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Background: The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy outcomes, the offspring’s cardiovascular health is understudied. We hypothesized that offspring exposed to in utero morphine exposure (IUME) would show increased CVD risk factors and endogenous opioid system dysregulation. Methods: Sprague Dawley dams were treated with saline (vehicle, n=10) or escalating doses of morphine (5–20 mg/kg per day, SC, n=10) during gestation. Cardiovascular and metabolic parameters were assessed in adult offspring. Results: Litter size and pups’ birth weight were not different in response to IUME. Female and male IUME offspring showed reduced body length at birth ( P P P P P P Conclusions: Among the effects of IUME, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.

The opioid overdose and opioid use disorder (OUD) epidemics are concomitant with nearly a 2-fold increased risk of cardiovascular disease (CVD). Opioid abuse during pregnancy increases the incidence of neonatal opioid withdrawal syndrome (NOWS) by 5-fold; however, the long-term effects on the offspring’s cardiovascular health are understudied. Previously, we have shown that both male and female offspring from dams exposed to mu-opioid receptor agonist morphine (MOR) during pregnancy display high blood pressure and reduced renal function as adults. Further, cardiovascular tissues of MOR-exposed offspring show downregulation of the endogenous opioid peptide proenkephalin (PENK) mRNA expression, which has been shown to play a role in modulating the adrenergic receptors signaling. This study aimed to investigate whether increased blood pressure in MOR-exposed offspring is associated with the activation of the sympathetic system.Sprague Dawley dams were treated with escalating doses of MOR (5-20 mg/kg/day, s.c) or saline (VEH) from gestational day 1 to 18. At 16 weeks, rats were implanted with femoral artery catheters for direct blood pressure measurements in response to the alpha-adrenergic receptor (A-ADR) blocker doxazosin (4 mg/kg/day, s.c) or saline. At the end of the study, plasma norepinephrine (NE) was measured by HPLC, and brain micropunches of the paraventricular nucleus of the hypothalamus (PVN), implicated in blood pressure regulation, were collected for RNAseq analysis.MOR-exposed offspring showed a greater reduction in the pressor response to mecamylamine (5 mg/kg, IP, delta change in mmHg: F-MOR -44.9±5.8 vs F-VEH -18.3±1.3, p0.05, n=6-8). Renal mRNA expression of the alpha-adrenergic receptor was downregulated ~3-fold (-2ddCt n=6-8, p HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Opioid use disorder (OUD) is one of the greatest public health threats in the US. In 2020, more than 69,000 Americans died of a drug overdose involving opioids. Starting in 2014, an alarming third wave is on the rise now caused by synthetic opioids, specifically illicit fentanyl (FEN). OUD among pregnant women is an understudied area related to the opioid epidemic, showing a 5-fold increase incidence of neonatal opioid withdrawal syndrome (NOWS). Currently, the only two FDA-approved medications indicated for medication assisted treatment (MAT) during pregnancy are methadone and buprenorphine. While some general guidelines have been established to place pregnant woman on MAT, the misuse of fentanyl has challenged the current pharmacotherapies, urging for the characterization of pre-clinical models.The aim of this study was to investigate the trasngenerational effects of opioids on the cardiovascular system. We subjected female rats to opioids exposure during pregnancy. We investigated: 1) In the newborns, the morphometrics and withdrawal symptoms; 2) In the adult offspring, the locomotor sensitization 3) The short and long-term plasma endogenous opioids peptides status, and 4) the transcriptomics of brain areas involved in the neural interface between motivation and action.We found that female and male neonates from opioids-treated dams are smaller through the lifespan compared to VEH-exposed counterparts (n=6, p This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

We have shown that male mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased blood pressure and sympathetic activation compared to controls (C) when fed a high fat diet (HF). Obese MSEW males also show exacerbated pressor response to the acute stimulation of epididymal white adipose tissue (eWAT) with capsaicin, a transient receptor potential cation channel subfamily V member 1 (TrpV1) ligand. Further, selective afferent denervation reduces blood pressure in MSEW mice only. We also reported that increases in serotonin (5-HT) levels in eWAT could serve as a potential endogenous factor stimulating sensory neurons. The goal of this study was to identify whether MSEW induces changes in the transcriptomes of eWAT and dorsal root ganglia (DRG) that could be associated with sensory neuron stimulation. In addition, we investigated MSEW-induced changes in lipid class and kinases activity. After weaning, C57BL/6J male C and MSEW pups (n=4/group) were placed on HF (60% Kcal from fat) for 16 weeks. Then, mice were euthanized and eWAT and DRGs were collected for tissue analysis. Pamstation12 instrument (PamGene International, Netherlands) was used for kinase activity profiles. For lipidomic analysis, lipids were extracted using acidified organic solvents, and dry residues were reconstituted for analysis using a Shimadzu Nexera UHPLC system coupled with an AB Sciex 6500+ Q-Trap linear ion trap/triple quadrupole mass spectrometer. RNA-sequencing was performed by Novogene Corp Inc.Overall, MSEW decreased the phosphorylation of ~20 kinases in eWAT (e.g. AKT, SGK, PKA, PKG, JNK, PAKA, ERK, AMPK), while increasing phosphatidylglycerols (PG) in eWAT (p HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Increased levels of pro-inflammatory cytokine Interleukin 17a (IL17) from adipose tissue have been linked to hypertension and metabolic syndrome in both humans and mice. Studies have demonstrated a causal role for IL17 in vascular dysfunction in angiotensin II-induced hypertension. IL17 secretion is modulated by T-helper 17 (Th17) lymphocytes downstream of mineralocorticoid receptor (MR) activation on dendritic cells (DC). In models of obesity, Th17 are known to infiltrate and expand in adipose tissue (AT). Perivascular AT (PVAT) directly modulates vascular function via secretion of adipose-derived factors. Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, display exacerbated obesogenic response to high fat diet feeding (HF) and metabolic syndrome-like phenotype that can be attenuated by the chronic treatment with MR antagonist spironolactone. Therefore, this study aimed to determine if there is an MR-dependent role of IL17 from PVAT on endothelial function in obese female MSEW mice. Female MSEW and control (C) mice were weaned onto HF (60 % Kcal from fat) for 20 weeks, then randomized to receive either vehicle (50% Ora swift in drinking water) or spironolactone (100 mg/kg/d in vehicle) treatment for 2 weeks. Upon euthanasia, plasma was to measure cytokines using a milliplex assay (n=5 per group). Thoracic aortas were then isolated and cleaned for vascular reactivity studies, and aortic and mesenteric perivascular adipose tissue (aPVAT and mPVAT, respectively) was collected in DMEM (2% BSA, 2-hour incubation, 37C). Cumulative concentration response (CCR) curves were performed for acetylcholine (Ach, 10-5 to 10-9 M) and sodium nitroprusside (SNP, 1x10-6 to 1x10-14 M) after pre-constriction with serotonin (2×10-3 M, 5 ul). Maximal vascular relaxation of aortic rings was similar between groups, however, preincubation with mPVAT media explant impaired vascular relaxation only in MSEW mice (p HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Supplemental Digital Content is available in the text., Previously, we have shown that male mice exposed to maternal separation and early weaning (MSEW)—a mouse model of early life stress—display increased mean arterial pressure compared with controls when fed a high-fat diet. As the stimulation of sensory nerves from fat has been shown to trigger the adipose afferent reflex, we tested whether MSEW male mice show obesity-associated hypertension via the hyperactivation of this sympathoexcitatory mechanism. After 16 weeks on high-fat diet, MSEW mice displayed increased blood pressure, sympathetic activation, and greater depressor response to an α-adrenergic blocker when compared with controls (P

EPI-X4 is a natural peptide antagonist of CXCR4, an established drug target in inflammatory diseases and cancer. Advanced derivatives of EPI-X4, such as EPI-X4 JM#21, have shown promising therapeutic effects in animal models of CXCR4-associated diseases but suffer from poor stability in blood. We here aimed to design and characterize EPI-X4 analogs that effectively antagonize CXCR4 while remaining stable in human plasma. We found that EPI-X4 analogs are stable against degradation by endopeptidases. However derivatives are are prone to degradation by exopeptidases which target the peptides’ N- but not the C-terminus. Modifications of the peptide N-terminus by introducing D-amino acids or acetyl residues resulted in EPI-X4 derivatives with greatly enhanced plasma stability. The identified lead candidates EPI-X4 JM#29, JM#173, and JM#174, which contain D-amino acids L or I at position 1, were as active in binding and antagonizing CXCR4 as EPI-X4 JM#21, and remained active even after 8 hours of incubation in plasma. Molecular dynamics simulations showed that the binding mode of these stabilized EPI-X4 derivatives to CXCR4 is similar to the binding of JM#21. The peptides establish conserved interactions with acidic residues in the minor subpocket and the extracellular loops 1 and 2 of the receptor. None of the novel EPI-X4 leads showed any signs of toxicity in zebrafish embryos, paving the way for further evaluation of the pharmacokinetic and therapeutic properties of this new generation of EPI-X4 analogs in rodent models.

Chronic opioid exposure and opioid use disorder are associated with nearly a 2-fold increased risk of CVD and 16% increase in coronary artery disease. Opioid abuse during pregnancy increases 5 fold the incidence of neonatal opioid withdrawal syndrome (NOWS) and is associated with low birth weight; however, the effect of OUD among pregnant women on their offspring health is understudied. Previously, we have shown that both male and female offspring from dams exposed to mu-opioid receptor agonist morphine (MOR) during the whole pregnancy are smaller and display high blood pressure. This study aimed to investigate the potential underlying mechanisms associated with increased blood pressure in MOR- exposed offspring. Sprague Dawley dams were treated with escalating doses of MOR (5-20 mg/kg/day, s.c) or saline (VEH) from gestational day 1 to 18, and pups were weaned on standard diet. Lipid profile was assessed as a risk factor for coronary artery disease using FPLC. MOR exposed offspring showed increased LDL (F-MOR vs. VEH ~2 fold; M-MOR vs. VEH ~1.5 fold mg/dL; n=6-8, p

Previously, we have shown that Maternal Separation and Early Weaning (MSEW) exacerbates high fat diet (HF)-induced visceral obesity in female offspring compared to normally reared female mice. Stress hormones such as glucocorticoids and mineralocorticoids are critical mediators in the process of fat expansion, and both can activate the mineralocorticoid receptor (MR) in the adipocyte. Therefore, this study aimed to, comprehend the specific effects of MSEW on adipose tissue basic homeostatic function, and investigate whether female MSEW mice show an exacerbated obesogenic response mediated by MR. Gonadal white adipose tissue (gWAT), a type of visceral fat, was collected to assess lipidomics, transcriptomics, and in vitro lipolysis assay. Obese female MSEW mice showed increased adiposity, elevated 44:2/FA 18:2 + NH4 lipid class and reduced mitochondrial DNA density compared to obese control counterparts. In addition, single-cell RNA sequencing in isolated pre- and mature adipocytes showed a ~9-fold downregulation of aquaglycerolporin 3 (Aqp3), a channel responsible for glycerol efflux in adipocytes. Obese MSEW mice showed high levels of circulating aldosterone and gWAT-derived corticosterone compared to controls. Further, the MR blocker spironolactone (Spiro, 100 mg/kg/day, 2 weeks) normalized the elevated intracellular glycerol levels, the greater in vitro lipolysis response, and the number of large size adipocytes in MSEW mice compared to the controls. Our data suggests that MR plays a role promoting adipocyte hypertrophy in female MSEW mice by preventing lipolysis via glycerol release in favor of triglyceride formation and storage.

Literature, the study of human nature, has always appealed to people of different cultural backgrounds all over the world. Adaptation of classics to another medium or genre is the ideological attempt to modify an already existing study of human nature to suit another medium. In order to assess literary adaptations, it is quite essential to identify the kind of adaptation that the filmmaker has chosen and find out whether the filmmaker succeeds in her/his choice to suit the adaptation’s ideology. The aim of this study is to explore how far Andrea Arnold’s (2011) adaptation of Wuthering Heights has managed to challenge British nineteenth century social norms and cultural values by choosing the “fidelity” approach with minimum alterations in her attempt to adapt the ‘Other’. This study aims to assess Arnold’s adaptation by using Sarah Cardwell’s three contexts: “generic context”, “authorial context” and “[cinematic] context (and performance)” (55). An English filmmaker and former actress, Arnold is both the director and script writer of her third film Wuthering Heights based on the nineteenth century classic of Emily Bronte and starred Kaya Scodelario and James Howson. Taking into account that any film adaptation entails an ideological activity, the main focus of this paper is to investigate one ideological idea, that of challenging British nineteenth century social norms and cultural values by propagating a toleration of the ‘Other’. The current study aims to highlight the different ways in which Andrea Arnold’s (2011) adaptation of Wuthering Heights challenges British nineteenth century discrimination which are often based on race, color, class, or their combinations. Echoing Bronte’s text that gave voice to Heathcliff through Nelly’s narration, Arnold’s adaptation’s focus on Heathcliff’s point of view is an attempt to challenge British nineteenth century social norms and cultural values by tolerating the ‘Other’. Allowing a black man the point of view to tell the story of a British nineteenth century white woman’s dilemma, that ends by a wrong choice once she follows the social norms and cultural values of her age, reveals as well Arnold’s appreciation of the Other’s perspective. Hence, Arnold’s choice of the fidelity approach with alterations is both appropriate and effective in serving the adaptation’s ideology.

Male C57BL/6J mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased blood pressure (BP) and sympathetic activation compared to obese controls when fed a high fat diet (HF). Moreover, HF-fed MSEW males display exacerbated BP responses to the acute stimulation of the adipose afferent reflex (AAR) in epididymal white adipose tissue (eWAT). The aim of this study was to investigate the contribution of endogenous factors that could stimulate fat sensory neurons. MSEW and control (C) mice (n=8/group) were placed on a LF or HF (10% and 60% Kcal from fat, respectively) for 16 weeks. Then, serum obtained by decapitation and adipose tissue samples were collected to measure mRNA and protein expression of 15 factors and receptors known to activate sensory neurons. No differences were found across measurements on LF. Plasma AGT and AngII were decreased in HF-fed MSEW compared to C (AGT: 760±48 vs. 1267±161 ng/ml, p-ΔΔct , p

Some Melilotus species have been well acknowledged in worldwide traditional medicine, where its folk uses not only heal simple ailments but also used in vital disorders. The current review considers the comparative phytochemical and biological prospective survey of Melilotus messanensis (L.) All. and a medicinal Melilotus species; Melilotus indicus (L.) All., aiming to highlight the medicinal significance for the former species. A chemical survey of both species revealed around 135 metabolites (phenolic acids, coumarins, flavonoids, terpenoids, two saponins, fatty acid esters, and others). Also, their bioactivity studies have been directed to potential antioxidant, antidiabetic, and/or antimutagenic activities, while the folk medicinal properties, as well as the anti-microbial and anti-inflammatory assays were limited to M. indicus. Thus, this review draws attention to further biological research for M. messanensis to discover its medicinal uses. From the chemosystematics point of view, the fruit morphology and the structural chemical variations confirmed the significance of the two species. As well as their chemical resemblances with a well-known commercial medicinal species; Melilotus officinalis (L.) Pall., which predict the significance medicinal outcomes of M. messanensis.

Man’s eternal quest from innocence to experience is marked by his ability to face different challenges. Some experiences teach a lesson while others cause severe injury. People’s reactions are not the same when it comes to traumatic events. In moments of danger, some people manage to ‘fight’ for survival while others escape when they face life-threatening incidents. People who fail to ‘fight’ are helpless in repeated moments of danger. Lenore Terr declares that “psychic trauma occurs when a sudden, unexpected, overwhelming intense emotional blow or a series of blows assaults the person from outside. Traumatic events are external, but they quickly become incorporated into the mind”(8). The aim of this paper is to apply trauma theory to Bahaa Taher’s Sunset Oasis which was awarded the International Prize for Arabic Fiction in 2008. Taking place in the remote area of Siwa Oasis, the novel deals with Mahmoud Abd el Zahir, who is sent by the British authorities to Siwa Oasis as District Commissioner as a punishment for his participation in the outbreak with Urabi at the end of the 19th century. Mahmoud suffers serious blows as a result of the British bombing of Alexandria, Urabi’s defeat, the king’s betrayal and his friend Tal’at’s testimony. Nevertheless, Mahmoud’s real trauma results from his own testimony during the second investigation in which he fails to‘fight’ for his country. Focusing on the impact of the journey through the desert and life in Siwa Oasis, this study investigates the narrative techniques employed by the author to recall devastating moments of helplessness which drag Mahmoud into severe injuries until his final dramatic end.

Virginia Woolf once said, “I want to write a novel about silence. The things people don’t say.”1 What people do not say or what they cannot say, what people usually hide and what most writers refrain from dealing with is known as atrocity. Atrocities are usually concealed, kept hidden and rarely voiced either by those who witness them or those who are their targets. Judith Herman declares “[t]he ordinary response to atrocities is to banish them from consciousness. Certain violations of the social compact are too terrible to utter aloud: this is the meaning of the word unspeakable” (1). Atrocities are the taboo of humanity nevertheless in her last novel, God Help the Child (2015) Toni Morrison skillfully tracks the childhood atrocities of her characters in an attempt at healing. Voicing childhood abuse is not Morrison’s first attempt to speak about the “unspeakable”. However, in God Help the Child, Morrison is more intent at warning people from the drastic outcome of childhood abuse. The current study aims to apply Trauma Theory to Toni Morrison’s God Help the Child from Judith Herman’s perspective in an attempt to show the damaging impact of emotional abuse and neglect on adult victim’s psyche. In Trauma and Recovery, Judith Herman not only depicts the devastating impact that childhood trauma can have on people but also gives guidelines to means of recovery. This can clearly be applied to Toni Morrison’s God Help the Child in which the author shows how most of the characters suffer from, what Herman designates as “psychological distress symptoms”(1) due to the “chronic” injury resulting from either witnessing or being a target of one or more forms of child abuse. Though “[e]motional abuse and neglect is an under-recognized, but actually common, form of child abuse”(Glaser 697), Morrison’s focus on depicting the damaging impact of emotional abuse and neglect on her protagonist reveals her recognition of its long-term effects. Morrison uses the device of flashback in tracking unwelcomed childhood atrocities once triggered by new stimulus. While highlighting how her protagonist managed to “stitch” her “chronic” bruises through dissociation, Morrison skillfully leads her protagonist to confess those buried atrocities in a successful attempt at her protagonist’s recovery.

Life-writing differs from the traditional chronological narrative of autobiography and has a lot in common with the oral tradition of storytelling widespread in indigenous communities. A close relation can be detected between women’s life-writing and the storytelling tradition embedded in most of the indigenous cultures of North America. Since indigenous voices “had been historically silenced and excluded from the public discourse, published life stories have become an alternative site for indigenous people’s resistance to various oppressive regimes imposed by the dominant society”(Horakova 4). Maria Campbell is one of the first Metis women to write about the injustices faced by Metis people in Halfbreed (1973), paving the way for a new generation of Metis women writers. The Metis, one of Canada's three Aboriginal peoples, have always had to hide their identities out of the shame they were taught to feel when they attended residential schools. Belonging to and ashamed of her Metis origin, Campbell faced racial discrimination and social injustice in her early life until she found refuge in her cultural heritage. Halfbreed is directed towards the reinforcement of Metis cultural tradition in order to alter the Natives’ sense of shame. Campbell succeeded in transforming the meaning of ‘half-breed’ from within. Her pride in her Metis culture challenges the stereotypical image of the Native woman imposed by the Europeans. Her choice of the genre of life-writing including characteristics of the oral tradition, is not only a direct challenge to the prevailing norm of autobiography but also an attempt at questioning “historical” versions of the past that were developed in the “master narratives”. Encompassing both written and oral tradition, the genre life-writing allows Campbell to withhold her Great Grandmother’s teachings (Cheechum’s narrative) together with her own narrative in an attempt to use both narratives to alter or change Metis people’s life. This research aims to show how Campbell’s use of the genre of life-writing with its focus on the Metis people signifies a reconciliation with her cultural heritage and a successful attempt towards an alter/Native narrative. For its theoretical framework, the paper will draw on Frantz Fanon’s The Wretched of the Earth. إن الکتابة الحياتية تختلف عن السرد الزمنى التقليدى للسيرة الذاتية و تشترک مع تقليد الرواية الشفهية المنتشرة فى مجتمعات السکان الأصليين. فهناک علاقة وثيقة بين الکتابة الحياتية للمرأة و الرواية الشفهية فى معظم ثقافات السکان الأصليين لأمريکا الشمالية. و لأن صوت السکان ألأصليين کان قد تم إسکاته و إستبعاده تاريخيا من الخطاب العام، فإن القصص الحياتية التى تم نشرها أصبحت موقع بديل يتيح للسکان الأصليين الفرصة لمقاومة مختلف الأنظمة القمعية التى يفرضها المجتمع السائد. تعتبر ماريا کامبل من أوائل النساء الميتي (الهجناء) التى کتبت عن الظلم الذى يواجهه السکان الهجناء فى روايتها "السلالة الهجينة" (1973)، حيث مهدت الطريق لجيل جديد من الکاتبات اللواتى ينتمين للميتى. و ينقسم السکان الأصليين فى کندا الى ثلاثة أقسام و يعتبر الميتى أحد هذه الأقسام الثلاثة الذين إعتادوا على إخفاء هويتهم بسبب الشعور بالخزى الذى نما لديهم أثناء تواجودهم بالمدارس الداخلية. و قد واجهت کامبل التفرقة العنصرية و الظلم الإجتماعى فى بداية حياتها حيث أنها تنتمى لسلالة الميتى ومثلهم تشعر بالخجل من هويتها الهجينة حتى وجدت ملاذا آمنا فى التراث الثقافى الذى تنتمى اليه. و يعتبرکتابها "السلالة الهجينة" موجهة نحو تعزيز التراث الثقافى لسلالة الميتى لتغيير الشعور بالخزى لدى السکان الأصليين. و قد نجحت کامبل فى تغيير معنى ’الهجين‘ من الداخل. إذ أن فخرها بثقافة الميتى کان تحديا واضحا للصورة النمطية التى فرضها الأوروبيون على المرأة الأصلية. و لا يعتبر إختيار کامبل لهذا النوع من الکتابة الحياتية و الذى يتضمن خصائص من الرواية الشفهية تحدى صريح للسرد التقليدى للسيرة الذاتية السائدة فحسب و لکنه أيضا محاولة للتشکيک فى الإصدارات التاريخية للماضى فى ’روايات السادة‘. و بما أن الکتابة الحياتية تشمل خصائص کلا من الرواية التقليدية المکتوبة و الرواية الشفهية، فإن الکتابة الحياتية سمحت لکامبل بإحتواء تعاليم جدتها لوالدها (رواية شيشم) جنبا الى جنب قصة حياتها فى محاولة لإستخدام الروايتين فى تغيير حياة السکان الأصليين للأفضل. يحاول هذا البحث توضيح أن إستخدام کامبل لإسلوب الکتابة الحياتية مع الترکيز على سلالة الميتى يدل على التصالح مع موروثها الثقافى کما يعد خطوة ناجحة نحو الحصول على الرواية البديلة للسکان الأصليين. و يستخدم البحث منهج فرانز فانون فى کتابه "معذبو الأرض".

Sağır, Özlem (Balikesir Author), Introduction More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. Methods and analysis EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. Ethics and dissemination EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369. ©

Exposure to a combination of more than 3 adverse childhood experiences (ACEs) is an independent risk factor for obesity and metabolic syndrome. Since women have a higher risk of developing obesity than men, this study was designed to investigate the effects of ACEs on BMI and adipokines while considering sex and menopausal status. We analyzed 41,226 ACE questionnaires (comprised of 10 questions) from the Southern Community Cohort Study (SCCS). Overall, BMI and plasma adipokines were similar between pre- and post-menopausal women, while men displayed lower BMI and plasma leptin compared with age-matched women (p F: 0.0183), elevated plasma leptin (Prob > F: 0.0046), and reduced plasma adiponectin (Prob > F:0123). BMI was increased in all high-ACE women, whereas leptin increased while adiponectin reduced in high-ACE pre-menopausal women only (table 1A). Age-matched men did not show a significant effect of ACE on BMI or adipokines (table 1B). Taken together, our data indicate that high-ACE exposure strongly predicts metabolic risk in women, particularly in pre-menopausal status. These outcomes become fundamental to support the use of our mouse model of neglect as a translational tool to address the sex-specific obesogenic response to stress.

To clarify the role of Angiotensin II (Ang II) in the sensory system and especially in the trigeminal ganglia, we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of Ang II and substance P in the rat and human trigeminal ganglia. The rat trigeminal ganglia expressed substantial amounts of Ang-N- and ACE mRNA as determined by quantitative real time PCR. Renin mRNA was untraceable in rat samples. Cathepsin D was detected in the rat trigeminal ganglia indicating the possibility of existence of pathways alternative to renin for Ang I formation. In situ hybridization in rat trigeminal ganglia revealed expression of Ang-N mRNA in the cytoplasm of numerous neurons. By using immunocytochemistry, a number of neurons and their processes in both the rat and human trigeminal ganglia were stained for Ang II. Post in situ hybridization immunocytochemistry reveals that in the rat trigeminal ganglia some, but not all Ang-N mRNA-positive neurons marked for Ang II. In some neurons Substance P was found colocalized with Ang II. Angiotensins from rat trigeminal ganglia were quantitated by radioimmunoassay with and without prior separation by high performance liquid chromatography. Immunoreactive angiotensin II (ir-Ang II) was consistently present and the sum of true Ang II (1-8) octapeptide and its specifically measured metabolites were found to account for it. Radioimmunological and immunocytochemical evidence of ir-Ang II in neuronal tissue is compatible with Ang II as a neurotransmitter. In conclusion, these results suggest that Ang II could be produced locally in the neurons of rat trigeminal ganglia. The localization and colocalization of neuronal Ang II with Substance P in the trigeminal ganglia neurons may be the basis for a participation and function of Ang II in the regulation of nociception and migraine pathology.

Objectives This work was designed to evaluate the therapeutic efficacy of Alectryon tomentosus F. Muell leaf extract against CCl 4 -induced hepatic injury in albino rats and anti-HIV effect in vitro . Proximate analysis, phytochemical screening and assay of total flavonoid (TFC) and phenolic contents (TPC), were carried out according to standard methods. Materials and methods The TPC and TFC were estimated spectrophotometrically. The median lethal dose (LD 50 ) of the total ethanol extract of A. tomentosus F. Muell leaves was evaluated. The effect on acute HIV-1 infectivity was measured with the syncytium formation assay using AZT (3΄-azido-3΄-deoxythymidine) as a positive control. Moreover, carbon tetrachloride-induced acute hepatic damage was used to evaluate the hepatoprotective effect of the leaves. Results and conclusion Proximate analysis of air-dried leaves of A. tomentosus F. Muell revealed 8.3% moisture content, 9.2% total ash, 0.48% water-soluble ash and 2.56% acid-insoluble ash. Preliminary phytochemical screening revealed that the dried powdered leaves of A. tomentosus F. Muell are rich in carbohydrates and/or glycosides, volatile constituents, sterols and/or triterpenes and tannins; however, flavonoids (free and combined) and coumarins are present in a lesser concentration. Alkaloids, saponins, cardiac glycosides and anthraquinones are absent. The evaluated TPC was 71.59 mg gallic acid equivalent/g dry weight, whereas TFC was 63.64 mg quercetin equivalent/g plant dry weight. The median lethal dose (LD 50 ) of the total ethanol extract was found to be 9.2 g/kg body weight, indicating the safety of the leaves of the plant. In carbon tetrachloride-induced acute hepatic damage model, the methylene chloride extract showed the highest protection percentage as shown by reduction in the level of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels, followed by aqueous extract. These may be attributed to their phenolic and flavonoidal content. The anti-HIV-1 activity was assessed by evaluating syncytium formation. The results showed that the extract was minimally toxic and showed a weak anti-HIV-1 activity in comparison with AZT.