CorA/MRS2/ALR type Mg2+ transporters are essential for maintaining Mg2+ homeostasis in plants. However, the candidate protein and its potential functions in the tomato plant have not been fully understood. In this study, we identified seven MGT genes (SlMRS2) in tomato based on sequence similarity, domain analysis, conserved motif identification, and structure prediction. Two SlMRS2 genes were analyzed in the bacterial strain MM281, and a functional complementary assay demonstrated their high-affinity transport of Mg2+. Quantitative real-time PCR analysis revealed that the expressions of these Mg2+ transporters were down-regulated in leaves under Mg2+ limitation, with a greater impact on lower and middle leaves compared to young leaves. Conversely, under Mg2+ toxicity, several genes were up-regulated in leaves with a circadian rhythm. Our findings indicate that members of the SlMRS2 family function as Mg2+ transporters and lay the groundwork for further analysis of their distinct functions in tomato.Magnesium (Mg As the center atom of chlorophyll, it is essential for chlorophyll synthesis and degradation [2+ plays an important role in energy metabolism because ATP only has biological activity in conjugated form with Mg, and Mg-ATP accounts for about half of the total Mg2+ content in plant cells [2+ participates in the activities of more than 300 enzymes involved mainly in signal transduction, secondary metabolism, the synthesis of nucleic acids and proteins, and the bridging of ribosomes during translation [2+ in plant cells and organelles is strictly controlled to ensure normal physiological and metabolic processes [2+ transporters have a vital role in controlling the influx and efflux of Mg2+ and maintaining Mg homeostasis [Magnesium . According to the study by Knoop et al. (2005) [2+ transporters share a conserved tripeptide Gly-Met-Asn (GMN) motif on the penultimate TM.In the bacteria, three kinds of Mgkaryotes . The Corotes [2+ ,7. Anothmembrane . Becausemembrane ,10. All . (2005) , the maj2+ transporters play vital roles in both Mg2+ transport and homeostasis [2+ deficiency conditions, Mg2+ accumulates in the roots via mass flow and is absorbed via cell-membrane-located Mg2+ transporters, such as AtMGT1/AtMRS2-10, AtMGT6/AtMRS2-4, and AtMGT7/AtMRS2-7 in Arabidopsis [2+ concentrations [2+ upward into the blade when there was excess Mg2+ in the external environment [In higher plants, CorA/MRS2/ALR-type Mgeostasis ,4. Underbidopsis ,13,14, abidopsis  and ZmMGbidopsis . AtMRS2-trations , and AtMironment .2+ could be stored in the vacuole via the transport system located on the tonoplast to maintain the cytoplasmic homeostasis of Mg2+, and three Mg2+ transporters, AtMGT2/AtMRS2-1, AtMGT3/AtMRS2-5, and AtMHX, participated in this process [2+ between chloroplast stroma and the cytoplasm, mainly in vascular tissues [2+ between the ovary and the tapetum [2+ transporters also played a role in the development of organelles and reproductive organs. MGT10/AtMRS2-11 is essential for the tissue-specific regulation of chloroplast development [mgt10) caused the loose stacking of thylakoid membranes in the chloroplast, lessening the light protection and reducing the repair of the damaged PSII [AtMRS2-11 was induced by light with circadian rhythm [ZmMGT12 [SsMGT6, SsMGT9, and SsMGT10 [AtMGT4/AtMRS2-3, AtMGT5/AtMRS2-6, and AtMGT9/AtMRS2-2 played important roles in pollen development. Among these, AtMRS2-3 is located on the endoplasmic reticulum and mainly acts during the pollen development stage from double cells to maturity, while the pollen in the Atmgt4 mutant was inactivated in the double cell phase [AtMRS2-6 was essential for the male gamete mitosis and inner wall formation [AtMRS2-2 has been found essential for pollen development, while pollen grains were aborted in deletion mutants [PbrMGT7 was also expressed in the pollen, and acted on the mitochondria to keep the homeostasis of Mg2+ in pollen development [2+ transporters also alleviate the aluminum (Al) toxicity of plants. AtMRS2-1, located on the vacuole, showed no sensitivity to the Al stress, while AtMRS2-10 and AtMRS2-11 exhibited high sensitivity to the Al toxicity [2+ in rice cells [Excessive Mg process ,20. AtMG tissues ,21,22, w tapetum . Mg2+ trelopment , and itsn rhythm ; a simil[ZmMGT12 , SsMGT6, SsMGT10 . In addill phase . AtMRS2-ormation . The fun mutants . PbrMGT7elopment . Mg2+ trtoxicity . Similarce cells .2+ transporters, to our knowledge no systematic work has been carried out on tomato . Tomato is an important cash crop and vegetable in China, and the yield and consumption of tomato are increasing rapidly [2+ transporter genes in tomato would be of great help to reduce Mg2+ deficiency via exploring the internal genetic potential. In this study, seven CorA/MRS2/ALR-type Mg2+ transporters were identified to constitute the typical Mg2+ transport system of tomatoes. The biochemical information, phylogenetic relationships, sequence characteristics, gene distribution, and collinearity were analyzed, and protein quaternary structures were predicted via bioinformatics technology. A complementation assay was used to verify the Mg2+ transport function of SlMRS2. Also, the expression profiles of SlMRS2 genes, including their expression patterns and responses to Mg2+ stress, are shown in this article.Although much work has been conducted on Mg rapidly . Moderat rapidly , and it 2+ transporters of tomato were detected via blast using the Mg2+ transporter sequence of the model plants as a query. Bioinformatics analysis indicated that the isoelectric points of Mg2+ transporters in tomato ranged from 4.56 to 6.09, and the relative molecular mass was between 42.53 and 54.98 kDa , Arabidopsis thaliana, maize, and rice, were used to build the phylogenetic tree . There were fairly high up-regulated expression levels of SlMRS2-2, SlMRS2-3, and SlMRS2-4 in roots.The relative expressions of Mgreatment . All SlMSlMRS2 genes  from the tomato cultivar Qianxi were cloned and sequenced. They were then reconnected into the pTrc99A vector and transferred into MM281 to grow in media with different Mg2+ concentrations. The results indicated that only SlMRS2-3 and SlMRS2-11 restored the growth of MM281 on the medium containing low Mg2+ concentration, and these two genes had relatively high affinities to Mg2+, so that the transformed MM281 could grow on the medium with 0.01 mM Mg2+  motif of the TM1 helices was the key structure used to identify the CorA/MRS2/ALR superfamily  [2+ transporters only controlled the influx of Mg2+ [2+ transporters was anchored in the membrane, and the N-terminal was exposed to the interior of organelles or cytoplasm, as suggested by Lunin et al. (2006) [Mgeristics . At the eristics , and a stide LLE ,35,36. T complex , so we gerfamily c, and bi. 2013) . Based o3 . Based of Mg2+ , we sugg. (2006) .2+ transporters identified in tomato were significantly less than those in other model plants; for instance, there are 11 MGTs in Arabidopsis, 9 in rice, and 12 in maize [Arabidopsis, rice, and maize had no homologous proteins in tomato (NIPA (Nonimprinted in Prader-Willi/Angelman syndrome) gene family, which is rarely studied in plants, are involved in tomato [2+ to supplement the functional defects of CorA family proteins in some transport processes, or possibly the Mg2+ transporters of the CorA family in tomato are non-redundant and possess functions of several transporter genes in other plants. This non-redundant characteristic might be of great merit to analyze the function of specific Mg2+ transporters in tomato.The Mgin maize ,36,39. Tin maize ,41. Thern tomato . It mighn tomato ,43. Such2+ transporter genes  [AtMRS2-5 is expressed in the veins of Arabidopsis seedlings, it could be speculated that SlMRS2-5 might mainly control the content of Mg2+ in the vacuoles of root cells, and transport Mg2+ from vein cells to the extracellular fluid of mesophyll cells in the leaves.The expression of seven  tissues . Howeverand 2-5) . Based o2+ deficiency showed obvious leaf age differentiation, only SlMRS2-5 in young leaves and SlMRS2-1 in old leaves responded to Mg2+ deficiency. In particular, SlMRS2-3 in tomato might be involved in the long-distance transport of Mg2+ in tomato seedlings. Previous studies have shown that the function of AtMRS2-3, which is the homologous protein of SlMRS2-3, was related to the development of pollen at the two-cell stage [SlMRS2-3 was consistent with SlMRS2-4 and both showed a similar expression in various tissues of tomato seedlings. The high and low Mg2+ concentrations induced the expression levels of SlMRS2-3 and SlMRS2-4 in all tested tissues and showed a more than twofold increase relative to the normal Mg2+ level  were significantly up-regulated under Mg2+ deficiency conditions to repair the magnesium ion content in the middle and upper leaves. Similarly, in rice, the Mg2+ deficiency symptoms appeared more in the middle leaves [2+ deficiency were SlMRS2-3 and SlMRS2-1. The expression levels of SlMRS2-3 increased by more than six times in middle and lower leaves (L2–L4) compared with control, and were three times higher than MgT, and the expression level of SlMRS2-1 in lower leaves (L1–L2) increased by more than six times compared with control and MgT. SlMRS2-2, 2-3, 2-4, 2-5, and 2-11 were significantly up-regulated in roots under Mg2+ deficiency conditions. Among them, SlMRS2-4 was expressed significantly higher than other genes and could be selected as a marker of Mg2+ deficiency in tomato. The differential expressions of Mg2+ transporters have previously been reported in Arabidopsis, rice, and corn under Mg2+ deficiency. For instance, the expression level of AtMRS2-4 under Mg2+ deficiency was significantly increased in Arabidopsis, and peaked at 12 h after treatment [AtMRS2-7 was up-regulated under low Mg2+ condition [OsMGT1 in leaves and the leaf sheath of rice was only expressed under Mg2+ deficiency [OsMRS2-6 in the young mature leaf of rice was down-regulated with moderate Mg2+ deficiency [ZmMGT10 in the maize root system increased and reached the peak at 24 h after low Mg2+ treatment [ZmMGT12 was down-regulated in the root system and down-regulated in the aboveground part [The leaves of tomato seedlings are most sensitive to Mge leaves . Among treatment ; the expondition ; OsMGT1 ficiency ; the expficiency ; the expreatment ; and ZmMund part .SlMRS2-2 was highly expressed in the root system of tomato seedlings subjected to excessive Mg2+ stress. In addition, SlMRS2-2, 2-3, 2-4, and 2-I were more sensitive to high Mg2+ concentration. Studies have also shown that AtMRS2-4, a homologous protein of SlMRS2-4, was affected by excessive Mg2+ [SlMRS2-3 and SlMRS2-4 to Mg2+ toxicity was generally lower than that of Mg2+ deficiency. Although the expression level of SlMRS2-I in various tissues was significantly down-regulated under Mg2+ toxicity, however, its expression level was low and hard to detect. Therefore, it is considered that SlMRS2-2 in the root can be used as a sign of tomato being subjected to Mg2+ stress.In this study, the ive Mg2+ , but the2+ transporter genes were identified and confirmed in tomato in this study. Furthermore, their physicochemical properties, gene structure, conserved motifs, and cis-acting elements were detected. This study might provide fundamental data and clues to functionally characterize the Mg2+ transporters in tomato.In summary, seven CorA/MRS2/ALR type MgArabidopsis, maize, and rice were attained by using TAIR , MaizeGDB  and RGAP  databases, respectively. These sequences were used as the queries to search for the candidate SlMRS2 genes via blastp (E ≤ 1 × 10−10) in a local tomato genetic database using the sequence downloaded from Phytozome  and National Center Biotechnology Information  [SlMRS2 genes were further confirmed by Pfam  [http://smart.embl-heidelberg.de/ accessed on 5 May 2023) to verify the CorA domain (PF01544). Based on the peptide sequences of SlMRS2, the molecular mass and isoelectric point were calculated using BioXM 2.6, then the online program TMHMM Server v.2.0  was used to predict whether the proteins have 2 transmembrane domains, and the WoLF PROST online tools  were employed to predict the subcellular location of Mg2+ transporters.The peptide sequences of MRS2/MGTs of ay 2023) . The putay 2023)  and Smarhttps://itol.embl.de/, accessed on 5 May 2023). Chromosome length, gene distribution density, and collinearity analysis were carried out using the software TBtools and the MCScanX [Multiple peptide sequence alignment was conducted using software DNAMAN and aligned by clustalW. Then, the phylogenetic tree was constructed by Mega X with the neighbor-joining method, with 1000 bootstrap replications used to ensure confidence , and the MCScanX .http://gsds.cbi.pku.edu.cn/, accessed on 5 May 2023) [http://meme-suite.org/tools/meme, accessed on 5 May 2023) [https://www.dna.affrc.go.jp/PLACE/?action=newplace, accessed on 5 May 2023) was used to search for the cis-acting elements [2+ transporters were built using the SWISS-MODEL server  [The distribution of the coding region on the genomic sequence was analyzed with the gene structure display server (GSDS) tool (ay 2023) . Conservay 2023) . The onlelements . The moday 2023)  and thenay 2023) .2+ in the seedling and were then placed into the Yamazaki tomato nutrient solution with 0 mM Mg2+ , 1 mM Mg2+ , and 5 mM Mg2+ . The Mg treatments were applied in a completely randomized design with three replicates for each treatment. The composition of nutrient solutions was as follows: Ca(NO3)2·4H2O 354 mg/L, KNO3 404 mg/L, NH4H2PO4 77 mg/L, Na2Fe-EDTA 25 mg/L, H3BO3 2.13 mg/L, MnSO4·4H2O 2.86 mg/L, ZnSO4·7H2O 0.22 mg/L, CuSO4·5H2O 0.08 mg/L, (NH4)6Mo7O2·4H2O 0.02 mg/L [Qianxi, a commercial hybrid tomato, was used in this study. The seedlings were cultivated in nutrient solution in the plant incubator under the condition of 25 °C/16 h light and 16 °C/8 h dark. The seedlings at the four-leaf stage were transferred to double deionized water for a week to eliminate background Mg.02 mg/L . The pH SlMRS2 genes, the roots, leaves, and stems of seedlings were sampled with three biological replications at 0, 6, 12, 24, 48, and 96 h after treatment. To detect the response of gene expressions to different Mg2+ statuses, all tested tissues, including leaves (subdivided into L1–L6 according to the age of leaves), stems, roots, and cotyledons, were sampled with three biological replications after 144 h of Mg treatment. All samples were immediately frozen in liquid nitrogen and stored at −80 °C until use.To detect the temporal expression of SlMRS2 genes obtained by alignment and functional domain detection were amplified using gene-specific primers . Recombinant plasmids were transferred into Salmonella typhimurium strain MM281 lacking Mg2+ transporter genes (CorA/MgtA/MgtB). The experiment was conducted as described previously [2+  at 37 °C for 48 h. The growth rates of transgenic strains were performed in the N minimal medium with Mg2+  and antibiotics. The initial concentration of cells was adjusted to an OD600 of 0.001. The media were incubated at 37 °C, with 180 r/min rotation, and the optical density was measured every 2 h for 30 h.After sequencing, the eviously ,61. The 2+ transporter gene in different tissues from 2 tomato varieties (LA1589 and LA4345), and the data were downloaded from the Tomato Functional Genomics Database . TBtools was employed to draw a gene expression heatmap. Total RNA was extracted using RNAprep Pure Plant Plus Kit (TIANGEN) and reverse transcription was performed with FastKing RT Kit (with gDNase) (TIANGEN). Then, the cDNA was used for quantitative real-time PCR with TB Green Premix Ex TaqTM II (Tli RNaseH Plus)  in AB7500 (Thermo) using gene-specific primers (SlActin was used as the internal reference, and the relative expression was calculated using 2−∆Ct or 2−∆∆Ct [Digital expression analysis was conducted using the RPKM values of the Mg primers . Three tr 2−∆∆Ct .


Alcohol abuse is a risk factor for affective and cognitive disorders, with evidence indicating that adolescent-onset excessive drinking can result in long-term deficiencies in emotional regulation and cognition, with females more susceptible to the negative emotional and cognitive consequences of excessive alcohol consumption. However, our prior examination of the interactions between sex and the age of drinking-onset indicated minimal signs of anxiety-like behavior during alcohol withdrawal, which may have related to the concurrent anxiety testing of male and female subjects.The present study addressed this potential confound by assaying for alcohol withdrawal-induced negative affect separately in males and females and expanded our investigation to include measures of spatial and working memory.Following 14 days of drinking under modified Drinking-in-the-Dark procedures , adolescent and adult binge-drinking mice of both sexes exhibited, respectively, fewer and more signs of negative affect in the light-dark shuttle-box and forced swim tests than their water-drinking counterparts. Adolescent-onset binge-drinking mice also exhibited signs of impaired working memory early during radial arm maze training during early alcohol withdrawal. When tested in late (30 days) withdrawal, only adult female binge-drinking mice buried more marbles than their water-drinking counterparts. However, adolescent-onset binge-drinking mice exhibited poorer spatial memory recall in a Morris water maze.These findings indicate that a subchronic (14-day) binge-drinking history induces mild, age- and sex-selective, changes in negative affect and cognition of potential relevance to understanding individual variability in the etiology and treatment of alcohol abuse and alcohol use disorder. One of the most common risk factors for the development of dementia and cognitive decline is a history of alcohol abuse . NumerouCharacterized as stage of rapid neurodevelopment, adolescence normally takes place between 12 and 17 years of age in humans and 28–50 postnatal days (PND) in laboratory mice. Adolescence is commonly recognized as a transitional period marked by the onset of puberty and accompanied by rapid neurobiological, social, and cognitive development ,b. As a The motivational factors that drive drinking to intoxication differ between biological sexes in both humans and laboratory rodents. Evidence suggests that human females are more likely to engage in alcohol binge-drinking to alleviate physical and psychological distress, compared to males . AlthougToward this end, we published a study in 2020 designed to examine for sex by age interactions in the expression of negative affect during early (1 day) versus protracted (70 days) alcohol withdrawal in C57BL/6J (B6) mice . In contThe present study attempted to address both procedural issues by staggering binge-drinking procedures so that anxiety-like behavior was assayed separately in male and female mice on withdrawal days 1 and 30 . As recent work indicated that mature adult females are more sensitive than their male counterparts to alcohol-induced cognitive impairment , mice inad libitum, except during the 2-h alcohol-drinking session. In accordance with standard vivarium protocols, drinking cages were lined with sawdust bedding. To minimize any external stressors from unfamiliar handling and changes in the environment, routine cage cleaning activities were halted 5 days before behavioral testing. All experimental methods remained complaint with The Guide for the Care and Use of Laboratory Animals (2014) and all protocols were approved by the Institutional Animal Care and Use Committee of the University of California, Santa Barbara.This experiment employed adolescent  and adult (PND 49), male and female B6 mice sourced from The Jackson Laboratory . Upon arrival to the vivarium, the mice were immediately housed in groups of four with others of the same age and sex. Mice were allowed 7 days to acclimate to a colony room in a temperature-controlled vivarium under a 12-h reverse light/dark cycle (lights off at 10:00 h). To accommodate space constraints in our vivarium and testing facility, the mice in both withdrawal groups were subdivided into two cohorts, each cohort with a relatively equal number of animals in each group, matched for age, sex and drinking history. In the first cohorts, male mice began drinking a day before the female mice, to ensure that males and females were tested for anxiety-like behavior on different days, thereby minimizing the influence of chemosensory stimuli from the opposite sex; the inverse was done on the subsequent cohorts , 2022. AA total of 92 mice were subjected to 14-days of binge drinking using a multi-bottle DID procedure that involved concurrent access to unsweetened 10, 20, and 40% (v/v) ethanol. At 13:00 h, all alcohol-drinking mice were relocated from their home cages to individual drinking cages, fitted with a wire lid, located on a free-standing rack in the same colony room within the vivarium. All animals were given 1 h to habituate to their drinking cages prior to alcohol presentation. At 14:00 h, the binge-drinking mice were provided with three alcohol-containing sipper tubes atop the wire cage lid for 2 h (14:00 h–16:00 h), with the position of the sipper tubes randomized each day. As a result of limited space on the freestanding rack, the water-drinking control mice were group housed in drinking cages with their cage mates and received one sipper tube containing water as conducted in comparable studies e.g., , 2022. FOn the 13th day of drinking, submandibular blood samples were collected from the alcohol-drinking mice immediately following their 2-h drinking session. Analytical methods for determining blood alcohol concentrations (BAC) are similar to those employed in our previous studies , 2022. BEvidence from our prior work indicated that adolescent male B6 mice with a 2-week history of binge-drinking do not display any noticeable signs of negative affect when tested at 1 day withdrawal e.g., , 2022, wThe light-dark shuttle box test is a behavioral paradigm employed in preclinical research to evaluate anxiety-like behaviors in rodents . In thisThe marble burying test is an established rodent behavioral paradigm that is sensitive to alcohol withdrawal-induced changes in negative affect , 2022. MThe Porsolt forced swim test is a behavioral paradigm often used to evaluate the reversal of passive coping behavior by antidepressant therapies . The incFollowing the 1-day test battery for negative affect, conducted on either withdrawal day 1 (WD1) or 30 (WD30), all mice underwent a Morris water maze procedure to assay spatial learning and memory see . The MorFollowing a 1–2 day break, mice were then trained to locate 4 hidden platforms in a water version of the radial arm maze to evaluate working and reference memory. Akin to prior studies , the mazn = 6/sex/age/drinking history.The results of the large-scale study described above yielded relatively few signs of alcohol withdrawal-induced negative affect. As assays were conducted concurrently with other testing, we attempted to reduce the influence of any concurrent testing and related personnel traffic in a replicate study more in line with prior studies by our group e.g., . We alsoa priori predictions that: (1) adolescent water-drinking mice would exhibit higher baseline emotionality than their adult counterparts  was used for all statistical tests, and GraphPad Prism software (version 9.3.1 for Macintosh) was used to create all graphs.To ensure comparable alcohol intake and BECs between the groups of mice slated to be tested on withdrawal day 1 versus withdrawal day 30 , these variables were analyzed using a Sex × Age × Withdrawal ANOVA. The data for alcohol intake in the replicate study was analyzed using a Sex × Age ANOVA. Previous findings from our laboratory suggest that the magnitude of alcohol withdrawal-induced negative affect is influenced by the length of withdrawal . Therefoterparts , 2017a,bterparts ; and (3)terparts , 2018a,bIn addition to our primary analyses employing a general linear model, we sought to enhance the comprehensiveness of the data analysis for the large-scale study by employing generalized linear models (GLMs) for our between-subjects analyses. Within this framework, we selected specific GLM types provided by SPSS that were suitable for the nature of our response variables. GLMs are particularly used when assumptions underlying traditional general linear models are violated, allowing for a more flexible modeling approach that adapts to various data distributions and response types . For conTo address concerns pertaining to sphericity and homogeneity of variance, we re-analyzed our mixed-model ANOVA results using multilevel models. In contrast with traditional mixed-model ANOVAs, multilevel models do not make assumptions of sphericity or homogeneity of variance . MoreoveF = 3.99, p = 0.049, η2p = 0.045], its practical significance may be limited due to the relatively weak effect size and the unequal sample sizes in our study. As such, the data are presented as collapsed across the two withdrawal time-points in F = 45.491, p < 0.001, η2p = 0.351], as well as higher alcohol intake by female mice than males . No significant 3-way interaction was observed for the average alcohol intake  and no other significant interactions were observed .A univariate Sex × Age × Withdrawal ANOVA was conducted to determine group differences in the amount of alcohol consumed during the 14 days of drinking and to confirm equivalent intakes between mice slated to be tested for behavior on WD1 and WD30. While a statistically significant main effect of Withdrawal was observed  and consistent with this, a Pearson’s correlation showed a positive relationship between BEC levels and alcohol intake  or WD30 .A Sex × Age × Drinking History ANOVA failed to detect any significant differences for the latency to first enter the light-side of the light-dark shuttle-box on either WD1   = 6.65, p = 0.012, η2p = 0.073] and a Sex × Age interaction  were found for the time spent in the light side  and adolescent binge-drinking mice . Adolescent water control mice also spent less time in the light side when compared to their binge-drinking counterparts . The Sex × Age interaction , with no sex difference apparent in adolescent animals . Additionally, adolescent males spent more time in the light-side compared to the adult males . On WD30, no significant effects or interactions were detected .On WD1, an Age × Drinking History interaction  and an Age × Drinking History interaction  for the number of entries into the light-side . Although inspection of p = 0.119, d = 0.459; Adults: p = 0.135, d = 0.456). On WD30, a main Sex effect was observed for the number of light-side entries , with females entering the light-side more, overall, than males  = 4.01, p = 0.048, η2p = 0.044], but no other effects or interactions were found at this withdrawal time-point . The data for the number of marbles buried on WD30 by all of the groups are presented in p = 0.104, η2p = 0.030; all other interactions p’s > 0.255]. However, significant main effects of Sex  = 10.16, p = 0.002, η2p = 0.104]; Age effect: F = 3.77, p = 0.055, η2p = 0.41], indicating that females buried more marbles versus the male mice, and adult mice buried more marbles compared to their adolescent counterparts.The data for the number of marbles buried on WD1 by all of the groups are presented in s of Sex  and Age s of Sex  were detp = 0.161, η2p = 0.024, all other interactions p’s > 0.525]. However, a significant main effect of Drinking History was detected  = 4.34, p = 0.040, η2p = 0.051] that reflected a longer latency to immobility in binge-drinking mice, relative to their water-drinking counterparts. For the mice tested on WD30, a significant main effect of Sex  reflected a shorter immobile latency for females versus males, irrespective of their binge-drinking history or age of binge-drinking onset (p’s > 0.102).The data for the latency to first float in the forced swim test on WD1 are presented in detected  . To investigate potential age differences, this interaction was split along the Sex factor and revealed a significant Age x Drinking History interaction for the male mice  = 4.41, p = 0.042, η2p = 0.093], but no significant main effect or interactions for the females  and the adult male binge-drinking mice . To analyze for sex-related differences in the time spent immobile, the 3-way interaction was also deconstructed along the Age variable. This deconstruction found a Sex × Drinking History interaction for the adolescent mice, but not for the adult mice . As illustrated in p = 0.050, d = 0.844). Additionally, the adolescent male binge-drinking mice also spent more time immobile than the water-drinking control mice .The data for the time spent immobile during the forced swim test on WD1 are presented in ale mice , right . This interaction reflected a longer time spent immobile by female binge-drinking mice compared to the male binge-drinking mice . No other significant interactions were observed for this variable on WD30 . To examine for age differences, the interaction was first deconstructed along the Sex factor, which resulted in significant Age × Drinking History interactions for both male  and female subjects . As illustrated for males in p = 0.082, d = 0.727). Additionally, adolescent male binge-drinking mice had a higher number of immobile episodes versus adult binge-drinking males . In contrast, as illustrated in p = 0.056, d = 0.849). We also observed a higher number of immobile episodes for adolescent water-drinking females versus their adult counterparts . To examine for sex-related differences in basal and withdrawal-induced behavior, the 3-way interaction was analyzed also along the Age factor. This deconstruction revealed a significant Sex × Drinking History interaction for both adult  and adolescent mice . Thus, the data in p = 0.028, d = 1.035). For the adolescent mice .The data for the number of immobile episodes on WD1 are presented in ent mice , left, nF = 3.88, p = 0.052, η2p = 0.043] and Age x Drinking History  interactions were detected. As illustrated in p = 0.022, d = 0.674), while female binge-drinking mice exhibited more immobile episodes than their male binge-drinking counterparts . As illustrated in p = 0.037, d = 0.618) and the adolescent water control mice also exhibited more immobile episodes than their adult counterparts . No other significant interactions were observed .The data for the number of immobile episodes on WD30 are presented in p’s > 0.582] or later withdrawal [all p’s > 0.343]. The data are presented in Sex × Age × Drinking History ANOVAs failed to detect any significant interactions or main effects for the time taken to locate the flagged platform during either early . We also detected no significant Day × Sex × Age × Drinking History interaction for the time taken to complete the Morris maze by mice tested in later withdrawal . However, a significant Day × Age interaction was detected in later withdrawal . As illustrated in p = 0.004).No significant Day × Sex × Age × Drinking History interaction was noted for the time taken to locate the hidden platform across the 4 days of the Morris maze acquisition for the mice tested in early withdrawal ; however, a Age x Drinking History interaction was detected for this variable . This interaction reflected a shorter latency to first enter the platform location by adolescent-onset mice relative to their age-matched water-drinking counterparts , and to the adult binge-drinking mice . For the mice tested in later withdrawal, no significant main effects or interactions were found with respect to this variable .The data for the latency to enter the platform’s former location on WD1 are presented in p = 0.444, η2p = 0.007; all other p’s > 0.386]. However, a significant Age x Drinking History interaction was observed for the number of former platform entries for the mice tested in later withdrawal . This interaction reflected a trend for more entries by adolescent-onset water controls versus their binge-drinking counterparts, with a medium effect size , with a similarly sized, but opposite, group difference was noted for the adult-onset mice . Lastly, adolescent-onset water-drinking controls made more entries, overall, than their adult-onset counterparts .As alternate indices of spatial recall, we also examined the number of entries into the platform’s former location. No significant main effects or interactions were observed for the number of entries into the platform’s former location for mice tested in early withdrawal [p’s > 0.158]. In contrast, a significant Trial x Age interaction was detected for the mice tested in later withdrawal  = 5.66, p = 0.001, η2p = 0.065] that reflected a longer time taken to find the repositioned platform by adult-onset versus adolescent-onset mice on the initial reversal trial (p = 0.034). No other significant interactions were observed between the binge-drinking and water-drinking groups, however, a main effect of Trial illustrated a progressive reduction in the time required to locate the platform .For the mice tested in early withdrawal , a Trialthdrawal  . This 4-way interaction was first analyzed along the Sex factor and indicated a significant Day × Age × Drinking History interaction for the female mice . The Day x Age x Drinking History interaction observed in female mice was further deconstructed along the Age factor and indicated a significant Day × Drinking History interaction for the adolescent-onset females . However, while it appeared that adolescent-onset binge-drinking females committed more reference memory errors than their water-drinking counterparts on several days during this initial training . The comparable follow-up analysis of the significant Day × Age × Drinking History interaction for adult-onset females indicated only a significant main effect of Day  = 3.76, p = 0.009, η2p = 0.146]. Thus, a prior history of binge-drinking during adulthood did not influence reference memory in adult females tested during early alcohol withdrawal. For the males tested in early withdrawal, no significant Day × Age × Drinking History interaction was found upon deconstruction of the significant 4-way interaction along the Age factor . However, a Day x Age interaction was observed , that reflected a trend toward more reference memory errors committed by adult versus adolescent males on day 6 of training only (p = 0.061).For the mice tested in early withdrawal, a significant Day × Sex × Age × Drinking History interaction was detected for the number of reference memory errors during the first week of radial arm maze training   was detected. However, post hoc analyses indicated that this interaction reflected more reference memory errors committed by adults vs. adolescents only on day 4 of training (p = 0.041) and thus, this interaction is not depicted.For mice tested in later withdrawal , a signiF = 2.43, p = 0.041, η2p = 0.027]. While deconstruction along the Sex factor indicated no significant interactions , deconstruction along the Age factor revealed a significant Day x Sex interaction for the adolescent-onset mice , that reflected a greater number working memory correct errors in males versus females only on day 3 of radial arm maze training . In contrast, no interactions were detected in adult-onset mice, with all mice exhibiting a progressive reduction in working memory correct errors with training  = 4.89, p < 0.001, η2p = 0.100].Analyses of the data from the mice tested in early withdrawal identified a significant Day × Sex × Age × Drinking History interaction for the number of working memory correct errors during the first week of testing   that reflected fewer working memory correct errors committed by binge- versus water-drinking mice on the first two days of radial arm maze training (p < 0.001)–a result suggestive of better working memory performance in binge- versus water-drinking mice. However, it is notable that the time-course of working memory errors committed by binge-drinking mice during later withdrawal was relatively flat (more working memory correct errors later during training than at the start of training (p’s < 0.027). In contrast, the number of working memory correct errors committed by water-drinking mice declined progressively over the course of training, indicative of intact learning (p’s < 0.046).Analyses of the data from mice tested in later withdrawal failed to indicate a significant 4-way interaction . Deconstruction of this interaction along the Age factor indicated a significant Day x Drinking History interaction for both age groups . On days 2, 4, and 5, adolescent-onset binge-drinking mice made more working memory incorrect errors versus their water controls . In contrast, adult-onset binge-drinking mice committed fewer working memory incorrect errors than water controls but only on day 3 (p = 0.014). As depicted in No significant Day × Sex × Age × Drinking History interaction was detected for the number of working memory incorrect errors committed by the mice tested in early withdrawal  = 2.68, p = 0.030, η2p = 0.029] was detected that reflected a lower number of working memory incorrect errors in binge- versus water-drinking mice, but only on day 2 of training . Consistent with the data for the number of working memory correct errors, water-drinking controls tested in later withdrawal exhibited a progressive decline in the number of working memory incorrect errors with training (p’s < 0.041), while the time-course of behavior was flat in binge-drinking animals (p = 0.032), indicative of little to no learning.For the mice tested in later withdrawal, no significant Day × Age × Sex × Drinking History interaction was found for the number of working memory incorrect errors . However, a significant Day × Sex × Drinking History interaction was observed . Deconstruction of this interaction along the Sex factor yielded a significant Day × Drinking History interaction for the female mice  = 3.96, p = 0.005, η2p = 0.079]. As illustrated (p = 0.002) and day 5 (p = 0.008) of training. No significant interactions were detected for the male mice tested in early withdrawal  = 21.63, p < 0.001, η2p = 0.320; post-hoc tests, days 2 and 3 versus days 4–7, all p’s < 0.010].The Day × Sex × Age × Drinking History ANOVA for the mice tested in early withdrawal indicated in no significant four-way interaction for chaining behavior  that reflected more chaining episodes in females versus males on day 2 of training, while males exhibited more chaining episodes on day 4 . As illustrated in p’s < 0.033]. While chaining behavior declined early during training in the females tested in later withdrawal (p’s < 0.003), this behavior plateaued, with females exhibiting more chaining on day 6, relative to day 4 (p = 0.032) and day 7 (p = 0.037).The analyses of the data for the mice tested in later withdrawal failed to detect a significant Day × Age × Sex × Drinking History interaction [p’s > 0.147]. All mice exhibited a progressive decline in the amount of time taken to complete the maze .No significant interactions between Day × Sex × Age × Drinking History were detected for the total time taken to find all the platforms in the radial arm maze when the mice were tested in early withdrawal  was found that reflected a shorter time taken by binge- versus water-drinking mice on days 2 and 3 of training . In this replicate study, the interaction reflected higher alcohol intake by male adolescent mice versus their adult controls , with no age difference detected for the relatively high alcohol intake exhibited by female subjects .An analysis of the average total alcohol consumed over the 2-week drinking period indicated a significant Sex × Age interaction  reflected a shorter latency of adolescent versus adult males to enter the light-side , with no age difference observed in females . We also detected a significant Age X Drinking interaction for this variable  = 5.59, p = 0.023; η2p = 0.123]. Although inspection of t-tests, p’s > 0.158). Rather, the Age × Drinking interaction reflected a longer latency to enter the light side by alcohol-experienced adults versus their adolescent counterparts , with no age difference noted for water controls .Under these more insulated testing conditions, we detected two significant interactions with respect to the latency to first enter the light-side of the light-dark shuttle box . As illuvariable  , which reflected less time spent by alcohol-experienced adults versus their water controls  with no water-alcohol differences detected in adolescent mice . Although it appeared that adult female alcohol-experienced mice entered the light-side fewer times than their water controls  = 2.93, p = 0.095; η2p = 0.068; other p’s > 0.133; η2p’s < 0.056].A summary of the data for the time spent on the light side is depicted in controls , we detecontrols   that reflected a longer latency of adolescent versus adult males , with no age difference noted for females . We also detected an overall Drinking effect  that reflected a shorter latency to bury in alcohol-experienced mice versus water controls, irrespective of the animals’ age or sex .A summary of the data for the latency to begin marble burying is provided in F = 5.482, p = 0.024; η2p = 0.121; other p’s > 0.117; η2p’s < 0.061], that reflected more marbles buried by adult versus adolescent mice ent mice .F = 70.15, p = 0.050; η2p = 0.825]. This interaction reflected a longer latency to float by alcohol-experienced males versus their water controls , with no significant alcohol-water difference detected in females . No Age effect or interactions were detected for this variable .As depicted in p’s > 0.187; η2p < 0.044) or the number of floating episodes  or in the forced swim test. Instead, we detected only main Age effects for both variables  = 8.73, p = 0.005; η2p = 0.179; for float time (sec), Age effect: F = 6.86, p = 0.012; η2p = 0.146] that reflected less floating-related behavior in adult vs. adolescent mice.In contrast to the latency to float, we detected no alcohol or sex effects for the time spent floating  history of binge-drinking, the age of drinking-onset and sex in the affective consequences of alcohol assayed at 1 versus 70 days withdrawal . The resn = 6/sex/age/group), the sex and age differences were less robust, owing to the relatively high alcohol intake of the adolescent males .It is interesting to note that we detected more male-selective effects of alcohol withdrawal in the present large-scale study , compareAt the time we completed the larger scale study herein, we considered two additional procedural factors that might account for the discrepancy across our sex difference : (1) theA more plausible explanation relates to the locations of the colony rooms in which mice consumed alcohol/water and the procedural space employed for behavioral testing. The mice in all our earlier studies  were houd’s∼0.5) and reflected poorer spatial recall by adolescent-onset binge-drinkers, but better spatial recall by adult-onset binge-drinkers (The extant human e.g.,  and rodedrinkers . No othedrinkers . Thus, wdrinkers , it may drinkers .Consistent with this, we detected more alcohol effects in the radial arm maze than in the Morris water maze in the present study . HoweverHerein we show that a 2-week history of binge-drinking by male and female, adult and adolescent, B6 mice induces relatively few signs of negative affect, some of which were sex-selective. Further, this binge-drinking history is sufficient to induce some signs of mild cognitive impairment in both adolescent- and adult-onset binge-drinkers that persist for greater than 1 month following the cessation of drinking.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of the University of California Santa Barbara.KS and CJ: conceptualization, supervision, formal analysis, writing—original draft preparation, writing—review and editing, and visualization. KS: project administration. CJ, ED, GS, ER, JT-G, JH, SK, AG, CJED, and MC: investigation and writing—review and editing. KS, CJ, and ED: funding acquisition. All authors contributed to the article and approved the submitted version.


When one representation of a mathematical entity is transformed into another representation, more cognitive resources such as the visual and motor systems can come into play to understand the target entity. Because of their nature, some curves, which are one group of visual representations, may have a great motor strength. It is suggested that directedness, straightness, length, and thinness are some possible features that determine degree of motor strength of a curve. Another possible factor that can determine motor strength of a curve is the strength of association between shape of the curve and past experiences of the observer (and her/his prior knowledge). If an individual has had the repetitive experience of observing objects moving along a certain curve, the shape of the curve may have a great motor strength for her/him. In fact, it can be said that some kind of metonymic relationship may be formed between the shapes of some curves and movement experiences.This article discusses the cognitive process of transforming one representation of mathematical entities into another representation. This process, which has been called  For example, in abstract algebra, groups and operations defined among elements of groups can be represented through tables, diagrams, graphs, or algebraic symbols. Learning how to represent a mathematical entity and how to transform one representation into another representation in order to find the best way to solve a problem is one of the principal mathematical skills. A mathematical concept, idea, or problem may have a variety of representations. When we are faced with a mathematical problem, we may represent it in the form of a table, a diagram, a graph, words, algebraic symbols, numbers, or other possible channels of representation. Since mathematical entities and relations are inherently abstract, we operate on them through their representations . ThroughRepresentations are tools through which people construct mathematical ideas and think and communicate about them . People When one representation of a mathematical entity is transformed into another representation, the two representations share an underlying structural similarity. In other words, it is the superficial representation that is changed not its underlying conceptual structure. Therefore, a set of parallel representations of a mathematical entity are isomorphic with each other at an abstract level. That is, while they share a basic abstract structure, they seem to be different concretely. Based on f(x) oscillates between-1 and 1 describes a function in terms of the movement of an object that oscillates between the two extreme points of-1 and 1. The strong version of embodiment theories holds that the same cognitive resources that are employed during observing the oscillation of a moving object are also employed to process the mathematical metaphor f(x) oscillates between-1 and 1. Therefore, the strong version of embodiment theories predicts that processing this metaphor involves the activation of the motor system as this metaphor describes a function in terms of a motion domain . Transforming abstract mathematical entities into visual representations is a very common practice in learning mathematics and other fields of science. For example, the function 2f(x) = x can be represented by a curve in the Cartesian coordinate system  in a more effective way . An exame system . The visf(x) = x2 is transformed into a visual representation in the Cartesian coordinate system. In this figure, a one-to-one comparison is made between the features of the two representations.Visual tools have a strong degree of imageability. Therefore, from the perspective of strong version of embodiment theories , when anAnother example is the transformation of arithmetic operations into finger-based representations. Some finger counting studies have provided evidence that supports this idea e.g., . For exaThe extent to which the abstract entity can be grounded through sensory system depends on perceptual strength of the base entity. If the base entity has a high visual strength, the visual system is effectively employed to ground and understand the abstract entity. In recent years, a number of studies have examined degree of perceptual strength of concepts in a variety of languages e.g., . These sA recent comprehensive study  examinedFindings of some studies suggest that static pictorial stimuli showing implied motion can be the cause of motor system activation e.g., . Some nef(x) = −x2, the hand movements that are involved in drawing this visual representation can be simulated  and motor systems are employed to process the photo. The same thing can happen when the abstract representation of a mathematical entity is transformed into a visual representation. Visual representation of a function in a Cartesian plane is an example in which a mathematical entity is transformed into a visual representation. The visual representation of a function could be a curve in a Cartesian plane. The curve has a high degree of visual strength. Furthermore, it may have some degree of motor strength as well. Shape of a curve may be a key factor in the degree of activation of the motor system. The experience of observing some curves may involve a greater degree of motor activation compared to other curves. In other words, some curves may have a greater motor strength. In g(x) and h(x), the visual representation of f(x) may have a greater degree of motor strength. Also, g(x) may have a greater degree of motor strength than h(x).If fictive motion sentences create a sense of fleeting motion in the mind of the comprehender and activate the motor system, it may be said that visual tools that show such sentences can also have a similar effect on the comprehender. For example, when an observer looks at a photo that shows a road passing through a forest, s/he may experience a fleeting sense of motion. In the same way that the fictive motion sentence A question that may be raised here is that what factors may affect degree of motor strength of the visual representation of a function. Findings of several studies can help us provide an answer for this question. In one of these studies, f(x) in h(x). Therefore, observing this curve may lead to a small degree of motor system activation or even no activation at all. In fact, it can be said that some kind of metonymic relationship is formed between the shapes of some curves and movement experiences. The strength of metonymic relationship is greater for some types of curves depending on past experiences of the observer. However, it should be noted that the way that a mathematical representation is viewed by a person depends on the person’s prior knowledge of the representation  or a blockage may create an opposite sense (being static and immobile). In fact, even very common daily experiences support this idea that some static visual representations or images cause a sense of motion in the observer, while others create a sense of being static. This phenomenon is not limited to our visual experiences. Even some of our aural experiences may cause a sense of motion in us. For example, some types of music cause a sense of movement in people , while others may create an opposite sense. In this case, it may be said that the first type of music has a stronger degree of motor strength.The activation of the motor system may happen in mental imagery and in the absence of the object in the environment. Reviewing a number of works on mental imagery e.g., , PalmierWhen a function is transformed into a graph as its visual representation, the graph and motor systems come into play and help us to process that function in a more effective way. The graphical representation of a function reveals some features of the function that cannot be easily discovered through non-visual representations. The graphical representation of a function clearly shows where the local maximum and minimum points are, where the function is ascending, where it is descending, and many other features that are much more difficult to discover through non-visual representations. As mentioned in the second section, transforming one representation of a mathematical entity into a visual representation is in fact a mathematical metaphor. Mathematical metaphors allow us to employ a wider range of cognitive resources to ground and understand mathematical entities. Among these resources, the visual and motor systems were discussed.f(x) never goes beyond 1 is an example of such metaphors. When the algebraic representation of the function y = f(x) is transformed into a visual representation and the metaphor f(x) never goes beyond 1 is used, the visual and motor systems are employed to process the behavior of this function. As mentioned, shape of the visual representation could play an important role in determining the extent to which the motor system is employed to process the behavior of this function. f(x)], it may be said that this curve has a great motor strength. Therefore, when we observe or even imagine this curve, our motor system may be activated. For more complex cases of curves, the past experiences of the comprehender may play an equally important role. If the comprehender has had the experience of observing complex movement of objects, that experience may help her/him to acquire a better understanding of those mathematical concepts whose visual and gestural representations are similar to those complex movements. This could have some implications for mathematics teaching classroom. We will return to this point in the following section.Since many of us have the experience of observing movement of objects along curves similar to the curve shown in x and y coordinates tends to infinity. The asymptote of the function y=x = 0 is the asymptote of the curve of this function. As x approaches zero, the curve of the function approaches the line x = 0, and the distance between the curve and the line approaches zero. The behavior of this function and its asymptote line can be effectively understood through its visual representation and a fictive motion that shows the visual representation. In the definition of asymptote, the word ‘approach’ is used, which indicates this behavior of the function and its asymptote is understood in terms of a fictive motion.A perhaps more complex example is the curve of a function that has an asymptote. The distance between the curve of a function and its asymptote approaches zero as one or both The following section discusses pedagogical implications of using visual representations of mathematical entities and motion-based mathematical metaphors in mathematics teaching classroom.Results of past studies have demonstrated how gestures could enhance the process of understanding mathematical concepts e.g., . It has In addition to these, priming mathematical concepts and ideas by their visual representations, by gestures that describe their visual representations, or by gestures that show a fictive motion related to their visual representations may facilitate the process of understanding mathematical concepts and ideas. This is particularly the case with those mathematical concepts and ideas which have components with great motor strength. Results of a study by This article discussed the cognitive process of transforming one representation of mathematical entities into another representation. Various representations of the same mathematical entity have an underlying structural similarity. Therefore, parallel representations of a mathematical entity are inherently isomorphic with each other. That is, while parallel representations of a mathematical entity share an abstract underlying structure, they seem to be different in their concrete forms. The process of transforming one representation of a mathematical entity into another representation can be seen as a kind of metaphor. Mathematical metaphors allow us to understand and embody a difficult-to-understand mathematical entity in terms of an easy-to-understand entity. When one representation of a mathematical entity is transformed into another representation, more cognitive resources can come into play to understand the base entity in a more effective way.Fictive motions are one special group of metaphors that are used to describe some important mathematical concepts such as limit and continuity. As mentioned, fictive motion sentences may create a sense of fleeting motion in the mind of the comprehender and activate the motor system. Therefore, visual tools that show such sentences can also have a similar effect on the comprehender, as visual tools can be seen as the visual translations of those fictive motion sentences. A similar process may take place when the abstract representation of a mathematical entity is transformed into a visual representation. Visual representation of a function in a Cartesian plane, which can be in the form of a curve, is an example in which a mathematical entity is transformed into a visual representation. The curve is a visual representation that may have some degree of motor strength. The experience of observing some curves may involve a greater degree of motor activation compared to other curves. In other words, some curves may have a greater motor strength. It was suggested that directed, straighter, thinner, longer curves have a higher degree of motor strength. These features of visual representation (curve) of a mathematical entity can enhance our understanding of that concept, as visual and motor resources are employed to process that concept. Another possible factor that determines motor strength of a curve is the strength of association between shape of the curve and past experiences of the observer. If an individual has had the repetitive experience of observing objects moving along a certain curve, the shape of the curve may have a great strength for her/him. Having more experience of observing moving objects along a certain curve could mean that the curve has a greater motor strength for the observer/comprehender. In fact, it can be said that some kind of metonymic relationship is formed between the shapes of some curves and movement experiences. The strength of metonymic relationship is greater for some types of curves depending on past experiences of the observer. Identifying other factors that may have a role in the degree of motor strength of visual representation is a question that can be investigated in future research.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.OK-Z wrote the first draft of this manuscript. DF and AB commented on it and revised it. All authors contributed to the article and approved the submitted version.This work was supported by the Norges Teknisk-Naturvitenskapelige Universitet.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


An arteriovenous malformation (AVM) of the mesoappendix is a very rare clinical entity. The clinical features, diagnosis and management of an AVM of the mesoappendix have yet to be sufficiently explained since reports about it are scarce. We report a 57-year-old man presented with hematochezia for 2 weeks. Upper and lower endoscopic could not find the source of bleeding. Abdominal contrast-enhanced computed tomography revealed an AVM of the mesoappendix. A laparoscopic appendectomy was performed, and he had a resolution of his symptoms. Intraoperative findings and pathological results confirmed the diagnosis of AVM of the mesoappendix. Acute gastrointestinal bleeding is a major cause of hospitalization in the clinical setting , and lowAn arteriovenous malformation (AVM) of the mesoappendix is extremely rare, and reports of AVM of the mesoappendix are limited; we cannot find any other report except one report about AVM of the appendix on Pubmed . Thus, tA 57-year-old male patient with a history of hypertension was referred to our hospital for multiple episodes of painless bloody stools for 2 weeks. No gastrointestinal symptoms were observed, such as abdominal pain, nausea or vomiting. A digital rectal examination showed bright red blood. On admission, laboratory evaluation revealed mild anemia with hemoglobin of 103 g/dL. Other than that, there were no other abnormalities. Lower and upper gastrointestinal endoscopy was performed, but the cause of the bleeding could not be identified. Due to the signs and symptoms of ongoing bleeding, we decided to perform imaging tests to make a diagnosis. Abdominal contrast-enhanced computed tomography (CT) revealed a thickened appendix  without signs of inflammation and images of vascular proliferation and dilated vein around the appendix . An angiBased on that information, the patient was diagnosed with LGIB due to AVM of the appendix and underwent a laparoscopic appendectomy. Intraoperative findings were consistent with imaging studies . The mesHistopathological results confirmed that this was an AVM of the mesoappendix . The patLGIB is a common problem in the clinical setting. Major causes of LGIB include diverticular disease, anorectal disease, ischemia and neoplasia. Other less common causes include infectious colitis, postpolypectomy, inflammatory bowel disease, angiodysplasia, radiation colitis or proctitis. In up to 25% of patients with LGIB, the source of bleeding is never accurately identified . HoweverAVM in the mesoappendix is a very rare clinical entity and has been reported by some authors where AVM is the etiology of appendicitis , 13. ConIn conclusion, LGIB secondary to the AVM in the mesoappendix is very rare, but we should always consider it in mind to consider in LGIB patients when we cannot find the source. A laparoscopic approach is effective and safe for managing AVM in the mesoappendix.


Case Presentation. We present the case of a 29-year-old woman with a history of oral contraceptive intake for 13 years, which was sent to evaluation in our Hepato-Bilio-Pancreatic and Splenic Unit because of a large nodular lesion in segment 5 of the liver, compatible with HCA, and was proposed to surgical resection. Histological and immunohistochemical investigation revealed an area with atypical characteristics, suggesting malignant transformation.  Hepatocellular adenoma (HCA) is an uncommon solid, solitary, benign liver lesion that develops in an otherwise normal-appearing liver. Hemorrhage and malignant transformation are the most important complications. Risk factors for malignant transformation include advanced age, male gender, use of anabolic steroids, metabolic syndrome, larger lesions, and beta-catenin activation subtype. The identification of higher risk adenomas enables the selection of patients most suitable for aggressive treatment and those who benefit with surveillance, minimizing the risks for these predominantly young patients.  HCAs share similar imaging characteristics and histopathological features with hepatocellular carcinomas; therefore, immunohistochemical and genetic studies assumes great importance to discriminate adenomas with malignant transformation. Beta-catenin, glutamine synthetase, glypican-3, and heat-shock protein 70 are promising markers to identify higher risk adenomas. Hepatocellular adenoma (HCA) is a rare solid, solitary, benign liver lesion that develops in an otherwise normal-appearing liver –4. OftenThe most important complications of HCA are hemorrhage 25–64%) and malignant transformation into hepatocellular carcinoma , which are the two main reasons for surgical treatment. Risk factors for malignant transformation include advanced age, male gender, use of anabolic steroids, metabolic syndrome, lesion size >5 cm, and beta-catenin activation subtype [5–64% andIn women the size of HCA has, by current consensus, remained the main decision criterion in determining whether or not resection is indicated, based upon the observation that intratumoral bleeding and malignant transformation only seldom takes place in lesions smaller than 5 cm . In men,However, with the evolving knowledge, especially on genetic and molecular characteristics of the disease, the treatment strategy could be also defined by the differences in risks of complications for the various adenoma subtypes .The highest risk of malignant transformation into HCC is found with HCA with beta-catenin activation (b-HCA) . InflammStratification according to molecular subgroups at risk for complication could modify patient care . A betteHowever, because HCA can progress to malignancy, borderline hepatocellular lesions can be expected. These HCA do not have a definite pathomolecular subtype, but are examples of an uncertain diagnosis between HCA and HCC .Bedossa et al. proposed the term “well-differentiated hepatocellular neoplasm of uncertain malignant potential” (HUMP) for neoplasms that cannot be confidently classified dichotomously as either HCA or carcinoma . HoweverHere, we report a case of a well-differentiated hepatocellular neoplasm with atypical features in a young woman, which constituted a clinical challenge for the difficulty in determine the malignant potential and prognosis.The patient is a 29-year-old woman, referred to our Hepato-Bilio-Pancreatic and Splenic Unit, with a history of continuous abdominal pain in the right upper quadrants with periods of sharpening, abdominal distension, perception of a mass in the right inferior quadrant, and constipation, for the last 3 months.2.She had a past history of polycystic ovary syndrome and gastritis. The patient had no children, had menarche at 14 years with regular menstrual cycles and had a history of oral contraceptive intake for 13 years. She had no history of hepatic disease, diabetes, hypertension, or dyslipidemia, and denied smoking or recreational drug usage. Presented an IMC of 16 kg/mHer regular medication was chlordiazepoxide + clidinium bromide and the oral contraceptive estradiol valerate 1–3 mg + dienogest 2–3 mg for the last 5 years.An abdominal ultrasound showed the presence of a solid nodular lesion with origin in the right hepatic lobe. A computerized tomography scan confirmed the presence of a solid pediculate nodular lesion in segment 5. An MRI with administration of paramagnetic hepatospecific contrast product, showed an exophytic nodular lesion with 56 mm × 83 mm heterogeneous signal in the different weightings, heterogeneously capturing the contrast product in a mainly peripheral way, maintaining areas of central hyposignal probably with a more fibrosis/hyalinization component , in an oLiver function tests were normal, with a slight increase in total bilirubin (BT 2.05 mg/dl). Other parameters, including leukocytes, hemoglobin, platelet counts, and renal function tests, were normal. Serum tumor markers  were normal. Serum virus markers  were negative.The case was discussed in our Hepato-Bilio-Pancreatic Multidisciplinary Tumor Board and it was decided surgical resection was appropriate.A laparoscopic approach showed a pedunculated hepatic lesion arising from segment 5, not adherent to adjacent structures, without ascites, with no evidence of peritoneal carcinomatosis, or other hepatic lesions confirmed by an intraoperatively ultrasound. The resection was carried out, and the patient was discharged at day 2.The surgical specimen revealed a well-defined tumor with 7.9 cm in largest dimension . On the Histological examination showed a hepatocellular tumor with a peripheral area with a predominant trabecular pattern with steatosis, cholestasis, and fibrovascular septa with a lymphocytic inflammatory infiltrate . In the Immunohistochemical study showed expression of HEP-PAR-1, liver fatty acid-binding protein (LFABP), C-reactive protein (CRP), and glutamine synthetase (GS) in the neoplastic cells  The betaThis tumor was diagnosed as a well-differentiated hepatocellular neoplasm with morphologic characteristics of an inflammatory adenoma, probably with a beta-catenin mutation  with a central area with atypia, absence of biliary ducts, loss of reticulin fibers, and sinusoidal capillarization Figures  and 7.Investigation for mutations in the CTNNB1 gene , was made through the polymerase chain reaction (PCR) technique, with direct sequencing of PCR products obtained from tumoral DNA. However, no mutations were found.Malignant transformation of HCA into HCC is a rare phenomenon with a reported frequency of 4–10% .The distinction of HCA from well-differentiated HCC can be difficult in some cases, because of similar imaging characteristics and histopathological features, and pose significant diagnostic issues , 9.The problematic lesions are neoplasms resembling HCAs, but with atypical pathological  and/or clinical features , which do not clearly fit within current HCA subtypes or well-established criteria for the diagnosis of HCC , 14.The recognition of a category designated HUMP is helpful to identify cases that require further study so that the diagnostic criteria, including histologic features and molecular signatures, for HCA and HCC can be clarified .As HCA are difficult to discriminate from HCC, it is important to have markers to identify high-risk adenomas .The immunohistochemical markers GS and nuclear beta-catenin characterize the b-HCA subtype that carry a high risk of malignant transformation , 8. HCC It should be noted that b-HCA is a heterogeneous group of tumors with various levels of activation of the WNT signaling pathway, as a result of mutations or deletions of the CTNNB1 gene involving exons 3, 7, and 8. Of the three subtypes, the one with exon 3 abnormalities except S45) has the highest risk for malignant transformation into HCC [5 has theLarge deletions and most hotspot mutations in exon 3 lead to high levels of beta-catenin activation, whereas exon 3 S45 and exon 7/8 mutations lead to moderate and weak activation of the pathway, respectively, leading to different GS patterns. Diffuse homogeneous GS staining is observed with mutations that lead to strong beta-catenin activation, whereas more-modest activation tends to show a diffuse heterogeneous pattern. Therefore, GS is a good surrogate marker to identify different types of CTNNB1 mutations .In a retrospective multicentric study, the predictive potential of three known GS patterns as markers for CTNNB1 exon 3, 7/8 mutations were investigated. Pattern 1 (diffuse homogenous) allowed recognition of 17/21 exon 3 non-S45 mutated b-(I)HCA. Pattern 2 (diffuse heterogenous) identified all b-IHCA harboring exon 3 S45 mutation (20/20). Pattern 3  distinguished 12/22 b-IHCA with exon 7/8 mutations. In exon 3 S45 and 7/8 mutations, both b-HCA and b-IHCA showed a GS+/CD34− rim with diffuse CD34 positivity in the center of the lesion .Importantly, nuclear expression of beta-catenin is not a sensitive marker of beta-catenin activation and is seen in less than half of cases. In addition, diffuse GS staining may not necessarily signify beta-catenin activation, the reported correlation between diffuse GS staining and CTTNB1 (beta-catenin) mutations ranges from 15 to 100% in HCC and 75–100% in HUMP. Despite the lack of complete correlation with beta-catenin activation, diffuse GS staining is currently considered a high-risk feature .In the immunohistochemical study of the presented case diffuse expression of GS and membranous immunohistochemical expression of beta-catenin, but not nuclear expression was noted.The concordance between nuclear beta-catenin staining and diffuse GS staining is high, but some tumors show diffuse and strong GS expression in the absence of nuclear beta-catenin staining. This phenomenon has been observed in HCA-like area in 29–44% of cases. The reason for the discrepancy between GS and beta-catenin expression is not known, some of these cases show beta-catenin mutation without nuclear beta-catenin or may have mutations affecting other components of the WNT signaling pathway, such as AXIN1 and AXIN2 . AccordiOther immunohistochemical biomarkers of malignancy can play an important role in identifying high-risk hepatocellular neoplasms, such as GPC-3 and HSP-70, and these may be useful tools to support the diagnosis of HCC , 9.In a study comparing gene expression between HCC and other hepatocellular nodules, HSP-70 was the most discriminatory gene. However, there is limited information about HSP-70 staining in HCA, with numbers ranging from 0 to 40% in three studies, further strengthening the argument that these areas may be extremely well-differentiated HCC .HSP-70, GS, and GPC-3 are usually negative in typical HCA, whereas positive staining with HSP-70 and/or GPC-3 would point towards HCC . In our The differentiation between HCA with benign or malignant characteristics is important to define the treatment and surveillance strategy, because of the risk of disease progression. For this reason, a case of HCA with atypical characteristics raises doubts and difficulties about the nature of the tumor, with treatment implications.In this case the label of a HUMP tumor was initially considered with a central foci of atypical cells, with diffuse heterogeneous expression of GS, but nuclear negativity for beta-catenin and no mutations found in the CTNNB1 gene, and expression of GPC-3 and HSP-70 was absent. However, extensive loss of reticulin fibers, considered greater than the “focal” loss described by the HUMP criteria, and diffuse CD34 positivity in the central area suggested instead that this was malignant transformation in a well-differentiated HCC.HCC developing from HCA is thought to behave less aggressively and the long-term prognosis for patients with HCA with malignant transformation who undergo resection is generally good, and recurrence is uncommon . HoweverIn a single-center experience of 122 patients with HCA, all patients treated by resection survived, without recurrent malignancy, and after a mean follow-up period of 78 months. 109 patients with benign HCA revealed recurrence or progression in 8% and regression in 9% of cases with residual HCA. Results of this study showed that complete resection of malignant HCA is a safe and efficient option because none of the patients experienced malignant recurrence over a mean follow-up period of 7 years . AnalysiA study  with 118Accordingly, MRI follow-up may be discontinued in patients with a solitary HCA after resection unless worrisome features are detected at pathologic assessment. Patients with HCA at risk of progression or multiple HCA should undergo continuous follow-up regardless of surgery .After multidisciplinary discussion, this case was considered a well-differentiated HCC and was decided a continuous surveillance. At 2-year follow-up, the patient remains asymptomatic with no imaging evidence of recurrence.However, what about lesions that do not meet the threshold for resection (<5 cm). It is known that beta-catenin mutated HCA has higher risk to progress to HCC. Subtyping of HCA has become increasingly important clinically, because HCAs that are more highly associated with malignant progression are more likely to be resected or ablated, whereas those that are not are more likely to be followed with imaging. Although subtyping is fairly widely available and is often requested by clinicians, the most recent American and European clinical guidelines do not require subtyping for routine practice .Would it be important to stratify according with the HCA subtype to better establish the treatment in lesions that do not have clear criteria to resection, proceeding with ultrasound-guided percutaneous fine needle aspiration (FNA), endoscopic liver biopsy, or even laparoscopic biopsy?Ultrasound-guided percutaneous FNA and endoscopic liver biopsy procedures are safe, low-cost, efficient, and minimally invasive procedures that have high sensitivity, specificity, and accuracy rate when diagnosing mass lesions of the liver , 22. In However, may be challenging to even unequivocally diagnose focal nodular hyperplasias, HCA, regenerative nodules, and well-differentiated HCC by FNA and the role and efficacy of FNA in small hepatocellular nodular lesions  is actively debated. On FNA and cell block material, these lesions are characterized by hepatocytes without significant atypia and trabeculae that are two cells thick. The diagnosis of HCA can only be made on needle core biopsies, because they are characterized by absent portal tracts and preserved hepatic trabeculae thickness, which are highlighted by the reticulin stain. In addition, in case of HCA, ancillary stains, including immunohistochemical stains, reticulin stain, and GPC-3 are required in addition to hematoxylin and eosin-stained sections, to subtype beta-catenin mutated adenomas –22.Additionally, FNA biopsy is not without its complications, albeit rare. They include intraperitoneal bleeding, needle tract seeding, and alleged intraprocedural hematogenous dissemination with tumor recurrence, and the rare fatality. A mortality rate of 0.018% was reported in a multi-institutional Italian series of 10,766 ultrasound-guided FNA biopsies .All these reasons have contributed to reluctance in obtaining routine pre-operative FNA diagnosis. The conundrum is to balance if the biopsy is really necessary and if it does change the outcome, against the risk of the procedure. If resection appears to be the best option, biopsy may not be performed .HCA share similar imaging characteristics and histopathological features with HCC; therefore, immunohistochemical and genetic studies assumes great importance to discriminate adenomas with malignant transformation. Beta-catenin, GPC-3, and HSP-70 are promising markers to identify higher risk adenomas.The prognosis for those afflicted with HCA is not predictable, and it remains clinically challenging to manage and counsel these patients.Because of the higher risk of malignant transformation of HCA, resection is recommended in men, patients with beta-catenin exon 3 mutations (except S45) irrespective of tumor size, large HCA (≥5 cm), and in borderline lesions.HCA is a rare entity; therefore, all cases must be discussed at multidisciplinary liver tumor boards that include specialized radiologists, pathologists, hepatologists, and surgeons to determine the most suitable patient-oriented treatment strategy.


Introduction: The incidence of kidney stones in the United States continues to increase. Although dietary interventions have shown to be effective in reducing stone events, adherence to medical management continues to be a limiting factor. For that reason, patient education has become a focus of many physicians. TikTok, a social media application with over one billion users worldwide, has emerged as an online center for medical knowledge sharing by physicians and non-physicians alike. TikTok users share kidney stone prevention information through short informational videos directly to the general public. Little is known regarding the quality of medical advice provided in these videos. The purpose of this study was to evaluate the reach and quality of kidney stone prevention information on TikTok.Methods: We conducted a cross-sectional analysis of renal stone prevention content on TikTok utilizing the search term #kidneystoneprevention to assess all the videos appearing on October 10th, 2022. Only videos in English, related to the topic, and with >1000 views were included. Videos were analyzed for descriptive statistics, including views, uploader profession, and stone prevention recommendations. Videos were assessed utilizing Denver International Study Center of Evaluative Rating of Information (DISCERN), a questionnaire used to appraise the quality of consumer health information (maximum score of 80 per video). The one-way analysis of variance (ANOVA) was used to determine statistical significance groups.Results: Out of a total of 131 videos, 87 fit the inclusion criteria, resulting in a total of 8.75 million views. An average DISCERN score of 27.0 was observed. Only eight videos were published by physicians, of which the average DISCERN score of 35.3 was significantly greater than an average score of 26.2 for non-physicians (p<0.05). The most common recommendation was increased fluid intake (38.0%) followed by monitoring calcium levels (9.02%) and decreasing oxalate-rich foods (9.2%).Conclusions: Kidney stone prevention content on TikTok has a wide reach with millions of consumers. The majority of videos fail to match American Urological Association recommendations regarding diet therapies for stone prevention. Further research is needed to understand the extent of kidney stone prevention misinformation on social media and how it contributes to patient outcomes. Increased engagement in TikTok by urologists and health organizations may improve public education. The prevalence of kidney stones in the United States has increased to about 11% ,3. AlthoLittle is known about the quality or quantity of kidney stone prevention information on TikTok. With kidney stone prevention information on the internet historically deemed incomplete , TikTok The purpose of this study was to evaluate the quality of kidney stone prevention information on TikTok using the Denver International Study Center of Evaluative Rating of Information (DISCERN) media evaluation criteria. DISCERN is a standardized questionnaire used to appraise consumer health information online. The study consisted of three objectives: 1) to evaluate the quality of kidney stone prevention content on TikTok, 2) to compare video quality based on creator characteristics and video content, and 3) to examine how existing TikTok videos match the latest AUA recommendations. This study can illuminate gaps in stone prevention information on TikTok and identify opportunities for kidney stone prevention education and distribution.Video selectionThe cross-sectional analysis of kidney stone prevention content on TikTok was performed by creating a new account and entering the search term #kidneystoneprevention. The search returned a total of 131 videos on October 10th, 2022. All videos in English and with more than 1,000 views were included. Videos that did not relate to the topic of kidney stones were excluded. Of the 131 videos initially returned by the search, 6 were not in English, 36 had fewer than 1,000 views, and 2 did not mention kidney stones. The remaining 87 videos were used for content analysis . Although no consensus to a “good” or “bad” DISCERN score has been established as far as we know, the standardized methodology for calculating a video’s total score provides an effective tool for comparing video quality relative to one another.Data analysisVideo information was categorized into various creator groups and types of content. A one-way variance analysis (ANOVA) was used to determine statistically significant differences in DISCERN scores between these groups. The proportion of videos that mention each AUA recommendation was determined by evaluating every video’s content.Overall video characteristicsA total of 87 videos met the inclusion criteria. Physicians accounted for 9% of all content creators. Males accounted for 25% while females accounted for 44% 21% unknown). The most common video type was “Management” accounting for 49% of all videos. The least common types of videos were advertisements and anecdotal videos at 6%. However, advertisements were the most popular type of video accounting for the most views, likes, and comments. The average DISCERN score across all videos was 27.0. Table % unknownPhysician vs non-physicianVideos made by physicians had an average DISCERN score of 35.3, significantly greater than an average score of 26.2 for non-physicians (p<0.05). However, they averaged 31.7% less views and 40.1% less likes.Top 10 most viewed videosNo statistically significant difference exists between the DISCERN scores of the most viewed videos and the remaining 77.Video typeAdvertisements about kidney stone-related products were the most viewed and commented video type with an average of 333,622 views and 314 comments per video. No advertisements reported on a product discussed in PubMed, Cochrane, or Medline. The average DISCERN score for advertisements (24.16) was lower than the average of all videos (27.02). TikTok recommendationsThe only AUA stone evaluation guidelines acknowledged were urinalysis  and 24-hour urine collection . The most common AUA diet therapy recommendations mentioned in the videos were increased fluid intake  followed by monitoring calcium levels  and decreasing consumption of oxalate-rich foods . The most commonly advised nutritional supplementation was lemon water . No pharmacologic therapies were addressed in any of the videos. A total of 11.5% (n=10) of videos did not mention any AUA evaluation or dietary therapy elements and 28.7% (n=25) reported only one element. A breakdown of the number of videos that acknowledge AUA diet therapy recommendations is presented in Table Out of a total of 131 videos, 87 fit the inclusion criteria, resulting in a large total viewership of 8.75 million. An average DISCERN score of 27 (maximum score of 80) was observed. Only eight videos were published by physicians, of which the average DISCERN score was significantly greater than the average score for non-physicians. This finding of low physician engagement on TikTok despite statistically higher video quality by physician creators suggests that urologists should engage more on TikTok.Many studies evaluating urology content on TikTok have reported similar findings. For example, one study evaluating men’s health on TikTok revealed that only 10.3% of all content creators were physicians and that physician videos were more accurate than non-physicians. Similarly, a study examining urinary tract infection information on TikTok in 2022 similarly found that only 20% of the creators were physicians . Both thThe observation that physicians on TikTok create higher quality videos is of no surprise. A survey study assessing patient satisfaction with kidney stone information advice during admission for acute renal colic concluded that “traditional patient education regarding kidney stones can be further strengthened through the use of a concise, informative, and readily accessible patient education video during and after point of care” . TikTok Encouragingly, the possibility of significantly increasing urologist engagement on TikTok with associated high quality has been demonstrated in other parts of the world. A study of the keyword “diabetes” in Chinese in 2021 included a total of 199 videos and found that health professionals contributed to 69.3% of all videos and that the DISCERN scores across these videos were higher than general users . A similIncreased engagement of urologists on TikTok is highlighted by the potential the platform has to reach incredibly large populations that traditional education fails to reach. The aforementioned study evaluating men’s health content on TikTok recorded about 2.3 billion total views across 234 videos (average ~9.8 million views/video) with the total number of views about testosterone, vasectomies, and erectile dysfunction at 703.5 million, 318.8 million, and 42.2 million respectively . Large cAlthough this study is the first to evaluate the kidney stone prevention information on TikTok, some limitations must be addressed. First, there is potential for incorrect identification of the physician identification of the content creator as this was ascertained on the basis of the information provided in the user's profile or self-identified in the video. Whenever this information could not be obtained, the user was designated as a non-physician. Second, we limited our search term to #kidneystoneprevention without using any other search iterations. Although this can result in an incomplete sample of all kidney stone prevention information on TikTok, our practice of limiting the search to just one term is in line with similar TikTok studies in other fields ,18. ThirLimitations notwithstanding, the findings of this study are significant for a few reasons. First, the finding that kidney stone prevention content on TikTok has a reach of millions of consumers highlights the reach of the platform. However, the popularity of the kidney stone prevention videos is small in comparison to other fields in urology like men’s health and UTI prevention, indicating a need for more content. Second, our study identified that the majority of videos failed to match AUA recommendations regarding diet therapies for stone prevention. Our findings suggest that this may be in part due to the low number of videos that are created by physicians who on average produce significantly higher quality videos. When comparing our study to similar TikTok studies in other healthcare subjects, the pattern of improved video quality with increased physician participation in content creation is seemingly ubiquitous. This suggests that increased engagement in TikTok by urologists and health organizations may improve public education. Lastly, our study identified specific areas of misinformation on TikTok which can serve as targets for further targeted kidney stone prevention education.Kidney stone prevention content on TikTok has a wide reach with millions of consumers. The majority of videos fail to match AUA recommendations regarding diet therapies for stone prevention. Increased engagement in TikTok by urologists and health organizations may improve public education.


Arteriovenous malformation (AVM) combined with aneurysms is not uncommon, but AVM of the basilar artery, brainstem, and right middle cerebral artery combined with multiple intracranial aneurysms (IAs) is rare. Cases of aneurysm protrusion into the optic canal are also rare. We report a distinctive case of intracranial AVM combined with multiple IAs and partial protrusion of a cavernous segment aneurysm of the right internal carotid artery into the optic nerve canal.Cases of partial protrusion of a cavernous segment aneurysm of the right internal carotid artery into the optic canal, resulting in widening of the optic canal compared to the contralateral side, compression, thickening and swelling of the subocular veins, and obstruction of venous drainage warrant the clinician’s attention. Intracranial arteriovenous malformation (AVM) combined with multiple intracranial aneurysms (IAs) is a complicated and specific cerebrovascular disease, with an incidence ranging from 2.7% to 16.7% and is a common risk factor for hemorrhage, with a high mortality rate [A 57-year-old man was rushed to the emergency room with intermittent convulsions. The patient had a five-year history of hypertension and a single seizure one year earlier. Axial computed tomography angiography (CTA) image  showed aThe final diagnosis was intracranial AVM combined with multiple IAs and a right internal carotid artery aneurysm. The patient was given antiepileptic, vasospasm-relieving, and blood pressure-controlling medication after being admitted to the hospital. When the patient had stabilized, the patient was transferred to another hospital. However, due to financial constraints, the patient and his family declined the further therapy and were self-discharged from the hospital.The mechanism of AVM combined with IA is complicated. IA mostly occurs in the supplying arteries of AVM and there is a blood flow correlation between IA and AVM. Moreover, fibrous degeneration and thinning of the AVM-supplying arterial walls, disruption of the intima, and alterations in the vascular musculature lead to a significant increase in pressure in the AVM-supplying vessel. These hemodynamic mechanisms may explain the development of AVM combined with IA.Given the patient’s imaging data, this case of AVM combined with IA is difficult to handle because of the following characteristics:IA occurred in the supplying artery of the AVM, which is different from the vascular structure of an ordinary IA and is clinically rare.Besides the IA in the intracranial arteriovenous malformation mass, IA was also present in the distal basilar artery and the right internal carotid artery.The IA of the cavernous segment of the right internal carotid artery partially protruded into the optic canal, resulting in widening of the optic canal compared to the contralateral side and compression, thickening, and swelling of the inferior ophthalmic vein by obstruction of venous outflow.The arteriovenous malformation vascular mass was supplied by the C5–6 segment of the internal carotid artery and the basilar artery, and several drainage veins were seen converging into the superior sagittal sinus. AndIA predominantly occurred in vessels other than ordinary IA vessels .Digital subtraction angiography (DSA), which is the gold standard for the clinical diagnosis of AVM and IA, its use is restricted because it is an invasive examination and more likely to cause cerebrovascular accidents than CTA . However, because CTA is a noninvasive, inexpensive, and quick imaging technique, it can be utilized as a reliable alternative to DSA in emergencies demanding immediate operation . CTA andWe reported a rare case of intracranial AVM combined with multiple IAs and partial protrusion of a cavernous segment aneurysm of the right internal carotid artery into the optic nerve canal, to increase awareness of this rare cerebrovascular disease.