This review will provide a summary of decellularized ECM bioscaffolds being developed for epicardial infarct repair in coronary artery bypass graft (CABG) surgery. Heart failure is a chronic and progressive condition characterized by maladaptive structural cardiac remodeling and poor cardiac pump function. The most common cause of heart failure is damage to the cardiac muscle caused by ischemic injury, otherwise known as myocardial infarction (MI) . There aAccording to current guidelines, the primary objective in the surgical management of MI is to restore blood flow to the infarct region in order to preserve myocardial viability and alleviate symptoms , 5. RevaFor patients who progress to end-stage clinical heart failure, cardiac transplantation remains the gold standard treatment modality , 12. HowAn array of stem cell-based approaches have emerged in the past two decades with the aim of restoring myocardial function and preventing the progression of heart failure. Despite the numerous clinical trials conducted and their important contribution to our current understanding of the treatment of heart failure following MI, an efficacious stem cell-based therapy with clinically relevant outcomes has yet to emerge –26. ClinIn the case of acute myocardial infarction, earlier trials such as BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) and REPAIR-AMI  showed improved LVEF in patients treated with bone marrow mononuclear cells (BM-MNCs) –30. Howen = 157) receiving cardiopoietic cell therapy compared to sham control (n = 158) at 39-weeks follow-up  trial has significantly contributed to uncertainty regarding the clinical efficacy of this approach  , 69. EPDDuring early cardiac development, the epicardium dictates myocardial maturation and compaction, and the formation of the coronary vasculature and Purkinje fibers , 83–85. Normally, the epicardium is quiescent in the healthy adult human heart, yet it may hold great regenerative capacity , 91, 92.Cardiac fibroblasts play an essential role in normal heart function, not only structurally and mechanically, but with regards to the biochemical and electrical properties of the cardiac environment as well –99. In tTherefore, targeting the epicardium post-MI by providing the necessary bioinductive cues capable of promoting a pro-reparative phenotype rather than a pro-fibrotic phenotype is compelling. Our research group and others believes that acellular ECM bioscaffolds offer an ideal approach by which the post-MI cardiac environment may be directed toward a pro-reparative phenotype by way of bioactive signaling , 2.in situ, and have been reported to preserve cardiac function and improve neovascularization in a rat model of MI , polyglycolic acid (PGA), poly-ε-caprolactone (PCL), polyester urethane urea (PEUU), polytetrafluoroethylene (PTFE), or varying combinations of the aforementioned materials , 123. FoAs such, the development of decellularized tissue-derived ECM bioscaffolds remains a focal point within the field. These acellular ECM bioscaffolds facilitate directing endogenous mechanisms of repair and regeneration at the site of ischemic injury by way of bioactive paracrine signaling , 125–128The small intestine is a highly vascularized organ and therefore the composition and structure of SIS-derived ECM bioscaffold is proposed to be highly conducive to revascularization itself , 126. Spin vivo, using a rat MI model: animals treated via surgical implantation of CorMatrix® ECM post-MI compared to animals treated with sham or inactivated CorMatrix® ECM displayed an FGF-2-dependent increase in vascularity, reduced LV dilatation, improved ejection fraction, and improved contractility  –66. We hactility . Furtheractility , 64 , amniotic membrane (AM), and cardiac tissue have been investigated –140. Giv+-EPDC to endothelial cell differentiation and to promote functional vessel formation in a mouse model of MI (Additionally, augmentation of the aforementioned bioscaffolds with additional growth factors and/or modified RNAs, may also play an important role in modulating the local paracrine environment and enhancing their therapeutic effect. While the specific details and challenges are beyond the scope of this review, modified RNAs may be utilized to promote angiogenesis following an MI –143. Intel of MI , 66. OveA unique opportunity exists to augment surgical revascularization via CABG surgery using acellular ECM bioscaffold therapy. The epicardial surface is readily accessible in open heart surgery. As it is an anatomic niche responsible for normal cardiac development and paracrine signaling, which becomes activated in response to ischemic injury, we can leverage the epicardium to direct endogenous repair at the site of an MI. Acellular ECM bioscaffold therapy has been shown to improve vascularization and attenuate cardiac fibroblast-mediated ventricular remodeling following an MI by way of its bioactive signaling. By providing an optimal ECM bioscaffold signaling environment the goal is to shift the damaged cardiac tissue toward a pro-reparative phenotype, and away from a pro-fibrotic phenotype, and to improve overall revascularization of the tissue. Overall, by targeting the underlying cellular and molecular causes of heart failure using acellular ECM bioscaffold therapy, this innovative strategy may be able to significantly improve the prognosis of patients who have suffered from an MI.SP, AF, and PF designed, drafted, and revised 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.


Optogenetic methods enable selective de- and hyperpolarization of cardiomyocytes expressing light-sensitive proteins within the myocardium. By using light, this technology provides very high spatial and temporal precision, which is in clear contrast to electrical stimulation. In addition, cardiomyocyte-specific expression would allow pain-free stimulation. In light of these intrinsic technical advantages, optogenetic methods provide an intriguing opportunity to understand and improve current strategies to terminate cardiac arrhythmia as well as for possible pain-free arrhythmia termination in patients in the future. In this review, we give a concise introduction to optogenetic stimulation of cardiomyocytes and the whole heart and summarize the recent progress on optogenetic defibrillation and cardioversion to terminate cardiac arrhythmia. Toward this aim, we specifically focus on the different mechanisms of optogenetic arrhythmia termination and how these might influence the prerequisites for success. Furthermore, we critically discuss the clinical perspectives and potential patient populations, which might benefit from optogenetic defibrillation devices. These may result in a drop in cardiac output, reduction of arterial blood pressure, syncope, and often in sudden cardiac death. VT and VF occur after myocardial infarction, myocarditis, in patients with reduced ejection fraction, during electrolyte imbalance or because of side effects of drugs and mutations of cardiac ion channels. The primary therapy of these acutely life-threatening arrhythmias is defibrillation by an electric shock to resynchronize the heart. Atrial fibrillation (AF) represents the most common arrhythmia with growing incidence and is accompanied by an increase in morbidity and mortality despite being not acutely life-threatening . In earl2+ release from intracellular stores. A re-entry mechanism is initiated, when the premature propagating wave front has to travel around a non-excitable region. Such regions can be non-excitable due to the anatomical structure  leading to re-entry wave fronts around the scar. Furthermore, electrophysiological heterogeneities such as partial refractory tissue , which can terminate the arrhythmia by applying rapid antitachycardia pacing or finally by delivering a strong and painful electrical shock . Even thne heart  probablyne heart , green bne heart  and can ne heart  and depene heart .de novo at the boundaries of a virtual anode potentially causing re-initiation of a re-entry mechanism and failure of defibrillation excitation. Such conduction block would extinguish the arrhythmic wave front if conduction through the illuminated region was essential for arrhythmia maintenance . Howeverse heart . For sucse heart . Furthermination . Similarmination  and in mmination . This womination .Transmural depolarization to induce conduction block seems to be less challenging in the atria, because of the much thinner myocardial walls. In consequence, optogenetic cardioversion of atrial arrhythmia was successful in a ChR2 expressing mouse model heterozygous for an AF-promoting connexin 40/Gja5 mutation. This mouse line allowed induction of sustained AF episodes by intra-atrial electrical burst stimulation, which could be terminated by epicardial illumination . OptogenIn contrast to creating a conduction block by continuous transmural optogenetic depolarization, filling of the excitable gap requires only brief (~few ms) depolarization of epicardial cardiomyocytes above the action potential threshold. In consequence, required light energy (intensity × duration) would be much lower and similar to optogenetic cardiac pacemaking. This concept was proven by the group of Leonardo Sacconi using patterned light stimulation to terminate VT with one specific reentrant wave front . The autin silico  excitable gap using brief light pulses with localized conduction blocks by sustained illumination. Experimentally, this could be enabled by the recent development of an all-optical heart platform, combining epicardial voltage mapping with spatially defined optogenetic stimulation using a digital-mirror device in a closed-loop feedback system . Such a + or Cl− pumps. Within this Research Topic article collection, we report an optogenetic strategy to analyze the effects of hyperpolarization within the intact heart and to determine the potential mechanism for defibrillation . Unfortunately, the overall success rate was lower compared to conduction block by continuous depolarization with ChR2, which can be explained by the low efficiency of light-driven pumps as well as by simultaneous VA stabilizing mechanisms of hyperpolarization . For future clinical perspectives, more effective optogenetic tools for hyperpolarization would be necessary. Unfortunately, the recently presented K+ channel-based optogenetic approaches have very slow kinetics in the range of minutes  anodes and cathodes. In contrast, optogenetic methods allow selective hyperpolarization using light-driven Hillation . By expr minutes . This woIn summary, we have identified two possible mechanisms for optogenetic termination of VA that can now be put into clinical context and be compared with current treatment strategies. (1) Optogenetic pacing to fill the excitable gap could be used for energy-reduced arrhythmia termination but requires either global illumination  or triggSince publication of the first landmark-trials in the early 2000s , implantUsing specific virus capsids  or promoBefore optogenetic therapies can be suggested to patients, the proof-of-concept studies mentioned above have to be verified in preclinical large animal models with human-like anatomy and arrhythmia. Furthermore, long lasting virus-based gene transfer without immunological reactions against viruses or the non-human optogenetic proteins must be established. Toward this aim, we were able to prove that optogenetic defibrillation of VT and cardioversion of AF is also possible in wild-type mouse hearts after systemic injection of AAV , 2018. Qin vivo. Recently, a hybrid system for automated AF detection and optogenetic cardioversion in anesthetized rats was described combining surface ECG leads, an external cardiac rhythm monitor, and an implanted atrial LED with a PDMS light guide (in vivo (“AF begets AF”) using fully implantable miniaturized bio-optoelectronic devices for closed-loop optogenetic control in freely moving rats in vivo  .PS and TBr planned the manuscript. PS, MF, TBe, and TBr wrote 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.


Wide-field imaging plays an increasingly important role in ocular oncology clinics. The purpose of this review is to describe the commonly used wide-field imaging devices and review conditions seen in ocular oncology clinic that underwent wide-field imaging as part of the multimodal evaluation.Wide-field or wide-angle imaging is defined as greater than 50° field of view. Modern devices can reach far beyond this reporting fields of view up to 267°, when utilizing montage features, with increasingly impressive resolution. Wide-field imaging modalities include fundus photography, fluorescein angiography (FA), fundus autofluorescence (FAF), indocyanine angiography (ICG), spectral domain optical coherence tomography (SD-OCT), and recently wide-field OCT Angiography (OCTA). These imaging modalities are increasingly prevalent in practice. The wide-field systems include laser, optical, and lens based systems that are contact or non-contact lens systems each with its own benefits and drawbacks. The purpose of this review is to discuss commonly used wide-field imaging modalities for retinal and choroidal tumors and demonstrate the use of various widefield imaging modalities in select ocular oncology cases.Clinical examination remains the gold standard for the evaluation of choroidal and retinal tumors. Wide-field imaging plays an important role in ocular oncology for initial documentation, surgical planning, determining the relationship of the tumor to adjacent ocular structures, following tumor size after treatment, and monitoring for recurrence. Clinical examination is the gold standard for the diagnosis of retinal and choroidal tumors that often involve pathology in the peripheral fundus. Historically, imaging technology could easily and clearly capture photographs of lesions located in the posterior pole to the edge of the equator. The first fundus camera had a 20° field of view, later expanded to 30°, and this was set as the standard for fundus photography. Over the last few decades advances in imaging modalities have vastly expanded the field of view photographed and enabled microscopic evaluation of the peripheral retina. Wide-field or wide-angle imaging is defined as greater than 50° field of view with modern devices that can reach far beyond this reporting fields of view up to 267° when utilizing montage images. Montage imaging requires photographic expertise to capture and align the images and often fails to obtain far peripheral views in focus with the posterior pole images. Wide-field imaging has found a particularly important role in ocular oncology for initial documentation, surgical planning, determining the relationship of the tumor to adjacent ocular structures, following tumor size after treatment, and monitoring for recurrence.The wide-field systems include laser, optical, and lens based systems that are contact or non-contact lens systems each with its own benefits and drawbacks Table . CommonlAs imaging characteristics of fundus tumors have been better characterized, using multiple imaging modalities may enhance the diagnostic accuracy of the clinician . Wide-fiAfter diagnosis, wide-field imaging can assist with surgical planning by documenting lesion margins and evaluate the response to treatment with serial images to quantify interval changes. It can also identify the extent of retinal non-perfusion, radiation retinopathy, and other tumor effects that may not be readily apparent on clinical examination.The purpose of this review is to discuss the most commonly used wide-field imaging modalities for retinal and choroidal tumors and demonstrate the use of various widefield imaging modalities in select ocular oncology cases.Retinoblastoma is the most common intraocular malignancy among children. Most often it presents with leukocoria, strabismus, or ocular inflammation and requires prompt examination under anesthesia and treatment once the diagnosis is confirmed. Retinoblastoma can have a wide range of clinical presentations but is classically a gray-white intraretinal mass fed and drained by retinal vessels and can have various associated ocular findings based on the affected structures Fig. Wide-field imaging offers a reliable and quantitative way to monitor response to treatment. Contact lens systems, such as the RetCam 3, are typically used for retinoblastoma evaluation and imaging because non-contact images are difficult to obtain on these young patients in clinic. The RetCam has a more limited field of view, but increased depth compared to Optos. Scleral depression can aid in obtaining the full retinal periphery in the RetCam field of view  malformations, and choroidal hemangiomas. Wide-field imaging particularly FA and ICG offer key diagnostic information for these lesions.von Hippel disease, however, if it is associated with cerebellar hemangioblastomas or other systemic symptoms it is termed von Hippel-Lindau syndrome. Referral for genetic testing, neurologic, nephrological, and systemic evaluation is critical as patients are at increased risk for cerebellar hemangioblastomas, renal cell carcinoma, and pheochromocytoma. Regular ophthalmic evaluation and early treatment of hemangioblastomas can reduce the late complications of this condition including exudative retinal detachment.Retinal capillary hemangioblastomas are a rare angiomatous tumor arising from the retina that presents as a reddish-orange mass with large, dilated feeding and draining retinal vessels. Wide-field imaging and FA play an important role as the lesions are often peripheral and demonstrate a classic FA pattern of rapid filling of the feeding retinal arteriole, later filling of the intralesional blood vessels, followed by drainage through the dilated venule and massive late leakage into the tumor and vitreous Fig. . In one FA is nearly diagnostic of retinal cavernous hemangiomas that are a rare retinal tumor that clinically presents with a “cluster of grapes” appearance. The tumor consists of dilated, thin-walled vascular channels and within these plasma-erythrocyte separation occurs. As a result, the FA reveals a slowly filling lesion with fluorescein that pools at the top of the space (within the plasma segment) and remains there for a prolonged period of time without leakage of the dye. Treatment of these lesions is rarely required, however, referral for systemic evaluation for dermatologic and neurologic manifestations is warranted.Wyburn-Mason syndrome. FA demonstrates characteristic rapid filling of both the afferent and efferent retinal vessels without an intervening capillary bed and no leakage of the dye.Also known as a racemose hemangioma Fig.  representomato ketchup fundus and is associated with encephalofacial angiomatosis (Sturge-Weber syndrome). FA highlights the large choroidal vessels in these lesions in the early phases with late staining of the tumor. Wide angle fundus photography can help monitor the degree and resolution of associated exudative retinal detachments. Sturge-Weber patients require dermatologic and neurologic evaluation for other potentially life-threatening hemangiomas.There are two distinct forms of choroidal hemangiomas: circumscribed and diffuse. Circumscribed lesions are benign, reddish-orange tumors with high reflectivity on ultrasound and do not have systemic associations. These are typically located within the posterior pole and are captured well with traditional fundus imaging. Diffuse tumors present with a saturated red appearing fundus referred to as These lesions represent a benign vascular mass in the retina often found in otherwise healthy individuals. The lesions can cause damage through direct mass effect, or adjacent exudation and resulting macular edema. They often have borders that extend into the mid-periphery that can be visualized with wide-field imaging and FA.The differential for a melanocytic choroidal lesion include choroidal nevus, melanoma, congenital hypertrophy of the retinal pigment epithelium (CHRPE), melanocytoma, adenomas and adenocarcinomas of the nonpigmented and pigmented ciliary epithelium, combined hamartoma of the RPE and retina, metastasis, atypical retinal or choroidal hemorrhage, hemangiomas. Wide-field imaging particularly FA in conjunction with examination, ultrasound, and if necessary tissue biopsy or CT/MRI can assist in determining the correct diagnosis and treatment plan.When evaluating melanocytic lesions, laser projection systems can leave shadows from any anterior opacity including focal cataracts, vitreous opacities, or the lashes or nose, that give the appearance of pigmented lesions or pseudomelanocytic lesions . FurtherChoroidal nevi are incidentally detected in 6–10% of subjects and represent a relatively common ophthalmic condition detected on routine examination , 10. NevOnce a lesion has been determined to be a choroidal nevus, regular follow-up and photographic documentation is recommended at baseline and follow-up. Wide-field photographs can capture the full margins of a nevus in the periphery as well as its relationship to other structures such as the retinal vessels to facilitate future comparisons . AlthougCHRPE is a sharply demarcated, flat, typically darkly pigmented lesion often with lacunae in young adults. Optomap imaging in the optometric population reported a 1.2% prevalence of CHRPE lesions most commonly in the far temporal peripheral retina . The lesChoroidal melanomas are the most common primary intraocular malignancy in adults. They typically present as large, pigmented, elevated, dome-shaped lesions that may be associated with orange pigment, subretinal fluid, RPE changes, or a serous retinal detachment. Orange pigment is due to the contrast of lipofuscin and melanin and is associated with malignant activity. Wide-field FAF enables detailed view of orange pigment and comparison over time Fig. .Clinical examination, multimodal imaging, tissue biopsy and systemic evaluation are critical in suspected uveal melanomas Figs.  and 7. WWide-field imaging offers the advantage of imaging tumors in the periphery  without Wide-angle imaging of melanomas during initial diagnosis documents the initial size of the lesion and its relationship to adjacent structure to monitor response to therapy. Wide-field photography has been reported to yield similar tumor size measurements as ultrasonography when the tumor is less than 3 mm in height and there is no associated subretinal fluid or detachment . There aThe most common intraocular and intraorbital tumor in adults is metastatic disease and thus the recognition of such lesions is critical. The choroid is frequently the site of involvement because metastatic foci spread hematogenously from distant organs. The most common primary site of the cancer varies by gender. Females most often present with breast carcinoma followed by lung carcinoma while males most often present with lung carcinoma . Wide-anRadiation retinopathy is a dose-dependent complication of radiation exposure with presentation similar to diabetic retinopathy Fig. . ComplicOver the last several decades there have been significant advances in retinal imaging technology that have enriched our understanding of various retinal conditions. High resolution images allow for visualization of pigment characteristics, vascular leakage, ellipsoid zone health, details of each retinal layer, presence or absence of the RPE, and recently blood flow and oxygenation, that provide further insight into choroidal and retinal tumors. Modern devices have rapid image acquisition times, short processing times, and offer transmission of photography data to other units or the electronic health record. Wide-field imaging plays an important role in the diagnosis, management, and follow-up of retinal and choroidal tumors as these lesions often extend or present in the periphery or have important vascular changes in the periphery that can be identified and better characterized with wide-field imaging. Machines with multiple modalities of simultaneous, or at least sequential, imaging aid in the evaluation and management of peripheral lesions. For this reason, it is now the standard of care to obtain multimodal imaging of choroidal and retinal tumors in ocular oncology clinic.The exact utility of each camera and wide-field imaging type remains controversial and further research is required in this field. Technology advances at an exponential rate so shortcomings such as resolution, color correction, and field of view will only continue to improve with time. It is important to recognize that despite their proliferation in ophthalmology, wide-field imaging systems have drawbacks that should be considered when evaluating their utility in clinical practice.As these technologies develop, the increasing field of view and resolution offer potential new insights into the pathophysiology of these tumors and better delineation of these lesions for surgical planning. In the future it is likely that various forms of wide-field imaging systems including OCTA will play an increasingly important role across the spectrum of retinal disease including ocular oncology and these wide-field systems may play a role in screening select high-risk populations. More research into these areas is required to better understand define utility of these images in the treatment of patients with retinal and choroidal tumors. Despite these exciting advances in technology, the gold standard for evaluation of choroidal and retinal tumors remains the clinicians examination.


Non-persistent chemicals, such as phthalates, environmental phenols, organophosphate pesticides, and others, are challenging to study because of their ubiquity in the environment, diverse exposure routes, and high temporal variability of biomarkers. Nonetheless, there is interest in understanding how gestational exposure to these chemicals may affect fetal growth, as perturbations to normal fetal growth are related to a plethora of adverse health outcomes in childhood and adulthood.in utero .The purpose of this review is to describe the state of the science on this topic. We searched PubMed for studies that included both 1) biomarkers of non-persistent chemicals collected during pregnancy and 2) fetal growth outcomes measured at birth  or by ultrasound The bulk of the literature we found uses biomarkers measured at a single time point in pregnancy and birth weight as the primary measure of fetal growth. There is a small, but growing, body of research that uses ultrasound measures to assess fetal growth during pregnancy. In addition to summarizing the findings of the publications we identified, we describe inconsistencies in methodology, areas for improvement, and gaps in existing knowledge that can be targeted for improvement in future work. This literature is characterized by variability in methodology, likely contributing to the inconsistency of results reported. We further discuss maternal, placental, and fetal pathways by which these classes of chemicals may affect fetal growth.To improve understanding of how everyday chemical exposures affect fetal growth, and ultimately lifelong health outcomes, mechanisms of toxicant action should be considered alongside improved study designs for future hypothesis-driven research.The online version of this article (10.1186/s12940-019-0480-8) contains supplementary material, which is available to authorized users. Birth weight is among the most commonly studied health outcomes in environmental epidemiology. It is readily acquired through birth records, has reliable recall, and is less subject to measurement error compared to other pregnancy outcomes . Extreme low or high birth weight is a well-known risk factor for neonatal mortality and various morbidities in infancy, adolescence, and adulthood –6.An alternative approach to examining fetal growth involves collecting ultrasound parameters of fetal size at multiple time points during pregnancy in conjunction with metrics at delivery. Using repeated ultrasound measures to assess growth reduces measurement error and allows for the assessment of growth over time. This approach may also enable identification of windows of gestation where growth is more sensitive to environmental perturbations and, with the availability of parameters beyond weight to estimate size, individual compartments that are particularly affected.Recent reviews have highlighted the associations between fetal growth and environmental exposures such as air pollutants and persistent organics pollutants , 8. HoweHerein we describe some potential etiologic mechanisms of environmental toxicant action on fetal growth. We then provide a comprehensive review of the studies that have examined these non-persistent chemical exposures during pregnancy in relation to the fetal growth measures described above. We summarize the available studies, followed by a discussion and interpretation of inconsistencies in methodology and synthesis of gaps in existing knowledge that can be targeted for improvement in future work.The mechanisms underlying associations between non-persistent environmental contaminant exposures and fetal growth restriction are poorly understood. However, there is strong biologic plausibility and animal evidence for mechanisms that could drive these perturbations. Here we summarize some of the known maternal, placental, and fetal factors associated with reduced fetal growth and offer some examples of how non-persistent environmental contaminants could act through these pathways Fig. .Fig. 1MaMaternal environment is a major factor in fetal growth and may be more important than genetics. This is exemplified in a study of pregnancies with ovum donation in which the authors observed correlations between birth weight of the mother, but not the ovum donor, and birth weight of the newborn . The folMaternal nutrient intake is one of the strongest risk factors for fetal growth restriction . ExtremeThere is strong evidence for an association between maternal oxidative stress and inflammation and fetal growth restriction. Residing in areas of high altitude, which leads to hypoxia and oxidative stress , is consIndependently or in connection with these pathways, maternal vasoconstriction and elevated blood pressure are important risk factors for fetal growth restriction that can be influenced by the environment. By way of impairing placentation and reducing nutrient delivery to the fetus, vascular disease is considered one of the most common causes of growth restriction . CigaretProbably the most plausible mechanism for associations between these compounds and growth restriction is through endocrine disruption pathways. Phthalates, environmental phenols, and many pesticides fall under the classification of Endocrine Disrupting Compounds (EDCs) because of their ability to interfere with hormones . Furtherovergrowth of the fetus in response to chemical exposures as well.Lastly, and largely entangled with endocrine factors, maternal metabolic function plays a major role in regulating fetal growth. Hyperglycemia, adiposity, and type 2 as well as gestational diabetes are associated with increased fetal growth , 53. ManChanges in the maternal environment can have a major influence on implantation, growth, nutrient transfer, and hormonal activity of the placenta. For example, oxidative stress early in pregnancy may interfere with normal trophoblast invasion and widening of spiral arterioles, leading to insufficient vascularization of the placenta . AdditioA major target of environmental exposures in the placenta could be epigenetic factors, including methylation, histone modifications, and miRNA activity, which affect transcription and expression of genes. IGF-2 expression in the placenta is particularly important for its growth and for regulation of nutrient delivery to the fetus . EnvironPlacental mitochondria are another potential target of environmental toxicants . MitochoNutrient transporters in the placenta may also be sensitive to environmental toxicants that make their way into the tissue, which occurs commonly for the chemicals discussed in this review. This could occur through direct interaction with activate transporters, as with the observed disruption of the amino acid transporter systems by nicotine and cocaine , 69, or in vitro studies some toxicants have demonstrated ability to inhibit secretion of hormones from placenta-specific cells [in vitro, but exploration of this mechanism in human populations remains to be seen [Lastly, the placenta is an endocrine organ itself and generates hormones in pregnancy that play a major regulatory role in maintaining pregnancy and in the growth of the fetus. Key players include estrogen and progesterone, placental lactogen, placental growth hormone, and placental corticotropin-releasing hormone . In in vic cells . Howeveric cells . A numbe be seen , 75.Congenital anomalies in the fetus, such as trisomy, are associated with fetal growth restriction, although whether they are a cause or consequence is not clear . NeverthAs with the placenta, genes regulated by epigenetic markers in the fetus are important for normal growth and may be sensitive to environmental exposures.  IGF-2 in the fetus influences the nutrient demand, which is one of the most important factors for fetal development, but epigenetic modifications in other imprinted and non-imprinted genes may be influential as well.in utero exposure to non-persistent chemical exposures in pregnancy and changes in cord blood hormone levels, which are thought to reflect fetal effects. For example, di (2-ethylhexyl) phthalate (DEHP) metabolites in urine have been associated with decreased fetal testosterone levels measured in cord blood in females [Finally, as pregnancy progresses, and the fetus begins to produce hormones on its own, the endocrine disrupting effects of these compounds that have been noted in the mother may occur in the fetus as well. In fact, the fetus may be even more sensitive to toxic effects of these compounds as mentioned above. Some studies have demonstrated associations between  females , and a d females . Likewis females . These hWe searched PubMed for studies published in English available online through June 2018 using combinations of key words for non-persistent environmental exposures and fetal growth outcomes  or size measured at birth . Among studies that used ultrasound measures, we further distinguish between clinical diagnoses of IUGR and ultrasound measures collected for research purposes. We included studies that defined IUGR as estimated fetal weight in the lowest 10th percentile for gestational age. In our presentation of results, we focused on findings that were statistically significant at an alpha level of 0.05. When results were analyzed both with and without adjustment for gestational age, we presented results without adjustment in tables, as gestational age may be a mediator along the causal path between toxicant exposure and fetal growth [PON1 genotype and status. Finally, because urine is the preferred matrix for measuring non-persistent organic pollutants [We organized results by three primary chemical groups: A) phthalates, B) environmental phenols and other non-persistent consumer product chemicals, and C) non-persistent pesticides. We further considered three sets of criteria: 1) whether the chemical or metabolite of interest was measured in urine or in a different matrix; 2) whether the study measured exposure at multiple time points; and 3) whether the study examined fetal growth measured l growth . We presllutants , 84, we n-butyl phthalate, and diisobutyl phthalate; high molecular weight phthalates include butylbenzyl phthalate, di (2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate, diisononyl phthalate [. This classification reflects both structural similarity and similar routes of exposure, as low molecular weight phthalates are often found in personal care and hygiene products, while high molecular weight phthalates are commonly used as plasticizers in polyvinyl chloride (PVC) materials, tubing, medical devices, and food packaging [. Humans are exposed to some phthalates such as DEHP, and increasingly, diisononyl phthalate, through contaminated food and drinking water [n-butyl phthalate, diiosbutyl phthalate, and butylbenzyl phthalate – is likely from the use of consumer goods and personal care products [Phthalates are a group of chemicals typically used as plasticizers in a wide variety of industrial and consumer products, including polyvinyl chloride products, medical devices, food packaging, toys, and personal care products , 86. Bechthalate , 90. Thiackaging , 87. Humng water . Exposurproducts , 93. Metproducts .We identified 19 studies conducted in China, France, Spain, Poland, Japan, Taiwan, and the U.S. that examined associations between maternal urinary phthalate metabolites and at least one growth outcome measured at birth  and fetal size and growth rates early in pregnancy (at and between 12 and 20 weeks gestation), they report positive associations between MBzP and MnBP and the rate of fetal growth between 20 and 34 weeks of gestation.Two small hospital-based case-control studies from the same research group reported that levels of DEHP metabolites measured at a single time point in the third trimester were associated with increased odds of IUGR or “fetal growth restriction” (diagnosis of either IUGR or low birth weight) , 126. A Finally, we previously examined ultrasound measures of fetal growth at up to three times per participant during pregnancy and phthalate measures collected at up to four times in pregnancy . AlthougWhile there is a large and growing base of literature exploring the relationship between gestational exposure to phthalates and fetal growth, the relationship remains in question. Studies that combined two or more samples of urinary phthalate metabolites collected during pregnancy found few associations with birth weight or other growth outcomes measured at birth , 109–112Phenolic compounds are used in thousands of consumer and industrial products, and human exposure to some of these chemicals is essentially ubiquitous throughout high income countries , 127–129We identified 27 studies conducted in the U.S., Europe, and Asia that examined associations between environmental phenols, parabens, or organophosphate ester flame retardants in maternal urine samples collected during pregnancy to at least one infant size outcome measured at birth Table . As withThe most frequently measured environmental phenol was BPA. Most of the 14 studies we identified found no statistically significant associations between prenatal maternal urinary BPA and birth size outcomes , 154. In12 studies examined prenatal exposure to triclosan (TCS) and size at birth, nine of which found no statistically significant associations, including two which collected urinary biomarkers at 3-4 points during gestation , 161. HoFour of five studies measuring dichlorophenols found statistically significant inverse associations with birth size , 156. TwThere was minimal evidence of any association between gestational exposure to parabens or benzophenones and size at birth. Of six studies of parabens, four found no statistically significant associations with birth size , 156, inTriclocarban (TCC) and non-persistent flame retardants have not been well studied in this field. Two U.S. studies found generally null associations between gestational TCC and birth size outcomes , 156. A We additionally identified nine studies that measured environmental phenols and other non-persistent chemicals in media other than maternal prenatal urine, with mixed results , atrazine, Metolachlor-S, and 2,4-Dichlorophenoxyacetic acid  – account for approximately half of the world’s pesticide usage [Almost 6 billion pounds of pesticides were used globally in 2012, with 20% of that application occurring in the U.S. . Herbicide usage . An estide usage . In the de usage . In humade usage , 176. Asde usage , 177.We identified 17 studies that evaluated associations between gestational exposure to biomarkers of non-persistent pesticides and birth size outcomes, the majority of which measured metabolites of organophosphate pesticides Table . Nearly PON1 genotype and status [PON1 gene control the levels and efficiency of paraoxonase, an enzyme that can detoxify OP pesticides such as chlorpyrifos, parathion, and diazinon [PON1 phenotypes – low, moderate, and high enzymatic activity – with low activity related to reduced detoxification. PON1192QQ and PON1-108TT genotypes generally correspond to low activity (and possibly greater vulnerability to adverse impacts of OPPs), while genotypes PON1192RR and PON1-108CC correspond to high activity [PON1192QQ genotype [PON1192QR and PON1-108CT genotypes [PON1192RR or PON1-108CT genotypes [PON1192RR genotype and positive associations between prenatal dimethylphosphate levels and birth length in infants with the PON1-108TT genotype [Several studies found statistically significant modification of associations between prenatal DAPs and birth size by d status , 187. Sidiazinon . There agenotype , 186; anenotypes ; while aenotypes . Most of) and head circumference in infants whose mothers had low PON1 enzymatic activity [Four studies of three different cohorts measured urinary metabolites specific to individual OPPs , 189. Thactivity .Four studies measured urinary metabolites of pyrethroid pesticides, the most commonly-measured of which was 3-phenoxybenzoic acid (3-PBA), with mixed results , 189. Whth percentile for birth weight and for head circumference at birth, while prenatal metolachlor levels were inversely associated with head circumference measured at birth [Other non-persistent pesticides measured in prenatal urine included the herbicide 2,4-D , the carat birth .Five studies also measured biomarkers of prenatal exposure to non-persistent pesticides in other matrices  across pregnancy. If the urine sample from this time point is pooled with those collected later in pregnancy, any potential associations would be diluted. Moreover, in studies with biomarkers and growth measures collected at multiple time points, it is sometimes unclear whether exposures truly precede outcomes. When samples are pooled or exposure levels are averaged across multiple samples it is possible that some of the individual samples were actually collected after the time point when growth was assessed, which violates the temporality assumption, i.e., that the measured exposure precedes the outcome of interest. It is important that researchers therefore consider and clearly convey when biological samples were collected in relation to when growth outcomes were measured.Thus, in an ideal setting, repeated urine samples would be collected within trimesters and across gestation and analyzed individually. Since this is not always feasible financially, alternative approaches—such as exploring windows of vulnerability in a subset and then subsequently pooling—are encouraged. Investigators should carefully consider the time period of exposure that one or more biomarkers reflect, as well as hypotheses regarding mechanisms of action when designing exposure assessment methods for large studies. It should be noted that the windows of exposure measured were highly variable across the literature reviewed here. If the growth of the fetus is more vulnerable to environmental stressors during one point in gestation than another, this variation likely contributes to the lack of consistency seen in results. While we did not formally evaluate whether associations were more consistent when biomarkers were measured earlier versus later in pregnancy, we observed no clear patterns in associations by timing of exposure assessment.In summary, careful consideration in study design must be given to determining the mode of urine sample collection, number of specimens, and whether or not to pool. Striking a balance between cost, participant burden, and scientific integrity can be challenging in this field.Many studies included in this review measured exposure to phthalates, environmental phenols, or other non-persistent consumer products at delivery , 188, anAnother limitation is the use of inappropriate biological matrices for measuring exposure. Urine is the preferred matrix for assessment of exposure to non-persistent chemicals, particularly at low concentrations . Levels Finally, variation in levels of exposure to non-persistent environmental chemicals, as well as differences in the susceptibility of populations under study, can contribute to differences in the true effect between studies of the same exposure and outcome. Reporting the concentrations of every chemical measured in every study described is beyond the scope of this review. Rather, we recommend that researchers compare chemical exposure levels in their study population to those in both other study populations and in population-based samples  to facilitate evaluation of these possible differences. Moreover, there is evidence that exposure to some non-persistent chemicals – such as BP3, TCS, and organophosphate pesticides – follow seasonal patterns –212. Birth percentile birth weight for gestational age at delivery) and intrauterine growth restriction, also referred to as fetal growth restriction  [The majority of the research we identified examined infant size measured at birth as a reflection of fetal growth in utero. While birth weight, for example, is a reliable metric, it is an incomplete measure of whether a fetus attained (or surpassed) its potential growth over the course of gestation. Other indices of suboptimal fetal growth, as established by the American College of Obstetricians and Gynecologists, include small for gestational age  . These mnd scan)  or custond scan) ), but inin utero fetal growth outcomes  are also options. While it is not clear what impact this choice has on associations between environmental exposures and fetal growth, this is a question worth investigating [Another consideration in the analysis of ultrasound data is the approach for calculating standardized measurements  for each measurement. Most studies apply population-specific references  , 220–222tigating , 224.We identified a single study that examined overgrowth as a potential adverse endpoint . MacrosoThe epidemiologic literature regarding the potential effects of non-persistent environmental chemicals on fetal growth has increased substantially over the past decade. However, there remains variability in the statistical approaches employed by researchers in this field that is likely contributing to inconsistency and possibly bias in published effect estimates.The majority of the research we identified used linear regression models of associations between continuous biomarker measures and continuous fetal size measures. These models assumed a monotonic, if not linear, relationship between exposures and outcomes. However, a number of studies that examined categories (tertiles or quartiles) of prenatal phthalate levels found few monotonic trends but identified non-monotonic statistically significant associations , 160. IfAn additional consideration with respect to model selection is how to include repeated (non-independent) measures for an individual. We noted several methods employed by studies included in this review, including averaging measures from two or more time points to create a single exposure metric for the entire pregnancy , 180–182in utero fetal size measures to gestational age at the time of ultrasound [Inclusion of covariates in statistical models differed greatly across the literature we identified. In particular, we noted variation in how studies incorporated gestational age in analyses of fetal size and evaluated potential modification or interaction by fetal sex. The majority of studies we identified adjusted models of fetal growth outcomes for gestational age. Researchers standardized trasound , 156 andtrasound . Some ustrasound , 156. Matrasound , 197. Setrasound , 182. Thtrasound –235. Adjtrasound , 237.Maternal diet during pregnancy influences fetal growth and is also a primary source of exposure to some non-persistent chemicals . IncreasThere is inconsistency in the literature in whether researchers evaluate fetal sex as an effect measure modifying variable. Effect modification by fetal sex in this context deserves special consideration because of differences in: 1) how male and female fetuses grow and respond to the environment , 247; 2)Reproductive-aged women are exposed to an unavoidable milieu of environmental chemicals that can be transferred to a developing fetus during pregnancy , 252. WhIn addition to maternal exposures, paternal environmental exposures may also be related to fetal growth and development. While the focus of this review was maternal exposure to non-persistent chemicals, three studies included in this review additionally examined paternal exposure to non-persistent environmental exposures in the context of fetal growth , 161. AsThe studies we identified in this review included only live born infants in their analyses. If an environmental toxicant both acts to reduce fetal growth and increases risk of fetal demise, conditioning on live birth can lead to biased effect estimates . The selThere is a broad and growing base of research examining associations between prenatal exposure to non-persistent chemicals and fetal growth. For the sake of concision, this review highlighted results that met statistical significance at p<0.05. However, lack of statistically significance does not necessarily imply no true causal effect. We have not quantified results in any meta-analyses, nor attempted to evaluate to what extent the available literature may be influenced by publication bias. Our focus, rather, has been to discuss the strengths and limitations of the state of the epidemiologic literature of the associations between maternal prenatal biomarkers of non-persistent environmental chemicals and fetal growth. There are a number of factors – from measurement of biomarkers to outcome assessment to statistical design – that may have influenced the lack of coherent conclusions amongst the studies we identified. This literature is characterized by variability in exposure and outcome assessment, as well as analytical decision-making. Such variability likely contributes to the inconsistency of published results. To improve understanding of how everyday chemical exposures affect fetal growth, it is necessary to examine these questions with improved study designs and more consistency across analyses.The purpose of this review was to summarize the existing literature regarding biomarkers of prenatal non-persistent environmental chemicals exposure and fetal growth. We highlighted three chemical groups: phthalates, environmental phenols and other non-persistent consumer product chemicals, and non-persistent pesticides. There is growing evidence that prenatal maternal exposure to some high molecular weight phthalates is related to perturbations in fetal growth measured during pregnancy and infant size measured at birth. BPA was the most extensively studies environmental phenol in this literature base, but it was generally not associated with fetal growth. Among the few studies of dichlorophenols and fetal growth, there is some evidence that exposure to this group of phenols is related to reduced fetal growth in utero and reduced size at birth. Organophosphates remain the most widely studied non-persistent pesticide in this literature, despite reductions in use over the past two decades. Research indicates that associations between levels of dialkyl phosphates and infant size at birth differ by genetic factors, though conclusions from the studies reviewed vary somewhat. We identified no studies of maternal prenatal biomarkers of non-persistent pesticides and fetal growth measured during gestation by ultrasound.The ultimate value in determining whether prenatal exposure to non-persistent chemicals affects fetal growth lies in understanding if, how, and when it is possible to reduce exposure and thus adverse outcomes. Exposure to these classes of chemicals may be reduced by both individual and regulatory action , 258. ThAdditional file 1:Keywords for literature review. Word document of keywords used in literature review. (DOCX 64 kb)Additional file 2:Supplemental tables. Word document of Supplemental Tables S1, S2, and S3. (DOCX 43 kb)


Cerebral hyperperfusion syndrome (CHPS) is a complication that can occur after cerebral revascularization surgeries such as superficial temporal artery- (STA-) middle cerebral artery (MCA) anastomosis, and it can lead to neurological deteriorations. CHPS is usually temporary and disappears within two weeks. The authors present a case in which speech disturbance due to CHPS lasted unexpectedly long and three months was taken for full recovery. A 40-year-old woman, with a history of medication of quetiapine, dopamine 2 receptor antagonist as an antipsychotics for depression, underwent STA-MCA anastomosis for symptomatic left MCA stenosis. On the second day after surgery, the patient exhibited mild speech disturbance which deteriorated into complete motor aphasia and persisted for one month. SPECT showed the increase of cerebral blood flow (CBF) in left cerebrum, verifying the diagnosis of CHPS. Although CBF increase disappeared one month after surgery, speech disturbance continued for additionally two months with a slow improvement. This case represents a rare clinical course of CHPS. The presumable mechanisms of the prolongation of CHPS are discussed, and the medication of quetiapine might be one possible cause by its effect on cerebral vessels as dopamine 2 receptor antagonist, posing the caution against antipsychotics in cerebrovascular surgeries. Superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis is a surgical procedure of direct revascularization to improve cerebral blood flow and potentially prevent brain infarction for patients with stenoocclusive cerebrovascular diseases . While tCerebral hyperperfusion state is defined as a major increase cerebral blood flow (CBF) following surgical repair that is well above the metabolic demands of the brain tissue, and it can be detected using single-photon emission computed tomography (SPECT) . When hyWe report a case of a patient who suffered from speech disturbance for more than three months due to CHPS after the surgery of STA-MCA anastomosis for symptomatic left MCA stenosis. The characteristics of this case and the mechanism of the long duration of CHPS are discussed.A 39-year-old woman, who had been taking medication of quetiapine as an antipsychotics for depression, experienced mild dysarthria and visited the department of neurology in our hospital. Her symptom was diagnosed as drug-induced lip dyskinesia, which disappeared in a week. Screening head magnetic resonance imaging (MRI) at this time revealed stenosis of the left MCA with no brain parenchymal lesions , why sheSeven months later, the patient experienced mild weakness and numbness in her right hand and visited our department. Although MRI showed no apparent ischemic change in her brain, arterial spin labelling (ASL) of MRI detected the decrease of CBF in the left cerebrum , which wPostoperatively, her speech was normal until postoperative day 1 (POD1). On POD2, she exhibited mild speech disturbance, which worsened day by day finally resulting in complete motor aphasia on POD6. Her comprehension was kept normal. On POD3, generalized convulsion occurred, which ceased quickly by diazepam, and levetiracetam was initiated. On the same day, she presented with mild weakness of right upper extremity, which improved gradually and disappeared on POD7. MRI and CT showed no ischemic or hemorrhagic changes, but ASL and SPECT revealed remarkable increase of CBF in the left cerebrum Figures , by whicCerebral hyperperfusion syndrome (CHPS) following cerebral revascularization is well recognized particularly in the context of carotid endarterectomy (CEA) and carotid artery stenting (CAS) , 10. STAIn the present case, the initial presentation of CHPS appears typical in terms of the symptoms as well as the pattern of hyperperfusion on SPECT, because the area of hyperperfusion is frequently in localized brain cortex after STA-MCA anastomosis –8, and tThere are two cases showing long duration of CHPS after STA-MCA bypass reported in the literature, both of which were the patients with moyamoya disease , 14. In Although underlying mechanisms for hyperperfusion remain undetermined, possible pathophysiology for CHPS has been suggested to be the impaired autoregulation, endothelial dysfunction mediated by free radicals, breakdown of the baroreceptor reflex, and breakdown of blood-brain-barrier (BBB), which results from a rapid increase in cerebral blood flow , 16. ThePositron emission tomography (PET) is another tool to detect hyperperfusion in different aspects than MRI or SPECT can detect, and the decrease of oxygen extraction fraction (OEF) and the tendency of high cerebral blood volume (CBV) are reported to be the factors observed on PET in patients who developed CHPS . In partConsidering that the symptoms persisted extremely long despite all possible treatments including strict control of blood pressure and the administration of edaravone and minocycline –21, therThis case represented a rare clinical course of CHPS. Factors causing long duration could not be determined, but we suggest a possibility of the involvement of antipsychotics by its effect on cerebral vessels as D2 antagonist. Further studies are needed to elucidate the mechanisms of CHPS and to establish the optimal treatment strategy for better prognosis.