Stigma toward sexual and gender minorities is an important structural driver of HIV epidemics among men who have sex with men (MSM) and transgender women (TW) globally. Sex-seeking websites and apps are popular among MSM and TW. Interventions delivered via Web-based sex-seeking platforms may be particularly effective for engaging MSM and TW in HIV prevention and treatment services in settings with widespread stigma toward these vulnerable populations.To assess the potential utility of this approach, the objectives of our study were to determine the prevalence of Web-based sex seeking and examine the effect of factors that shape or are influenced by stigma toward sexual and gender minorities on Web-based sex seeking among MSM and TW in Tijuana, Mexico.From 2015 to 2018, 529 MSM and 32 TW were recruited through venue-based and respondent-driven sampling. Interviewer-administered surveys collected information on Web-based sex seeking (past 4 months) and factors that shape or are influenced by stigma toward sexual and gender minorities . A total of 5 separate multivariable logistic regression models were used to examine the effect of each stigma measure on Web-based sex seeking.A total of 29.4% (165/561) of our sample reported seeking sex partners on the Web. Web-based sex seeking was negatively associated with greater endorsement of traditional machismo values  and greater levels of internalized stigma . Web-based sex seeking was positively associated with identifying as gay , greater outness , and a history of discrimination .Web-based sex-seeking is relatively common among MSM and TW in Tijuana, suggesting that it may be feasible to leverage Web-based sex-seeking platforms to engage these vulnerable populations in HIV prevention and treatment services. However, HIV interventions delivered through Web-based sex-seeking platforms may have limited reach among those most affected by stigma toward sexual and gender minorities , given that within our sample they were least likely to seek sex on the Web. Men who have sex with men (MSM) and transgender women (TW) are at increased risk of HIV infection worldwide, including those in low- and middle-income countries (LMIC) ,2. StigmStigma stems from power structures that promote or maintain social inequity -25 and mmachismo [Mexico’s HIV epidemic is concentrated within key populations ,34, inclmachismo -44, whicmachismo ,45. Findmachismo . Given tmachismo .machismo values, greater levels of internalized stigma related to same-sex sexual behavior or gender identity, and lesser outness about same-sex sexual behavior or gender identity and MSM who do not identify as gay or report a history of discrimination related to their same-sex sexual behavior).To assess the potential utility of this approach and inform the development of HIV prevention efforts for MSM and TW in Tijuana and other comparable low-income settings, we aimed to determine the prevalence of Web-based sex seeking and examine the effect of stigma on Web-based sex seeking among MSM and TW in Tijuana. We hypothesized that Web-based sex seeking would be more common among MSM and TW most affected by stigma toward sexual and gender minorities  and Proyecto Redes (Networks Project). Proyecto Enlaces was designed to compare the effectiveness of 2 recruitment methods—venue-based sampling (VBS) and respondent-driven sampling (RDS)—for the identification of undiagnosed HIV infection among MSM and TW. Proyecto Redes was embedded in Proyecto Enlaces and was designed to characterize the sexual networks of MSM and TW. Proyecto Enlaces was conducted between March 2015 and November 2018, whereas Proyecto Redes was conducted between March 2016 and September 2017.Data for this analysis came from 2 studies conducted in Tijuana, VBS was performed using time-location sampling across 36 venues identified during formative research as locations frequented by MSM and TW in Tijuana . Individuals identified via VBS were eligible for HIV testing if they were aged at least 18 years, cisgender male or transgender female, reported anal sex with a cisgender male or transgender female in the past 4 months, and did not report a previous HIV diagnosis. RDS is a chain-referral sampling technique often used to recruit hard-to-reach populations ,49. A toProyecto Redes. Rapid test–positive individuals provided an additional blood sample for confirmatory testing via immunofluorescence assay at the San Diego County Public Health Laboratory and were offered enrollment in Proyecto Enlaces. Confirmatory HIV test results were delivered to rapid test–positive individuals within 2 weeks, and those confirmed HIV positive were referred for free HIV care at Tijuana’s municipal HIV clinic.As individuals could be identified multiple times via the same or a different recruitment method, those who were identified more than once and who remained eligible for HIV testing were retested if it had been at least 3 months since their last test. Eligible individuals identified via VBS underwent rapid HIV testing  at recruitment venues or at the study site if they preferred, whereas those identified via RDS underwent rapid HIV testing at the study site. All rapid HIV test results and appropriate posttest counseling were delivered within a few days (VBS) or 20 min (RDS) at the study site. All rapid test–negative individuals identified via VBS and rapid test–negative individuals identified via RDS who reported anal sex with a cisgender male or transgender female in the past 4 months (for comparability with those identified via VBS) were offered enrollment in All study procedures occurred at the study site located in an unmarked office building staffed by local Spanish-speaking individuals with extensive experience working with sexual and gender minorities in Tijuana who were also trained to foster a nonjudgmental environment. In our previous research with key populations in Tijuana, our study site was recognized as a nonstigmatizing setting where participants felt comfortable visiting without fear of discrimination. All participants provided written informed consent, and all study procedures were approved by the Human Subjects Protection Committees at the Universidad de Xochicalco in Tijuana and the University of California, San Diego.Surveys collected sociodemographic, psychosocial, and behavioral data and were interviewer administered using computer-assisted personal interviewing.machismo, internalized stigma related to same-sex sexual behavior or gender identity, sexual orientation, outness about same-sex sexual behavior or gender identity, and history of discrimination related to same-sex sexual behavior  [machismo is relevant to this study because it reflects a heteronormative version of masculinities that may be at odds with stereotypes associated with sexual behaviors  and the sexual or gender identity of MSM and TW, and it likely shapes stigma toward sexual and gender minorities in Mexico. Traditional machismo was measured using a 10-item scale [machismo, including hypermasculinity, aggressivity, and being domineering . Participants indicated their level of agreement with these items using 4-point Likert scale responses . A mean score was calculated from item responses, with higher scores indicating greater endorsement of traditional machismo values [A total of 5 variables measured different factors that shape or are influenced by stigma toward sexual and gender minorities, including traditional ctively) . Traditiem scale ,51 that o values . To measo values  and beinWeb-based sex seeking was measured by asking, “In the past 4 months, how many different men did you meet online with the intention of having sex?” Participants who reported meeting at least one man online with the intention of having sex were classified as Web-based sex seekers.Sociodemographic data were collected on participants’ gender identity , age (in years), highest level of education completed , average monthly income in Mxn pesos in the past 4 months  , years oProyecto Redes participants  and newly diagnosed HIV-positive participants enrolled in Proyecto Enlaces (n=165). Analyses considering 3 of the 5 stigma measures  were restricted to specific subgroups of our sample because (1) HIV-positive Proyecto Enlaces participants completed baseline and supplemental (approximately 2 weeks post baseline when they returned for their confirmatory HIV test results) surveys, whereas HIV-negative Proyecto Redes participants only completed baseline surveys and (2) some survey questions were phrased for both MSM and TW, whereas others were only phrased for MSM. Data on traditional machismo and history of discrimination related to same-sex sexual behavior were collected via the supplemental survey among HIV-positive Proyecto Enlaces participants. As 27.3% (45/165) of Proyecto Enlaces participants did not return to complete the supplemental survey, analyses examining traditional machismo and history of discrimination related to same-sex sexual behavior were restricted to HIV-negative Proyecto Redes participants to reduce the potential for selection bias that could have been introduced by only including those Proyecto Enlaces participants who had returned. Analyses examining history of discrimination were then further restricted to MSM participants because the phrasing of the question was specific to experiences of MSM and not TW   were theApproximately half of our sample was recruited via VBS . Outness about same-sex sexual behavior or gender identity was positively associated with gay identification  and history of discrimination related to same-sex sexual behavior . Traditional machismo was negatively associated with outness about same-sex sexual behavior or gender identity  and gay identification . Internalized stigma related to same-sex sexual behavior or gender identity was inversely associated with outness about same-sex sexual behavior or gender identity  and sexual orientation .Bivariate associations between factors that shape or are influenced by stigma toward sexual and gender minorities were in the expected directions . Positivmachismo values , and they were more out about their same-sex sexual behavior or gender identity . Compared with MSM participants who did not seek sex partners on the Web, a greater proportion of Web-based sex seekers identified as gay  and reported a history of discrimination related to their same-sex sexual behavior .On average, Web-based sex seekers reported less endorsement of traditional machismo values  and greater levels of internalized stigma related to their same-sex sexual behavior or gender identity , whereas the odds of Web-based sex seeking were higher for those who reported greater outness about their same-sex sexual behavior or gender identity . Among MSM participants, the odds of Web-based sex seeking were higher for gay-identifying participants  and those who reported a history of discrimination related to their same-sex sexual behavior .After adjusting for sociodemographics and social support , the oddWe examined the relationship between stigma and Web-based sex seeking using cross-sectional data collected from MSM and TW in Tijuana, Mexico. Nearly one-third of our sample reported seeking sex partners on the Web in the past 4 months, which is consistent with estimates from Peru (36%)  but is nmachismo values, less internalized stigma related to same-sex sexual behavior or gender identity, were more gay identifying, and were more out about their same-sex sexual behavior or gender identity compared with those who did not seek sex on the Web. Prior research suggests that MSM and TW most affected by stigma often isolate themselves from other sexual and gender minorities to conceal their minority status [Our a priori hypothesis was that Web-based sex seeking would be more common among MSM and TW most affected by stigma toward sexual and gender minorities. However, for the most part, our findings do not support this hypothesis. More specifically, participants who met sex partners on the Web reported less agreement with traditional y status ,32. As sy status ,14, we imachismo) and internalized stigma related to same-sex sexual behavior or gender identity. Including a broader scope of factors that shape or are influenced by stigma provides a more multidimensional understanding of the role of stigma with respect to Web-based sex seeking, which may have been underappreciated by prior studies that considered only 1 or 2 factors [Overall, our findings suggest that Web-based sex seeking is more common among MSM and TW in Tijuana who are less affected by stigma toward sexual and gender minorities. Our findings are similar to those from exploratory studies in Peru , China ,17,18, L factors ,25.Our study has several limitations. First, because of the cross-sectional design of our study, we cannot establish a temporal relationship between the exposures of interest and Web-based sex seeking. Therefore, we cannot infer that the observed associations represent causal associations. Second, our use of nonprobability sampling methods may limit the generalizability of our findings. These sampling methods, however, were critical to our ability to recruit MSM and TW who are socially marginalized and often hidden in Tijuana. However, even with the use of these sampling methods, TW were underrepresented in our sample, which precluded us from stratifying our analyses by gender identity. As such, our results do not shed light on potential differences in Web-based sex seeking or its relationship with stigma between MSM and TW, which should be examined in future research. Third, our assessment of Web-based sex seeking was exclusive to meeting male partners. As a result, we may have underestimated the prevalence of Web-based sex seeking among MSM and TW in Tijuana because those who only met TW partners on the Web would not have been classified as Web-based sex seekers. Fourth, we did not collect data on smartphone or computer use, both of which are likely associated with Web-based sex seeking and should be considered in future research. Fifth, although surveys were interviewer administered to alleviate respondent burden, interviewer-administered surveys may have introduced social desirability bias if participants underreported sensitive information related to the exposures of interest or Web-based sex seeking. However, to minimize the potential for social desirability bias, all interviewers had extensive experience working with sexual and gender minorities in Tijuana and were trained to create a nonjudgmental environment and build rapport with participants to enhance their comfort with respect to responding openly and honestly. Finally, it is possible that poor recall could have led to the misclassification of history of discrimination related to same-sex sexual behavior and Web-based sex seeking in the past 4 months. However, such misclassification was likely nondifferential with regard to the outcome or exposure and, thus, may have only biased effect estimates toward the null.Despite these limitations, our findings suggest that Web-based sex seeking is relatively common among MSM and TW in Tijuana and that it may be feasible to leverage Web-based sex-seeking platforms to engage these vulnerable populations in HIV prevention and treatment services. However, such Web-based interventions may still poorly engage those most affected by stigma toward sexual and gender minorities, given that within our sample they were least likely to seek sex on the Web. Further research is needed to identify effective and acceptable strategies to link MSM and TW most affected by stigma to HIV prevention and treatment services. As trends of Web-based sex seeking among nationally representative samples of MSM in the United States have dramatically increased over time , future


Persons living with dementia (PLWD) often display declining communication and conversational skills, leading to reduced quality of life and social isolation. Given limited evidence for interventions targeting conversation skills in PLWD, we examined the transcripts of a creative group storytelling program, TimeSlips, offered in a memory care community in Central Texas. We analyzed communicative exchanges using modified rules of the ‘Conversational Act Profile’ . Utterances were coded for each participant’s interaction 1) with the facilitator and 2) with other participants. Preliminary evidence for six participants across six sessions is reported here. While the number and type of participant-to-facilitator utterances did not show a specific pattern, five of the six participants showed increased participant-to-participant communication across sessions. These findings suggest that a creative storytelling program such as TimeSlips may promote greater communication among PLWD, thereby improving social connectedness amongst them and possibly, their quality of life.


The etiology of ST-elevation myocardial infarction (STEMI) is either rupture or erosion of unstable plaque with subsequent thrombosis. With the widespread use of plaque-stabilizing lipid-lowering therapies (statins), plaque erosion, rather than rupture, now accounts for most cases of acute coronary syndromes (ACS). In the spectrum of ACS, STEMI usually results from the total occlusion of the culprit epicardial coronary artery, leading to the occlusion of blood flow to the affected myocardium. The differential diagnosis of ST-elevations on electrocardiograms are broad. However, an elevated cardiac marker, evidence of wall motion abnormality on echocardiogram or positive stress testing makes an alternate diagnosis less likely. This prompts emergent coronary angiography with an intent to fix the underlying cause. In some cases like ours, when the clinical suspicion of STEMI is high, the coronary angiography may be unrevealing of the diagnosis. ST-elevation myocardial infarction (STEMI) is usually caused by plaque rupture or erosion leading to the total occlusion of the coronary arteries. Myocardial infarction in the absence of critical epicardial coronary vessel disease is being increasingly recognized . However, STEMI usually involves some form of culprit lesion that might be either an unstable plaque with erosion or rupture with overlying thrombus formation leading to total occlusion of epicardial vessels . We descA 50-year-old female presented with intractable nausea and vomiting after a hiking trip. Due to severe dehydration and metabolic acidosis, she was started on bicarbonate drip and admitted to the intensive care unit (ICU). The patient did not have any history significant for anginal chest pain and declined any symptoms of angina during current admission. Her previous history did not reveal any coronary artery disease risk factors, including hypertension, diabetes, hyperlipidemia, or smoking. Family history was also unremarkable. However, EKG upon transfer showed anterolateral ST-elevations in leads V1-V6 , which revealed 70% mid-segment and 60% distal segment stenosis of the LAD while the other coronary arteries were normal Figure .Intraoperative echocardiogram showed corresponding wall motion abnormalities (WMA) involving the anterolateral wall of the left ventricle. Optical coherence tomography (OCT) showed uninterrupted intima with no evidence of plaque rupture, erosion, luminal thrombus, or acute occlusion Figure .The differential diagnosis at this time included myocardial infarction with non-obstructive coronary arteries (MINOCA) vs. stress-induced cardiomyopathy vs. severe demand ischemia. Given the clinical presentation of myocardial infarction suggested by elevated cardiac enzymes and supported by WMA on echocardiogram, it was decided to treat the mid-LAD lesion with a drug-eluting stent followed by dual antiplatelet treatment (DAPT) with aspirin and clopidogrel for 12 months.Acute coronary syndrome (ACS) encompasses a spectrum of unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). An 'unstable plaque' with a thin fibrous cap and a lipid-laden core usually is the culprit is such scenarios. An erosion or rupture of that plaque exposes the highly thrombotic material of the plaque to the circulating blood. This leads to platelet aggregation and activation as well as the activation of a clotting cascade, resulting in thrombosis -4. A STEHowever, epicardial vessel occlusion is not the sole cause of myocardial infarction. Several series have reported angiographically normal coronary arteries in patients with STEMI. Yet, the underlying etiology and prognosis in most of these cases remain unclear -8. PreviClinical data from clinical trials have shown that treating stable stenosis with an intervention does not decrease the incidence of future thrombotic events. One of these trials revealed that medical management provides as much protection from future coronary events as doing intervention -12.However, we describe a rare instance of a patient with no history of angina and with no current angina symptoms who had ST-elevation MI on EKG, supported by elevated cardiac enzymes and echocardiography but with no culprit lesion to suggest a total occlusion of the corresponding coronary artery. Since this happened in the setting of severe dehydration, the stable lesions in the diseased LAD can be postulated to be the culprit. However, it is rare to see, even in patients who have stable coronary artery lesions and significant dehydration, a picture of STEMI such as this .Current evidence for stenting the stable lesions in the absence of any anginal symptoms is weak -15. HoweSTEMI in the absence of an angiographically visualized culprit lesion is rare. When guided by further intravascular imaging like OCT, an uninterrupted intima may be seen. The treatment of noncritical lesions seen on angiography and OCT in this scenario is a topic of debate. When supported by evidence for significant myocardial injury , stenting of these lesions can be performed. However, in the absence of any coronary artery lesion and angiographically normal coronary arteries, medical management with risk factor control is reasonable.


The ever-increasing incidence of obesity and related disorders impose serious challenges on public health worldwide. Brown adipose tissue (BAT) has strong capacity for promoting energy expenditure and has shown great potential in treating obesity. Exosomes are nanovesicles that share the characteristics of their donor cells. Whether BAT derived exosomes (BAT-Exos) might exert similar metabolic benefits on obesity is worthy of investigation.Methods: Obese mice were established by high-fat-diet (HFD) feeding and were treated with Seum-Exos or BAT-Exos isolated from young healthy mice. Blood glucose, glucose tolerance and blood lipids were tested in mice with indicated treatments. Histology examinations were performed on adipose tissue, liver and heart by HE staining and/or Oil Red O staining. Echocardiography was performed to evaluate cardiac function of mice. In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging and in vitro effects of exosomes were evaluated by cell metabolism analysis. Protein contents of BAT-Exos were analyzed by mass spectrometry.Results: The results showed that BAT-Exos reduced the body weight, lowered blood glucose and alleviated lipid accumulation in HFD mice independently of food intake. Echocardiography revealed that the abnormal cardiac functions of HFD mice were significantly restored after treatment with BAT-Exos. Cell metabolism analysis showed that treatment with BAT-Exos significantly promoted oxygen consumption in recipient cells. Protein profiling of exosomes demonstrated that BAT-Exos were rich in mitochondria components and involved in catalytic processes.Conclusions: Collectively, our study showed that BAT-Exos significantly mitigated the metabolic syndrome in HFD mice. Detailed elucidation of the reactive molecules and mechanism of action would provide new insights in combating obesity and related disorders. At present, obesity is generally defined as having a body mass index (BMI) higher than 30 kg/mObesity is closely related with adipose tissue. There are two distinct kinds of adipose tissues in mammals, white adipose tissue (WAT) which stores energy and brown adipose tissue (BAT) which burns energy for heat. BAT mainly exists in infants and helps the babies to maintain their body temperatures by dissipating chemical energy as heat. BAT is rich in mitochondria and has high oxygen consumption rate. The fact that BAT can promote energy consumption has rendered it an ideal target for treating obesity and related disorders. Numerous researchers have focused on utilizing metabolically active BAT to treat obesity and the results are encouraging The secretome of BAT accounts for an important part of its metabolic influences In the present study, we explored the metabolic benefits of BAT-Exos in treating obesity and the underlying mechanisms. The results showed that BAT-Exos effectively mitigated the metabolic syndromes of obese mice including high blood glucose, hepatic lipid accumulation and cardiac dysfunction. Then we demonstrated that BAT-Exos exerted metabolic effects at least partially by targeting liver and promoting energy expenditure. Mass spectrometry revealed that BAT-Exos function possibly via conferring components related with metabolism. Our study not only confirms the benefits of BAT-Exos, but also sheds light on engineering exosomes similar as BAT-Exos.Mice were randomly allocated to high-fat diet (HFD) for induction of obesity or normal chow diet (NCD) to serve as lean controls. The differences of metabolism and cardiac function between obese mice and lean mice were then compared. After 16 weeks of feeding, mice in HFD group obtained significantly greater body weights and higher blood glucose levels, compared to mice in NCD group A-S1C. HiTo study the effects of BAT-Exos on obese mice, exosomes were thus isolated from the interscapular brown adipose tissue in young healthy mice and characterized via exosome identification methods, including particle size distribution, transmission electronic microscopy and western blotting . About 3In animal experiments, 6 weeks old male C57/BJ6 mice were divided into four groups: NCD, HFD, HFD plus treatment with Serum-Exos, HFD plus treatment with BAT-Exos. Detailed grouping and experimental design were illustrated in Figure We further tested the expression of inflammatory cytokines in the liver and visceral adipose tissue (VAT). The decreased expression of the two inflammatory genes (TNFα and IL1β) in liver and VAT by BAT-Exo was consistent with the reduced fatty liver and improved metabolism . HoweverMice were then sacrificed and major metabolic organs including heart, liver, BAT, iWAT  and eWAT  were harvested for further analyses Figure A. AccordAs liver and heart are closely associated with obesity-related adverse effects, we next explored the influences of BAT-Exos on the liver and heart of HFD mice. Serum ALT and AST were examined for evaluation of haptic function. The results showed that serum ALT and AST levels increased in HFD mice compared to NCD mice, suggesting impaired liver function in HFD mice Figure A and 3B.As regard to evaluation of cardiac structure and function, echocardiography, serum myocardial enzyme level tests as well as histology analysis by HE staining were performed. As shown in figure We further evaluated whether BAT-Exos regulate the metabolism in a dose-dependent manner by injecting different doses of BAT-Exos. Only some of the metabolic parameters showed improvement in mice received 50 µg BAT-Exos, but more robust changes were seen in mice treated with higher doses of BAT-Exos , furtherin vivo distribution of BAT-Exos after intravenous injection, as the distribution is prerequisite for the function. Exosomes were stained with fluorescent dye DiR and injected into mice via intravenous injection. Then the distribution of exosomes was analyzed by in vivo imaging system. The results showed that after intravenous injection, most of the fluorescence-labeled exosomes accumulated in liver  of cells with indicated treatments were monitored. The results showed robust increases of oxygen consumption in cells treated with BAT-Exos compared to cells treated with PBS or Serum-Exos, suggesting that BAT-Exos would boost energy expenditure in hepatocytes Figure D.To figure out the molecular mechanism for the metabolic benefits of BAT-Exos, we next profiled the protein contents of BAT-Exos by mass spectrometry since proteins are the main bearers of life activities. A threshold of unique peptides>1, fold change ≥2, P<0.05 was used for screening of differential proteins. The results showed distinctive protein expression pattern of BAT-Exos and Serum-Exos Figure A-C. A toEnrichment analysis for differentially expressed proteins demonstrated significant enrichment in mitochondria components and extensive involvement in metabolic pathways of BAT-Exos Figure D and 7E,To further confirm whether BAT-Exo delivery would cause increase of these proteins in the liver, we then examined the expression of Acadvl as an example in liver with control or BAT-Exos treatment. Acadvl is an enzyme also called very long-chain acyl-CoA dehydrogenase (VLCAD) and functions within mitochondria, which had both high abundance and fold change in the BAT-Exos, compared with Serum-Exos Table . As expein vivo studies. Protein profiling by spectrometry revealed that BAT-Exos were rich in mitochondria components and were deeply involved in catabolism, providing material basis for their regulation of metabolism. Together, BAT-Exos might serve as a promising strategy for treating obesity and related disorders.In this study, we proposed and verified the metabolic benefits of BAT-Exos from healthy young mice, which would be promising in treating obesity. The weekly treatment with BAT-Exos significantly reduced the body weights, lowered the blood glucose, and improved glucose tolerance of high-fat-diet fed mice. Abnormal cardiac function observed in HFD mice were also improved after BAT-Exos treatment. Consistently, lipid accumulation in the liver and adipose tissue were significantly reduced in BAT-Exos-treated HFD mice as compared to non-treated HFD mice. Cell metabolism analysis demonstrated that BAT-Exos could markedly boost energy expenditure in hepatocytes, which might account for the metabolic benefits observed in BAT features in its abundant number of mitochondria and high respiration rate and has been widely investigated as potential therapy for treating obesity and related metabolic disorders et al reported that BAT-Exos might regulate FGF21 expression in the liver, suggesting potential effect of BAT-Exos on metabolism et alExosomes are nanovesicles that contain a wide variety of bioactive molecules including dsDNA, mRNA, miRNA, and proteins. Exosomes are secreted by almost all cells and can be taken up by cells adjacent or far away, influencing the physiological and biochemical status of the recipient cells. Previous studies have revealed that exosomes harbor the characteristics of their parental cells or tissues. For example, exosomes from stem cells are often reported to contribute to immunoregulatory effects and regeneration ability of the stem cells et al reported that MSC-derived exosomes alleviated type 2 diabetes by reversing peripheral insulin resistance and relieving β-Cell destruction Numerous efforts have been put on exploring exosomes to treat metabolic disorders. For instance, Sun In regard with the specific working mechanism of exosomes, there is still a lot of work to do. Although we have demonstrated that exosomes predominately accumulate in liver after intravenous injection which is consistent with other researches, there are still a small population of exosomes that will circulate into heart and WAT It is common to identify the key molecules encapsulated in the exosomes responsible for the biological function. However, the purpose to reveal the causal effect between a specific exosomal protein cargo and the functional change in the present study should be challenged. It is technically difficult to knock-in or knock-out a protein from the tissue derived exosomes. Moreover, there might be a theoretical protein functions more importantly than others. As shown in the proteomic data, there are abundant of proteins associated to metabolism, and might be functional when entering the recipient cells. In fact, we prefer the model that all the proteins play minor roles when function independently, however they would play a big role when work as a whole.In reviewing the protein contents of BAT exosomes, we found that BAT-Exos also contain many other beneficial molecules, for example, eNAMPT which is reported to delay aging and extend lifespan. Meanwhile, BAT activity has been found to be inversely associated with aging Similar as most of the pioneering studies, there are some limitations concerning the present study. As to the purity of the exosomes, we used Exo-Quick for isolation of exosomes. Although the method was widely used to surely guarantee enough exosomes, it should be kept in mind that this method of exosome isolation cannot fully separate non-vesicular entities In summary, we have demonstrated in the present study with substantial evidence that BAT-Exos perform excellently in the fight against obesity, and thus could be considered as promising treatment for obesity. The results from cell metabolism analysis suggest that BAT-Exos could boost oxygen consumption. Ongoing studies decoding the detailed reactive molecules would further shed light on engineering of exosomes for the prevention and treatment of obesity and associated disorders.th week, mice fed a high-fat-diet developed obesity (weighing 20% more than mice in NCD group). Two groups of HFD mice then started weekly treatment with 100 µg brown adipose tissue (BAT) exosomes or serum exosomes determined by protein concentration. The dosages of exosomes treatment vary from study to study Healthy male C57BL/6J mice aged 8 weeks were purchased from the laboratory animal center of Fourth Military Medical University. All animal experiments were carried out in accordance with ethical regulations approved by the Animal Care and Use Committee of Fourth Military Medical University. Animals were randomly allocated to normal chow diet or high-fat diet . Body weights of mice were monitored weekly. At the 8For blood glucose test, mice were fasted at 8 a.m. for 6 hours before measurements as suggested by Andrikopoulos For BAT exosome isolation, male C57BL/6 mice aged 6 to 8 weeks were used and brown adipose tissue were obtained from their interscapular region under sterile condition. Brown adipose tissues were cut into extremely small pieces and were cultured in serum-free DMEM for 24 hours. Supernatants of the cultured BAT were collected and centrifugated at 3,000 × g for 15 min for removal of tissue debris. The fluids were then filtered through 0.22 µm filter and the filtrate were precipitated with ExoQuick-TC overnight at 4 °C. Then the mixture was centrifugated at 4 °C, 1500×g for 30 min. Supernatants were discarded and precipitated exosomes were concentrated by another round of centrifugation at 1500×g, 10 min. The remaining fluids were aspirated and the obtained pellets were resuspended in PBS at an appropriate concentration. For isolation of serum exosomes, mice were anaesthetized and then their eyeballs were excised for collection of blood. The blood was placed at room temperature for 20 min and then centrifugated at 4 °C, 2000 × g for 15 min. The supernatants were carefully aspirated and subjected to same protocols for exosome isolation as described above. For characterization of exosomes, particle size analysis was performed using NanoPlus . Morphology of exosomes was observed under transmission electron microscopy , and western blot was performed for protein content analysis of exosomes. Specific procedures were the same as previously described Animal echocardiography was performed by experienced technicians using Vevo 2100 Imaging System  and each parameter was repeatedly measured for six times. Mice were anesthetized by isoflurane  on a heating pad and had their hair removed around their chest and abdomen. The heartbeat of mice was kept between 400-500 beats per minute during the examination. Parasternal long axis view (PLAX), short axis view and four-chamber view were scanned for multiple cardiac functional parameters.in vivo imaging system . Mice were anesthetized by isoflurane and had their thoracic and abdominal hair removed before imaging. After whole-body imaging, mice were sacrificed and their organs were taken out for subsequent fluorescence imaging.Exosomes were labeled with fluorescent dye DiR and injected into HFD mice through tail vein for exosome distribution analysis. Four hours later, the distribution of fluorescent-labeled exosomes was observed under using -5 cells per well 24 hours prior to detection and were treated with BAT-Exos or Serum-Exos 6 hours after the seeding. The dosage of exosome treatment was based on previous reports 2 for one hour. For mitochondrial stress test, cells were sequentially injected with Oligomycin, FCCP, and Rotenone + antimycin A to assess different components of oxygen consumption.Oxygen consumption rate (OCR) of cells was tested using Seahorse XFe24 Metabolism Analyzer . AML12 cells were seeded on XF24 cell culture plates at a density of 1×10Exosomes isolated from BAT or serum were resuspended in PBS and shipped to authorize institution at low temperatures in dry ice for mass spectrometry analysis. Exosomes isolated from 3 mice were assigned as one sample and each group contained 3 samples. The protein profiling by mass spectrometry and subsequent bioinformatics analyses were done by BangFei Bioscience . Briefly, total protein of BAT-Exos was extracted with RIPA lysis buffer and electrophoresis was done to grossly asses protein quality. Then, sample proteins were digested by trypsin and obtained products were separated by high performance liquid chromatography (HPLC) and then analyzed by Orbitrap Fusion Lumos . A threshold of unique peptides>1, fold change ≥2, P<0.05 was used for screening of differential proteins. Differentially expressed proteins were analyzed by gene ontology (GO) enrichment, KEGG pathway enrichment, as well as gene set enrichment analysis (GESA).Data are presented as mean ± SEM. Student t tests was used for two group comparison and ANOVA was used for comparison of differences between groups while multiple comparison were performed with post hoc analysis (GraphPad Prism 7.0). Statistical significance was defined as P < 0.05.Supplementary methods, figures and tables.Click here for additional data file.


Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has been observed in ASD patients and transgenic mice that model different monogenetic causes of ASD. A number of ASD-associated genetic variants are known to disrupt dendritic local protein synthesis, which is essential for spine morphogenesis, synaptic transmission, and plasticity. Most of our understanding on the molecular mechanism underlying ASD depends on studies using rodents. However, recent advance in human pluripotent stem cells and their neural differentiation provides a powerful alternative tool to understand the cellular aspects of human neurological disorders. In this review, we summarize recent progress on studying mRNA targeting and local protein synthesis in stem cell-derived neurons, and discuss how perturbation of these processes may impact synapse development and functions that are relevant to cognitive deficits in ASD. FMR1), TSC (TSC1 and TSC2), and Rett syndrome (MECP2) have been identified [Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social interaction failure, anxiety, intellectual disability, and repetitive behavior. According to the statistics from the Centers for Disease Control and Prevention, 1 in 59 children is diagnosed with ASD which affects all ethnic and socioeconomic groups [entified , 4. One Most excitatory synapses are located on dendritic spines of the postsynaptic neuron. These small  yet dynamic dendritic protrusions exist as various morphologies . These iSpine morphology is a crucial determinant of structural stability and functions of the synapse. Mushroom spines have better synaptic efficacy than thin spines because of the positive correlation between spine size and synaptic strength , 8, in wAlteration of spine number and morphology is believed to underlie many neurological disorders including ASD . AnalysiCYFIP1 and CTTNBP2. Therefore, alteration in actin dynamics and the subsequent dendritic spine defects are one of the major underlying causes for ASD and other ASD-related disorders.Dendritic spines are rich in filamentous actin. Spine morphology and number are intricately controlled by signaling pathways that involve multiple small GTPases , which act on various actin-binding proteins to modulate actin dynamics. The activities of the small GTPases in turn depend on guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which regulate their GTP loading state and hence activation of the downstream targets. Dysfunction of GEFs and GAPs that act upstream of Ras and Rap is associated with ASD. For example, truncated form of SynGAP, which is a major neuronal GAP that controls the activity of Ras, is expressed in individuals with ASD and intellectual impairment , 22. On The discovery that polyribosomes are dendritically localized in the granule cells of the rat dentate gyrus  raises tBdnf and CaMkIIα transcripts, two of the best characterized dendritic mRNAs [Bdnf transcripts [Local dendritic protein synthesis is crucial for controlling spine size and morphology. The increasing spine head volume in CA1 pyramidal neurons of hippocampal slices during to synaptic plasticity such as long-term potentiation (LTP) is attenuated by the application of protein synthesis inhibitors . Messaouic mRNAs –38. Notaic mRNAs , 40. Furic mRNAs , also imnscripts . It therShank and Cyfip have been identified as transcripts in the neuropil in those high-throughput studies. Shank is a scaffold protein present in the excitatory PSD. In human, the proteins are encoded by SHANK genes  and their mutations are strongly associated to ASD [Shank3 mutants (R12C and R300C) in cultured hippocampal neurons causes Shank3 dysfunction and disrupts spine induction and maturation [CYFIP1 have recently been associated with ASD and are believed to alter the balance between synaptic excitation and inhibition [The identities of dendritic mRNAs were elucidated by multiple large-scale transcriptomic studies. Deep sequencing analysis by Cajigas et al. revealed the local transcriptome of the synaptic neuropil in adult hippocampus. More than two thousand mRNA transcripts have been identified, most of which encoded synaptic proteins such as receptors, scaffold proteins, and signaling proteins . Other hd to ASD . Overexpturation . CYFIP1 turation . Intereshibition .FMR1 gene, leading to hypermethylation and silencing of transcription. The loss of FMRP production affects dendritic mRNA transport and translational regulation as well as dendritic spine maturation [Dysregulated protein synthesis is a plausible mechanism underlying the synaptic deficits in ASD , 54, andturation . For exaturation . Many FMturation , 60, undTSC1 or TSC2 genes which fail to control the activity of mammalian target of rapamycin (mTOR). Alteration in mTOR pathway leads to exaggerated protein translation in dendrites and resulting in intellectual disability [Disrupted control of mRNA translation also causes spine defects and autistic behaviors , 61, 62.sability , 64. Intsability . TherefoEmerging studies reveal that besides translation, other aspects of post-transcriptional regulation of RNA processing such as RNA splicing and editing are also dysregulated in ASD –68. GiveMost of our knowledge on the physiology of neurodevelopmental disorders such as ASD depends on rodent animal models. While rodent animal models can be conveniently used to screen molecular targets for various neurological disorders, it has limitations in mimicking the complex genetic background in human. Examination of postmortem human brain samples offers some insights on the abnormal neuronal properties such as dendritic spine number and morphology in neurons of ASD patients, but postmortem samples do not allow mechanistic studies which involve manipulation of living neurons. The development of induced pluripotent stem cell (iPSC) technology was introduced in 2006 which allows the conversion of adult somatic cells into pluripotent stem cells . Recent Using the compartmentalized microfluidic chambers to evaluate the axonal transcriptome of hESC-derived glutamatergic neurons, large number of mRNAs (3696 transcripts) are found to be expressed in the distal axonal projections of hESC-neurons, and this axonal transcriptome is largely similar to the primary rat cortical neurons counterparts . HoweverSHANK3 gene show abnormal morphology, including smaller soma and more neurites, prior to synaptogenesis. This is followed by decrease in pre- and postsynaptic puncta number in the more mature neurons, indicating the crucial role of SHANK3 in neuronal development and synapse formation [SHANK3 de novo heterozygous truncating mutations also display significant reduction in SHANK3 mRNA levels and a decrease in dendritic spine density and spine head volumes [SHANK3 mRNA puncta were visible in both cell soma and neuronal processes of human iPSC-derived cortical neurons, while SHANK3 protein expression is only dendritically localized [Shank dendritic transcripts from rodent neurons [Shank1 transcripts contains a dendritic targeting element that mediates dendritic localization. Interestingly, cortical neurons differentiated from iPSC of ASD patients with SHANK3 heterozygous deletion showed ~ 50% reduction in SHANK3 mRNA only within neuronal processes but not in the cell soma [SHANK3 are likely to undergo local translation in neuronal dendrites, and deficiency of the local translation alone is sufficient to lead to synaptic changes in ASD.Does dendritic local translation affect synapse functions in human iPSC-derived neuron? Olfactory placodal neurons differentiated from patient-derived iPSCs carrying microdeletions of the ormation . iPSC-de volumes . Using socalized . This is neurons , in whicell soma . TherefoMECP2 allele [MECP2 knockout ESC-derived neurons, indicating that correction of aberrant protein synthesis is a promising therapeutic strategy for ASD. While Rett syndrome neurons may represent one end of the ASD spectrum showing reduced protein synthesis, it is anticipated that human PSC-derived neurons that model ASD from FXS, TSC, or eIF4E mutations will display elevated protein synthesis. Elegant approaches involving super-resolution live imaging have been developed to monitor the synthesis of nascent polypeptides in rodent primary neurons [One important question that has not been well-addressed is whether aberrant protein synthesis is observed in human stem cell-derived neurons modeling ASD. While study that specifically examines dendritic local protein synthesis is not yet available, global protein synthesis as measured by metabolic labeling with radioactive-labeled Cys/Met is downregulated in human ESC-derived neurons that model Rett syndrome through knockout of the 2 allele . This is neurons . ExaminiTSC2-deleted human iPSC-derived neurons, hyperactive mTOR signaling leads to reduced excitability and excitatory postsynaptic currents (EPSCs), and the defects are corrected by the mTOR inhibitor rapamycin [TSC2 mutation also show reduced expression of transcripts encoding dendritic RNA-binding proteins including FMRP, suggesting that the absence of TSC2 can disrupt dendritic mRNA transport and protein synthesis which may subsequently contribute to the synaptic deficits. Recent study also reports differential effects of single or biallelic mutation on the TSC2 gene on patient-derived iPSC neurons, with increased synchrony of neuronal activity only observed in TSC−/− neurons [Although direct examination on the effect of ASD mutations on dendritic mRNA localization or protein synthesis in human stem cell-derived neurons is lacking, synaptic deficits have been observed in human stem cell-derived neurons harboring ASD-related gene mutations that are expected to perturb mRNA targeting and/or translation. TSC is a disorder that is associated with syndromic form of ASD. In apamycin . Similarapamycin . Interes neurons .FMR1 gene promotor without change in FMRP protein expression can negatively affect neurite growth and synapse development [FMR1 mRNA on neuronal function. Furthermore, FMRP plays multi-faceted roles in neuron. Besides mRNA transport and translational regulation, FMRP is also crucial for epigenetic control, chromatin stability, and DNA damage response [FMRP is crucial for dendritic protein synthesis by transporting the mRNA cargoes and regulating their translation . Multiplelopment , indicatresponse . TherefoCYFIP1 gene expression [CYFIP1 gene but also the neighboring genes NIPA1, NIPA2, and TUBGCP5, which encode proteins for Mg2+ transport and tubulin-interacting protein, respectively. Future work on human iPSCs with CYFIP1 deletion generated by genome editing should validate the specific role of this protein in the control of actin dynamics and spine maturation.Although overproduction of immature spines has been one of the major phenotypes in neurons lacking FMRP in both knockout mice and FXS patients , thus fapression , and thepression . It shouIn this review, we have summarized the recent attempts to examine mRNA targeting, protein synthesis, synaptic transmission, and dendritic spine morphogenesis using human pluripotent stem cell-derived neurons that should have important implications in future study of ASD. There are potential advantages and pitfalls in the study of local protein synthesis and dendritic spine morphology defects in human pluripotent stem cell-derived neurons. On one hand, the culture of patient-derived iPSCs can be scaled up to provide enough quantity of RNAs and proteins that are essential for high-throughput transcriptomic and proteomic studies. Ribosome profiling and RNAseq of neurites versus cell soma  in humanASD is strongly associated with aberrant protein synthesis which can lead to impairment of dendritic spine development. Application of human iPSCs has greatly enhanced the generation of human cellular models to unravel the causes and mechanisms that underlie inherited neurological disorders like ASD. Synaptic deficits are observed in ASD patient-derived iPSC neurons that carry mutations to disrupt mRNA translation, supporting the causal link between uncontrolled protein synthesis and ASD. Nonetheless, there are limited studies on dendritic mRNA targeting and protein synthesis in human pluripotent stem cell-derived neurons. In addition, technical difficulties of obtaining those neurons that possess mature dendritic spines remain. It is anticipated that the rapid advance of imaging, transcriptomic analysis, and development of brain organoids will soon facilitate the exploration on dendritic protein synthesis in human neurons, which allow us to understand how its regulation is altered in different ASD patients.


Acute-on-chronic liver failure (ACLF) is a severe life-threatening condition with high risk of multiorgan failure, sepsis, and mortality. ACLF activates a multifaceted interplay of both innate and adaptive immune response in the host which governs the overall outcome. Innate immune cells recognize the conserved elements of microbial and viral origin, both to extort instant defense by transforming into diverse modules of effector responses and to generate long-lasting immunity but can also trigger a massive intrahepatic immune inflammatory response. Acute insult results in the activation of innate immune cells which provokes cytokine and chemokine cascade and subsequently initiates aggressive systemic inflammatory response syndrome, hepatic damage, and high mortality in ACLF. Dysregulated innate immune response not only plays a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh, a model for end-stage liver disease, and sequential organ failure assessment score. A better understanding of the pathophysiological basis of the disease and precise immune mechanisms associated with liver injury offers a novel approach for the development of new and efficient therapies to treat this severely ill entity. Immunotherapies could be helpful in targeting immune-mediated organ damage which may constrain progression toward liver failure and eventually reduce the requirement for liver transplantation. Here, in this review we discuss the defects of different innate immune cells in ACLF which updates the current knowledge of innate immune response and provide potential targets for new therapeutic interventions. Acute-on-chronic liver failure (ACLF) is defined as acute decompensation of a patient with cirrhosis, associated with an intra- or extra-hepatic precipitating event resulting in one or more extrahepatic organ failures and high short term mortality . The AsiThe presence of existing chronic liver disease distinguishes ACLF from acute liver failure (ALF) where no chronic liver disease prevails . Unlike Though, the precipitating event in ACLF are mostly similar to ALF including drug-induced liver injury , viral , or autoOrgan-specific and systemic inflammation are the essential events in the development and course of CLD , where iDuring CLD, immune dysfunction mainly involves the components of the innate immune system which are distributed throughout the circulation as well as the tissue compartment and are critical to maintain homeostasis by preventing microbial invasion. Monocytes, macrophages, and neutrophils infiltration is a major contributing factor for CLD. These cells detect tissue damage and invading microorganisms and facilitate tissue healing and eradication of the infection. However, they also mediate intrahepatic and systemic inflammation by elevating inflammatory immune mediators through responding to damage-associated molecular patterns released from the injured cells , which fUncontrolled activation of both the innate as well as the adaptive immune system is a prerequisite for the development of systemic inflammation in ACLF . CytokinIn ACLF, functional impairment of almost all types of immune cells occurs. Few studies have endeavored to diagnose early events correctly to identify the role of the innate immune response in ACLF patients . The innImmune defects in ACLF are multifactorial and involve abnormalities in cellular and soluble components of the immune system. Cellular components involve functionally reprogrammed innate and adaptive immune cells; while soluble components include cytokines, chemokines, and complement molecules. Here, we are discussing defects in the innate immune cells. Neutrophils, also known as polymorphonuclear granulocytes, are the major players of the innate immune system. They are typically the first cells to be recruited to the site of infection where they provide defense against invading pathogens by eliminating them through multiple intracellular and extracellular mechanisms . Apart fChemokine receptors CXCR1 and CXCR2 have been shown to mediate neutrophil response to CXC chemokines primarily CXCL8, produced by several hepatic cells including hepatocytes, endothelial cells, stellate cells, and immune cells comprising macrophages,  Kupffer Liver cell necrosis promotes the secretion of cytokines which later initiates the innate immune response and leads to an abundant release of granulocytes from bone marrow to peripheral blood consequently decreasing the lymphocyte number. The neutrophil to lymphocyte ratio (NLR) is an easily measured marker to evaluate systemic inflammation . RecentlImpaired neutrophil function enables nosocomial infections . PatientMonocytes are well-known to originate in the bone marrow from common hematological myeloid precursors and then get released into peripheral blood where they circulate for several days before entering tissues. Monocytes have the capacity to differentiate into macrophages and myeloid lineage dendritic cells. Monocytes and neutrophils appear early at the site of infection to encourage innate immune responses. They present antigens through human leukocyte antigen (HLA) class II molecules and produce large quantities of pro-inflammatory cytokines. Low HLA-DR expression was observed in early stage ACLF patients which was even lower in the late stage. Importantly both early and late stage ACLF non-survivors had lower HLA-DR expression as compare to those who survived. Decreased HLA-DR expression has been shown to be associated with high mortality rates in ACLF . In fact+CD16− monocytes disclosed an upregulation of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. Moreover, the glutamine synthetase/glutaminase ratio of ACLF (EASL-CLIF ACLF) in patient-derived monocytes showed a positive association with disease severity scores including MELD. Remarkably, metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the inflammatory and phagocytic capacity of in vitro-generated as well as ACLF patients-derived monocytes and highlights its biological relevance (Monocyte dysfunction is linked with high MER receptor tyrosine kinase (MERTK) expression in the circulation, liver, and lymph nodes of ACLF patients (CANONIC ACLF) . Notablyelevance .A decreased ratio of CD3+ cells and monocytes (T/M) has been reported in the early to intermediate stage of ACLF which reached its lowest at the last stage; however an increased T/M ratio was seen in patients with good prognosis compared to patients with poor outcomes. An increase in programmed death 1 (PD-1) receptor expression in both CD4+ and CD8+ cells resulted in the loss of T cells in these patients. Both CD4 and CD8 T cells along with regulatory T cells tempered the monocyte innate immune function by inhibiting monocyte TNF-α secretion resulting in dysfunctional monocytes .Macrophages are essential components of the innate immune system and are present in most tissue types. Earlier macrophages were mainly known to be involved in host defense and elimination of apoptotic cells/bodies, however emerging evidence characterized macrophages as multifunctional cell types that are also implicated in tissue development, homeostasis, repair , and reghighCD163highCX3CR1highCCR7high which contains remarkably similar phenotypic and functional similarities to their circulatory counterpart. Liver explants tissue also confirmed the major expansion of MERTKhigh and CD163high hepatic macrophages in ACLF which negatively regulated the immune response.Recently, it has been demonstrated that TNF-α promotes the apoptosis of resident liver macrophages, also known as Kupffer cells, by increasing the expression level of large non-coding RNA hypoxia-inducible factor 1 alpha-antisense RNA (HIF1A-AS1). Silencing the expression of HIF1A-AS1 reduced TNF-α induced KCs apoptosis  and provThe pathological process in ACLF results in specific changes in the circulating protein level which could predict the outcome. Six proteins including macrophage inflammatory protein 3α (MIP-3α), hepatocyte growth factor, growth differentiation factor 15, carcinoembryonic antigen-related cell adhesion molecule 1, E-selectin, and osteopontin were found highly augmented in HBV-ACLF patients . MacrophCurrently, high HBV DNA has been shown to activate macrophages  that escDCs are professional and versatile antigen-presenting cells that operate at the interface of the innate and adaptive immune system. To perform their functions, whether endorsing immunity to pathogens or in maintaining tissue tolerance, DCs require migration to the target site. Based on phenotypic and functional characterizations, two distinct circulating DCs subsets, myeloid, and plasmacytoid (mDCs and pDCs) have been identified in humans. DCs have been studied in HBV , HCV infLow frequencies of both mDCs as well as pDCs have been observed in ACLF patients (APASL ACLF) which was even lower in non-survivors. Lower DC numbers had a strong association with the CTP and SOFA scores and could be causative factors for high mortality. One-month therapy with a granulocyte colony-stimulating factor (G-CSF) enhanced the frequency of both type of DCs . Another+CD15−CD11b+HLA-DR− M-MDSCs in ACLF patients occurred because of continuous immune stimulation from microbial and non-microbial inflammatory signals. These MDSCs exhibit immunosuppressive properties by declining T cell proliferation and less TNF-α and IL-6 production in response to TLR stimulation  presented on the surface of infected cells, initiating cytokine release and thus causing cell lysis or apoptosis. However, NK cells have the unique ability to identify stressed cells even in the absence of MHC which allows for a much faster immune reaction. This exceptional function of NK cells is quite important for those detrimental cells which miss the detection of MHC I markers and are destroyed by other immune cells.dim CD16bright NK cells have been observed in the circulation of HBV-ACLF patients  expression due to the abundance of circulating IL-6 and IL-8 in these patients  . Systemiin vitro and may prevent hepatoprotection likely in a context-specific manner, but may also prevent the adverse effects of IL-22. It has been shown that IL-22BP inhibits hepatic IL-22 signaling and the acute phase protein  have been studied in ACLF patients (EASL-CLIF ACLF) . A stron protein . Other d protein . IL-22Fc protein , pro-reg protein , and ant protein , while A protein . CytokinThe present knowledge and understanding of the innate immune response of ACLF patients is limited. There are a number of specific issues left somewhat ambiguous, like whether a dysregulated innate immune response is the cause or outcome of ACLF. Few studies outlined abnormal innate immunity of ACLF patients which is associated with systemic inflammation, disease progression, and pathogenesis; however extensive research is required to find out the mechanisms responsible for disease severity and high mortality in these severely ill patients. In this review we elaborated several defects in innate immune cells and abnormal cytokine responses that compromise host immunity, make them susceptible to secondary infections, and cause systemic inflammation and further complications increasing the risk of high mortality. Techniques for identifying an accurate immune phase of ACLF patients whether it is the inflammatory phase or the immunosuppressive phase and distinguishing precise defects in innate immune cells will promote the development and application of dynamic new immunotherapies, which will help in the management of these diseases.AK conceptualized, wrote the manuscript, and designed the illustrations. SK edited the manuscripts. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Stroke is a severe brain disease leading to disability and death. Ischemic stroke dominates in stroke cases, and there are no effective therapies in clinic, partly due to the challenges in delivering therapeutics to ischemic sites in the brain. This review is focused on the current knowledge of pathogenesis in ischemic stroke, and its potential therapies and diagnosis. Furthermore, we present recent advances in developments of nanoparticle-based therapeutics for improved treatment of ischemic stroke using polymeric NPs, liposomes and cell-derived nanovesicles. We also address several critical questions in ischemic stroke, such as understanding how nanoparticles cross the blood brain barrier and developing in vivo imaging technologies to address this critical question. Finally, we discuss new opportunities in developing novel therapeutics by targeting activated brain endothelium and inflammatory neutrophils to improve the current therapies for ischemic stroke. Stroke is an unexpected and acute brain disease. It is reported that one of nineteen deaths is related to stroke in the United States, and the mortality rate of stroke is as high as 30% . Stroke Cerebral ischemia initiates a cascade of pathological processes, eventually causing neuron death. Reperfusion is a clinical method to restore the blood flow in the brain by administration of tissue plasminogen activator (t-PA) or mechanical thrombectomy (MT) for treatment of ischemic stroke . HoweverRecently, nanotechnology emerges as innovative tools in drug delivery and diagnosis to treat a wide range of diseases, such as cancer and inflammatory disorders ,11,12,13Acute ischemic stroke and subsequent reperfusion cause a series of pathophysiological changes including neuronal damage, oxidative stress, local inflammation, and loss of blood brain barrier (BBB) integrity . The celNeurons are the major components in brain and are particularly vulnerable to ischemia. Studies have shown that acute cerebral ischemia causes the vasculature infarction, thus leading to neuronal death in rodent models . Due to Oxidative stress is involved with the production of reactive oxygen species (ROS), which activates apoptosis, necrosis, and autophagy pathways during ischemic stroke . OxidatiInflammation response is an important event in ischemic stroke and the subsequent reperfusion. Ischemia and reperfusion activate immune system to respond to tissue injury including activation of endothelium and leukocytes. Specifically, the immune response is involved with the intravascular and parenchymal damage triggered by the interruption of blood supply. In other words, the immune system plays a central role in regulating the outcomes of stroke patients . For theInnate immune cells are major components during inflammation response because they sense endogenous danger signals through several receptors such as toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-1-like receptors, nucleotide oligomerization domain (NOD)-like receptors, C-type lectin receptors, and absent in melanoma (AIM2)-like receptors . These rBlood brain barrier (BBB) plays an important role in ischemia/reperfusion (I/R). During ischemic stroke, there are two phases of BBB breaking. In the early phase of reperfusion (6 h), endothelial transcytosis dominates in increased permeability of BBB, and it may be associated with endothelial vesicle transport . In the The immune response also causes the loss of BBB integrity, leading to cell death in stroke . MicroglBlood brain barrier maintains the brain homeostasis, but ischemic stroke disrupts this barrier, resulting in increased vascular permeability. As we discussed, the permeability is regulated by transcellular pathways in the early stage and the breaking TJs in the later stage . TherapeTreating ischemic stroke is to restore blood flow to the brain as soon as possible, and reperfusion is a major tool to bring the blood back to the brain. The clinical methods include intravenous administration of tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) . Tissue Except for the reperfusion, supportive care is also very important. For example, 25% of patients may show neurological deficiency in 24–48 h, and care is needed to prevent further brain damage . AlthougThere are several drugs that have been tested to target inflammatory pathways in ischemic stroke. NXY-059 is a scavenger of free radicals and shows the neuroprotective effect in a pre-clinical stroke model . HoweverThere are several challenges in treating ischemic stroke. Most therapeutics have short blood circulation and cannot easily cross the blood brain barrier to reach the ischemic tissues. In addition, controlling drug release and developing novel drug delivery vehicles are important factors to improve therapies of ischemic stroke. Nanotechnology is used to design nanoscale materials that can be applied in biomedical applications. Nanoparticles with the sizes of 50–200 nm are generated and can encapsulate drugs to increase drug water solubility and tissue targeting. Nanoparticles are smaller than a cell and larger than small molecules; thus, nanoparticles are excellent carriers to deliver therapeutics (drugs) and control their release for improved therapies in a wide range of diseases ,43,44. NEarly recanalization (thrombolysis) and neuroprotection are the two major steps for stroke patients . NeuroprLiposomes are the first generation of nanocarriers for drug delivery used in academia and pharmaceutical industries . LiposomIshii and co-workers developed asialo-erythropoietin (AEPO)-modified PEGylated liposomes (AEPO-liposomes) to treat cerebral I/R injury . Asialo-ZL006 is another neuroprotectant that can selectively block the ischemia-induced binding between nNOS  and PSD-95 (a scaffolding protein) to prevent ischemic damage . HoweverBasic fibroblast growth factor (bFGF) has demonstrated the neuroprotective effect in acute stroke; however, bFGF encounters the same issue that it cannot cross the BBB. To overcome this problem, liposomes were developed to deliver bFGF (bFGF-NL) to the brain in a rat model of cerebral I/R. After treatment with bFGF-NL, in three consecutive days, mice showed improved neurological function, reduced infarct volume, and decreased nuclear fragmentation of neurons. The therapeutic effect is associated with PI3K/Akt activation by bFGF-NL . To address the problem of narrow therapeutic time window of tPA (4.5 h), Fukuta et al. combined tPA and liposomal fasudil (fasudil-Lip) and examined whether they can increase the benefit of tPA to treat cerebral I/R. The results showed that the combined therapy increased neuroprotective effects compared to the administration of tPA or fasudil alone. In addition, the study indicated that administration of fasudil-Lip decreased the cerebral hemorrhage and extended the therapeutic time window of tPA compared to treatment with tPA .To determine when drugs should be administered after reperfusion surgery, Al-Ahmady et al. selected a liposomal formulation made from HSPC:CHOL:DSPE-PEG2000 because PEGylated-liposomes have a long blood circulation. In the study, liposomes were intravenously administered at 0.5 or 48 h after reperfusion. Transmission electronic microscopy, histological, and immunostaining were performed, and the results indicated a higher accumulation of liposomes in cerebral ischemic mice than that in healthy mice. The possible mechanism was that the increased accumulation of liposomes in brain in the early phase (0.5 h) was due to transcellular transport. However, at 48 h after stroke, the liposome deposition was associated with both transcellular and paracellular pathways . This isBiodegradable polymeric NPs have also been developed as carriers for drug delivery to treat neurological diseases because they are not toxic and biocompatible, and they have the sustained-release feature . Liu andNanoparticles were also bioengineered with ROS-responsive features that can control drug release in ischemic brain. In a study , Lv et a3-n-Butylphthalide (dl-NBP)  has demoGuo et al. designed AMD3100 (a targeting ligand)-conjugated and size-shrinkable nanoparticles (ASNPs) with the features of protease-responsiveness and brain-targeting. The nanoparticles specifically targeted the CXCR4 (C-X-C chemokine receptor type 4)-enriched ischemic brain tissue and penetrated the ischemic brain. Glyburide, a promising anti-stroke drug, was delivered by the nanoparticles, and this system enhanced the therapeutic outcomes in the ischemic stroke model . Peptide inhibitors for caspases possess neuroprotection effects, but they also cannot cross the BBB. Based on this problem, Karatas et al. developed chitosan nanospheres loaded with N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a caspase-3 inhibitor. Anti-mouse transferrin receptor monoclonal antibody (TfRMAb) was conjugated to polyethylene glycol-coated nanospheres because the antibody can selectively bind to TfR type 1 expressed on cerebral vasculature. Nanospheres suppressed the caspase-3 activity and improved neurological repair after ischemic stroke .3O4 nanoparticles , and this complex formulation may scavenge free radicals and change hypoxia environments in the ischemic brain. They found that MNET had a long circulation time and were capable of crossing BBB. In subsequent studies, MNET scavenged free radical and oxygen supply to rescue neurons during ischemic phase, and possibly MNET helped to remove oxygen generated by reperfusion [Cell-derived biomimetic carriers have provided new options for drug delivery due to their advanced targeting abilities and better biosafety than artificial carriers. Shi et al. reported a T7 peptide (a brain targeting peptide)-linked erythrocyte membrane nanovesicles loaded with Mnerfusion .2O3 magnetic nanoparticles (PAMNs) to achieve dual therapeutic and diagnostic purposes. The PAMNs were able to adhere to the damaged cerebral vessel induced by thrombosis and deliver L-arginine when the external magnetic field was applied. Furthermore, the release of L-arginine at ischemic lesions promoted vasodilation and the thrombosis was disrupted to restore the blood flow. This study showed that PAMNs may be a useful tool for both MRI imaging and targeted therapy for ischemic stroke [Platelet membrane-derived nanovesicles were loaded with L-arginine, a nitric oxide (NO) donor, and γ-Fec stroke . Studies have showed that metallic NPs can function as scavengers of ROS. ROS includes superoxide anion, hydrogen peroxide, and hydroxyl radical, and they are generated during ischemic stroke. ROS is involved with oxidative tissue damage that is the mechanism responsible for brain injury in ischemic stroke.4+ (oxidized) species from Ce3+ (reduced) species [2) modified with Angiopep-2 (ANG) and poly(ethylene glycol), which were able to cross BBB via receptor-mediated transcytosis  compared to P-CeO2 [2 was also confirmed on healthy rats by determining the ratio of ceria nanoparticles in brain tissue and injected  are novel ROS scavengers because the large surface area and the high electron density can potentiate their catalytic activity to quench ROS . Takamiyvβ3, highly expressed on cerebral vascular endothelial cells of ischemic tissues, cRGD-Exo was significantly accumulated in the stroke lesion. Administration of curcumin with exosomes  suppressed the inflammatory response via the NF-κB pathway and protected the brain from ischemic injury.Inflammation plays a central role in ischemic stroke, thus delivering anti-inflammatory drugs may be a novel strategy to treat ischemic stroke. Exosomes are endogenous vesicles made from cell membrane with cellular targeting features, therefore, they may be drug delivery tools ,77,78. IDexamethasone is an anti-inflammatory drug and can reduce proinflammatory cytokines, which prevent cellular damage in the ischemic brain . Lee andIncreased leukocyte infiltration is another factor to damage the brain in stroke. Within minutes after ischemia, adhesion molecules, such as P-selectin, are highly expressed on endothelial cells, and proinflammatory signals are rapidly generated . AnotherNeutrophil infiltration is regulated by interactions between neutrophils and endothelial cells. Therefore, delivering drugs to the cerebral endothelium may effectively inhibit neutrophil infiltration without interfering neutrophils . Dong etSmall interfering RNAs (siRNAs) can suppress the expression of a specific gene and are also used in ischemic stroke treatment . CaspaseIn another study, a gene delivery vector, PAMAM-Arg, consisting of a polyamidoamine (PAMAM) dendrimer amide grafted with basic L-arginine residues (e-PAM-R), was used to deliver the high mobility group box-1 (HGMB1) siRNA . HMGB1 sMagnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and ultrasound are employed for the diagnosis of stroke. Brain CT and MRI imaging are important to detect the early stage of stroke in patients . CT angiShen’s research groups developed a method to track administered stem cells and investigated cell-based therapies in ischemic stroke. Cationic polymersomes formed polymeric vesicles and they were loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and quantum dots (QDs) as imaging agents. Cationic polymersome vesicles were incubated with neural stem cells (NSCs) to label the NSCs, thus NSCs could be tracked after they were injected to the striatum contralateral of the ischemic hemisphere. The migration and location of NSCs were monitored using MRI imaging in six weeks in a rat MCAO model and the optical imaging tracked the cells for four weeks . AnotherAndreas et al. conducted a clinical phase II pilot trial using ultra small superparamagnetic iron oxide (USPIO)-enhanced MRI for macrophage imaging since USPIO particles have been introduced as a cell-specific MRI contrast agents taken up by macrophages. USPIO contrast agent was infused in ten patients 5 to 6 days after stroke onset, and MRI was performed within 24–36 h or 48–72 h after the infusion. Results showed that USPIO was much better than gadolinium . The study indicates that USPIO-enhanced MRI may provide an in vivo tool to track cells in stroke and other CNS pathologies .Theranostics nano-platform is a new way to combine diagnostics and therapeutics in ischemic stroke. In a study, HSP72 antibodies against HSP72, a specific molecular biomarker of the peri-infarct region, were conjugated to liposomes. Rhodamine/gadolinium labelled- and citicoline (CDP-Choline)-loaded liposomes specifically targeted the peri-infarct tissue in cerebral ischemia. MRI results demonstrated that the nanoparticles were accumulated in the injured brain and significantly reduced lesion volumes .4:Yb/Er@NaGdF4) and coated with PEG (PEG-UCNPs). PEG-UCNPs showed the high diagnostic sensitivity to image acute ischemic stroke at a low dosage (5 mg Gd kg−1) compared to the clinical dosage of 108 mg Gd kg−1 [Clinically used gadolinium (Gd) chelates as contrast agents have several issues, such as short circulation time, rapid clearance, and low T1 signal. These issues limit the imaging time and resolution . Upconve Gd kg−1 . This neStroke is an acute disease, therefore treating stroke requires the early diagnosis and immediate therapies. This review has highlighted the recent advances in design and engineering of new nanomaterials to target ischemic stroke tissues and new technologies used to image and monitor the disease progression in vivo.Specifically delivering therapeutics to the injured brain is essential in treating ischemic stroke. While many nanoparticle-based formulations or cell-based platforms have been developed, the fundamental question of how they target ischemic stroke lesion has not been clearly addressed. For example, BBB is the blood vessel barrier to prevent therapeutics across the blood vessels. Most studies showed the dramatic therapeutic effects of using nanoparticle-based formulations compared to free drugs. The enhanced outcomes claimed that nanoparticles transported therapeutics across BBB, but the direct in vivo experimental data were vague to support this conclusion. Developing advanced in vivo imaging systems ,97 is neBrain vasculature during stroke shows the temporal opening, and this disruption of BBB may be a target to guide small molecules across the BBB. Further investigation is needed on the time course of BBB opening to design ideal drug delivery platforms. Although ischemic stroke increases brain vascular permeability, the endothelial gaps are unlikely to allow the efficient transport of nanoparticles because their size is usually larger than endothelial gaps. Therefore, developing new and novel concepts is needed to solve the drug delivery across BBB. Ischemic stroke and reperfusion cause acute inflammatory responses including neutrophil infiltration across blood vessels. Recent studies have shown that rational design of nanoparticles  enables neutrophils to transport nanoparticles across the blood vessel barrier in infection and cancer mouse models ,100,101.Ischemic stroke is strongly correlated to inflammatory responses. Inflammatory responses include endothelial activation and neutrophil infiltration, which damages the brain tissues. Targeting activated endothelium using cell membrane-derived nanovesicles has demonstrated the value in delivering therapeutics to treat ischemic stroke . To tranTargeting inflammatory neutrophils in situ to block brain neutrophil infiltration is a new opportunity to treat ischemic stroke. A recent study  shows thIn addition, developing new drugs that can target inflammatory pathways for management of the host injury during ischemic stroke is needed. The pathogenesis of ischemic stroke is complicated, and it is involved with multiple signaling pathways. The molecular mechanisms of ischemic stroke-induced brain injury are needed to be further determined. The timing of administering drugs or nanoparticle-based therapeutics is also very critical. Optimizing therapeutic windows in the future is needed.2O3 magnetic nanoparticles can achieve the therapy and imaging. In the future, developing more similar drug delivery systems is needed to treat ischemic stroke. However, considering that many inorganic materials do not naturally exist in the body  have been approved by the US food and drug administration (FDA) to treat anemia), fully evaluating the biodistribution and toxicity after systemic administration is required.Theranostics formulations are interesting and promising in treating ischemic stroke since they combine diagnosis and therapies. Nanoparticle-based platforms are novel constructs because they can contain imaging agents and drugs in single nanoparticle platforms. For instance, formulations with both neuroprotectants and FeIn summary, we have discussed various nanoparticle-based formulations and cell-based platforms used in treating ischemic stroke. It is essential to understand the pathogenesis of ischemic stroke and how nanoparticles interact with ischemic tissues. The fundamental question on how nanoparticles transport therapeutics across BBB is yet to be addressed, and advances in design and synthesis of nanoparticles and novel in vivo imaging systems  may address this question. The development of new drugs and novel nanoparticle-based therapeutics will improve the outcomes in treating ischemic stroke patients.


Cancer-related stroke has been regarded as an emerging subtype of ischemic event. Acute treatment for this subtype may include the antiplatelet agents, anticoagulants, or endovascular intervention.A 63-year-old woman with sudden-onset right hemiparesis and conscious change was sent to our emergency department. The patient had underlying sigmoid adenocarcinoma and received chemotherapy FOLFIRI  with targeted therapy cetuximab following lower anterior resection since the diagnosis was made.Brain magnetic resonance angiography revealed a filling defect in left carotid bulb, and neurosonography showed a thick atherosclerotic plaque (size 4.9 mm) in the left internal carotid artery on day 5 after the onset of stroke.During the first three hours after onset, administration of IV tissue plasminogen activator did not resolve the thrombus. Dabigatran (110 mg bid) started on day 7.The atherosclerotic plaque dissolved on day 24. The patient recovered her muscle strength but still had nonfluent speech in mild extent.Thrombolytic and anticoagulant medications in this patient suggested the thrombus formation with fibrin-rich content which may be attributable to both cancer and chemotherapy. Dabigatran, an oral anticoagulant, had a benefit for this subtype of ischemic stroke among patients with cancer. It is already known that early reperfusion therapy for acute ischemic stroke after administration by tissue plasminogen activator (tPA) has a better prognosis and is the mainstay of treatment for those without contraindications.Stroke may be a critical complication among patients with cancer, regardless of venous occlusion or arterial ischemia. It has been regarded as the most common cause of complex disability and the 3rd most common cause of death in Taiwan, Here, we report the case of a 63-year-old female patient with cancer with acute cerebral arterial embolism, in which the thrombus in the carotid bulb did not dissolve after tPA but did so later after dabigatran. There have been several case reports describing thrombus resolution after dabigatran, which acts as an anticoagulant by directly inhibiting thrombin.–6 We will discuss some interesting issues regarding the pathogenesis and pharmacologic effects.Cancer-related stroke has been regarded as an emerging subtype of ischemic event.2A 63-year-old woman presented to our emergency department with sudden-onset right hemiparesis and consciousness change. The patient got a diagnosis of sigmoid adenocarcinoma  4 months before this stroke, and she had been on chemotherapy FOLFIRI  with targeting agent cetuximab as systemic therapy after lower anterior resection. Her last FOLFIRI chemotherapy (5th cycle) with cetuximab had been administered 4 days prior.Sudden conscious change and fall took place 1 hour before arrival at our emergency room. Upon arrival, she was alert, normal vital signs, and the neurologic examination revealed right-sided limb weakness with speech problems. She exhibited nonfluent speech output, incorrect naming, word substitution, but intact repetition, fair comprehension, and obedience on secondary commands. The initial National Institute of Health Stroke Scale scored 6 out of 42. Brain computed tomography excluded intracranial hemorrhage, and then IV bolus of tPA  was administered soon. Mechanical thrombectomy was deferred because of her weak physical condition after the recent chemotherapy course. Echocardiography did not reveal any intracardiac thrombus. Brain magnetic resonance imaging showed acute infarction in left middle cerebral artery territory, mainly involving left insula and parietal lobe, and magnetic resonance angiography revealed a vague plaque image in left internal carotid artery (ICA) of the neck and occlusion of the Sylvian and cortical M3 segment of left middle cerebral artery . Nagamoto et al reported an example that dabigatran (110 mg twice daily) resolved a left ventricular thrombus. Akiyama et al described the thrombolytic action of dabigatran (110 mg twice daily) on an ICA thrombus. Kaku and Nagamoto et al reported cases with the resolution of intracardiac thrombi, whereas Akiyama et al reported a carotid thrombus. The intracardiac thrombus dissolved completely in 21 and 27 days in Kaku's and Nagamoto's cases, respectively   in patients with cancer at different sites and among those with advanced stages. Cancer can activate platelets, increase expression of procoagulants, and suppress fibrinolytic activity.–20 Activation of these procoagulant factors can take place during the apoptosis of tumor cells induced by chemotherapy or radiation. Both chemotherapy and radiotherapy cause endothelium damage, which induces the activation of platelets and the coagulation cascade. In addition, a reduction in fibrinolysis is involved in tumor growth and metastasis. Furthermore, 5-fluorouracil, a pyrimidine analogue used in the treatment of colorectal cancer, may cause direct endothelial damage leading to platelet and coagulation cascade activation.The multifactorial pathogenesis of ATEs in cancers may include individual cardiovascular risks, comorbidities, immobilization, primary cancer location, and treatment by chemotherapy or radiotherapy.In this patient with colorectal cancer, it was unlikely that the stroke was the result of metastasis or arterial invasion of tumor growth based on the evidence that dabigatran resolved the thrombus. Both cancer itself and chemotherapy give rise to a hypercoagulable state; therefore, it is difficult to say which one induced the thrombus. However, we figured that chemotherapy was the primary factor in thrombus formation because the onset of stroke was within a short period after the chemotherapy courses. We did not perform IA thrombectomy for this patient. If we did, the content of thrombus by pathologic analysis, platelet- or fibrin-rich, would cast more interest in the pathogenesis of the thrombus.Thus, in our case, we hypothesized a “two-step” mechanism in this cancer-related stroke. First, the cancer made an environment with higher procoagulants predisposing the patient to thrombus formation. Second, on the following adjuvant chemotherapy, accelerated thrombus formation by damaging the endothelium and inducing the coagulation cascade occurred. Given that our patient developed stroke after several cycles of chemotherapy, the diagnosis of chemotherapy-induced stroke was reasonable as these events occurred chronologically. We also observed the thrombus resolution effect of dabigatran, which could be explained as stated in this article. In this stroke patient with colon cancer, thrombus formed in a “two-step” mechanism, which was later resolved by an oral anticoagulant. Oral anticoagulation had benefit for this subtype of ischemic stroke. Thrombolytic and anticoagulant medications in this patient suggested the thrombus formation with fibrin-rich content which may be attributable to both cancer and chemotherapy.The authors thank Editage-Taiwan (#VIANG_4) for providing this editing service.Bo-Chang Wu: review of the medical history; literature search; manuscript drafting.Ming-Hung Hu: cancer history review; consultation of medication effects.Vinchi Wang: stroke patient care; draft review and discussion; literature search.


Superior mesenteric artery (SMA) syndrome is an uncommon phenomenon caused by the compression of the third portion of the duodenum between the aorta and the SMA. Here, we present a previously healthy 15-year-old male who presented with early satiety and 20 kg weight loss. Computed tomography (CT) demonstrated a massive retroperitoneal liposarcoma displacing the entire small intestine into the right upper quadrant. Following resection of the large mass, the patient was intolerant of oral intake despite evidence of bowel function. Abdominal CT revealed a narrowing of the duodenum at the location of the SMA. A nasojejunal feeding tube was placed past this area, and enteral nutrition was initiated before slowly resuming oral intake. Post-operative SMA syndrome is an uncommon complication but should be considered in patients intolerant of oral intake following resection of large abdominal tumors associated with extensive retroperitoneal fat loss, even in the absence of concomitant major visceral resection. Abdominal computed tomography (CT) revealed a massive retroperitoneal tumor shifting the entire small bowel into the right upper quadrant, with significant lateral displacement of the superior mesenteric artery (SMA) from its normal anatomic course (A previously healthy 15-year-old male was referred to our hospital presenting with early satiety, 20 kg weight loss (body mass index = 18.1 kg/mc course . The tumen bloc visceral resection; surgical margins were negative with no capsular disruption or intra-operative tumor spillage. It is worth noting that the duodenum was visualized crossing the midline, and the ascending, transverse, and descending colons were in their normal anatomic positions, excluding pre-existing malrotation. At the conclusion of the resection, he was noted to have near-complete absence of lipomatous tissue in his retroperitoneum. Post-operatively, he was persistently intolerant of diet advancement; despite apparently successful attempts at nasogastric decompression with evidence of bowel function, he demonstrated persistent bilious emesis with a benign abdominal exam. An upper gastrointestinal series revealed abrupt cutoff of contrast in the mid-duodenum, with significantly delayed transit of contrast distally (nil per os for 4 weeks after discharge with continued weight gain, before slowly resuming oral intake. The patient’s intolerance to oral intake has resolved; he is now independent of tube feedings and has returned to near the 50th weight percentile for his age and height.The patient underwent resection of the 11.1 kg, 70 cm mass without distally . Abdomindistally . A nasojSuperior mesenteric artery syndrome is an uncommon phenomenon with an estimated incidence in the general population between 0.013% and 0.3% ,3. SMA sPatients with SMA syndrome predominantly present with a history of chronic abdominal complaints characterized by signs and symptoms of duodenal obstruction but varying due to the degree of duodenum compression . SymptomEpidemiologically, females are more commonly affected, with two-thirds of patients 10 to 40 years of age . SMA synPost-operative SMA syndrome following intra-abdominal procedures is extremely rare, but has previously been reported following proctocolectomy and ileoanal pouch anastomosis , Nissen In the present case, the patient’s large intra-abdominal tumor was displacing the entire small bowel to the right upper quadrant, effectively “propping open” the aortomesenteric angle as seen by the perpendicular course of the SMA compared with normal anatomy . The patLam et al. assessed the clinical symptoms for SMA syndrome following surgical treatment of scoliosis and presented an algorithm on how to treat SMA syndrome . InitialOperative management is indicated only when conservative management fails . OperatiSuperior mesenteric artery syndrome is an uncommon phenomenon with post-operative SMA syndrome following intra-abdominal procedures even less prevalent. The unifying theme for most cases of post-operative SMA syndrome is a sudden major rearrangement of intra-abdominal anatomy. We report the first case of post-operative SMA syndrome occurring following resection of a giant retroperitoneal liposarcoma. Post-operative SMA syndrome should be considered in patients intolerant of oral intake following resection of large retroperitoneal tumors, even in the absence of major concomitant visceral resection.