Administration Of Prostaglandin E2 Research Articles

A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice.

Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E2 (PGE2). PGE2 induction requires a nuclear factor κB-independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not Rela or Tgfb1, in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (TH1)/TH17 infiltration and aggravated colitis development. PGE2 administration ameliorated colitis in mouse models with defective PGE2 production but not in animals with normal PGE2 induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE2 biosynthesis, in inflamed tissues, and especially in colon Vimentin+Twist2+ stromal cells, in about 60% of patients with active Crohn's disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE2 production.

Indoleamine-2,3-Dioxygenase Activates Wnt/β-Catenin Inducing Kidney Fibrosis after Acute Kidney Injury

Introduction: As disorder of tryptophan metabolism is common in CKD, the rate-limiting enzyme of tryptophan, indoleamine-2,3-dioxygenase (IDO), has been reported to be involved in CKD, while the accurate mechanism remains unknown. This study was designed to explore correlations between IDO and kidney fibrosis after ischemia-reperfusion injury (IRI). Methods: Wild-type (WT) mice and IDO knockout (IDO−/−) mice were divided into the sham group and acute kidney injury (AKI) group. Mice in the sham group underwent dorsal incision and exposure of renal pedicle without clamping renal artery, while mice in the AKI group received unique renal artery IRI, and the contralateral kidney was removed at day 13 after IRI. Blood and IRI kidneys were collected at day 14. Kidney function was analyzed by measuring serum Cr and BUN. Morphology was analyzed by tissue periodic acid-Schiff (PAS) staining and Masson staining. Further, fibrosis markers and Wnt/β-catenin pathway proteins were determined by Western blot. Prostaglandin E2 (PGE2) was administrated for 2 weeks after the IRI mice model was established to observe whether it ameliorates kidney fibrosis after IRI. Results: WT AKI mice revealed elevated expression of IDO compared with WT sham mice. Kidney function of IDO−/− AKI mice showed better than that of WT AKI mice. PAS staining exhibited less loss of tubular epithelial cells and atrophy tubules in IDO−/− AKI mice. Furthermore, kidney fibrosis areas and the expressions of fibrosis markers, including α-SMA, fibronectin, and vimentin, were increased in WT AKI mice. In addition, GSK-3β and β-catenin were significantly declined in IDO−/− AKI mice. On top of that, PGE2 administration revealed inhibited IDO expression and that reducing GSK-3β and β-catenin resulting in lower expressions of α-SMA, fibronectin, and vimentin in WT AKI mice. Conclusions: IRI could increase IDO expression to activate Wnt/β-catenin pathway resulting kidney fibrosis. PGE2 could ameliorate kidney fibrosis via inhibiting IDO expression.

Prostaglandin E2-induced anorexia involves hypothalamic brain-derived neurotrophic factor and ghrelin in chicks

Central administration of prostaglandin E2 (PGE2) is associated with potent anorexia in rodents and chicks, although hypothalamic mechanisms are not fully understood. The objective of the present study was to identify hypothalamic nuclei and appetite-related factors that are involved in this anorexigenic effect, using chickens as a model. Intracerebroventricular injection of 2.5, 5, and 10 nmol of PGE2 suppressed food and water intake in broiler chicks in a dose-dependent manner. c-Fos immunoreactivity was increased in the paraventricular nucleus (PVN) at 60 min post injection of 5 nmol of PGE2. Under the same treatment condition, hypothalamic expression of melanocortin receptor 3 and ghrelin mRNAs increased, whereas neuropeptide Y receptor sub-type 5 and tropomyosin receptor kinase B (TrkB) mRNAs decreased in PGE2-treated chicks. In the PVN, chicks injected with PGE2 had more brain-derived neurotrophic factor (BDNF), ghrelin, and c-Fos mRNA but less corticotrophin-releasing factor receptor 1 (CRFR1), CRFR2, and TrkB mRNA expression. In conclusion, PGE2 injection resulted in decreased food and water intake that likely involves BDNF and ghrelin originating in the PVN. Because the anorexigenic effect is so potent and hypothalamic mechanisms are similar in chickens and rodents, a greater understanding of the role of PGE2 in acute appetite regulation may have implications for treating eating and metabolic disorders in humans.

Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever.

Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.

The results of different labour induction approaches: A Cross sectional study

Background and Purpose: To evaluate the use of prostaglandins and oxytocin in labour induction according to different indications. Perinatal outcomes, rate of vaginal delivery and complation of labour were studied and compared. Methods: Cross-sectional descriptive study from January 2012 to December 2012. 530 women who required labour induction were included. Seven groups were created according to the methods of induction. Women with twin pregnancies, induction of dead foetus, two previous caesarean sections or an incomplete clinical history were excluded. Results: The rate of vaginal deliveries in women that only received prostaglandins the first day was 84.6%; similar in women with prolonged pregnancies, 85.2%. The induction with oxytocin directly showed the highest rate of caesarean section. The rate of vaginal deliveries was 50% in women with previous caesarean section. Conclusions: A high rate of vaginal deliveries with a single dose of prostaglandin and within 24 hours of beginning induction. Administration of prostaglandins must be used when cervix is unfavorable and previous to oxytocin stymulation.

Natural versus induced estrus indicators of Holstein heifers determined by an automated activity monitoring system

The objective of this study was to determine the association between estrus induction and estrus indicators, as well as the association between estrus indicators and subsequent fertility. A total of 609 Holstein heifers were fitted with an ear tag automated activity monitor (AAM; SCR by Allflex) and each estrus event was categorized as natural or induced. An induced estrus event was defined as an estrus occurring within 2 to 5 d of PRID removal and/or prostaglandin administration. Most heifers received sex-sorted semen for the first AI and conventional semen for subsequent AIs, with 6 opportunities to become pregnant. Pregnancy was diagnosed by ultrasound at 30 d and confirmed at 45 d post-AI. The AAM recorded the date and time of onset, peak and end of high activity, heat index (a measure of estrus strength), maximum activity change, maximum rumination change, and duration of high activity. Data from 1,269 estrus events were included in the analyses, 881 from natural and 388 from induced estrus events. In total, 70% of heifers started high activity between 20:00 and 08:00 and 73% of heifers hit peak activity between 02:00 to 14:00. Heat index (82 vs. 80, p = 0.09) and rumination change (-49 vs. -46 min/d, p = 0.06) tended to be greater for induced vs. natural estrus. There was no difference in pregnancy at 30 d (68 vs. 67%, p = 0.79) or 45 d (64 vs. 63%, p = 0.82) between the induced and natural estrus groups. However, for pregnancy at 30 d post-AI using conventional semen, natural estrus events tended to have greater pregnancy per AI (P/AI) than induced estrus events (72 vs. 63%; p = 0.09). For pregnancy at 45 d post-AI, induced estrus with sex-sorted semen tended to have greater pregnancy per AI compared to induced estrus with conventional semen (68 vs. 58%; p = 0.09). There was no difference in pregnancy loss between estrus types (p = 0.38). When comparing estrus events that resulted in pregnant or non-pregnant diagnoses at 30 d post-AI, the only difference in estrus indicators was for estrus events resulting in pregnancy to have a greater rumination change (-50 vs. -46 min/d; p = 0.04). Overall, the induction of estrus had no negative effects on estrus indicators, as measured by an AAM, or on fertility compared with natural estrus in dairy heifers.

Trichomonas vaginalis infection impairs anion secretion in vaginal epithelium

Trichomonas vaginalis is a common protozoan parasite, which causes trichomoniasis associated with severe adverse reproductive outcomes. However, the underlying pathogenesis has not been fully understood. As the first line of defense against invading pathogens, the vaginal epithelial cells are highly responsive to environmental stimuli and contribute to the formation of the optimal luminal fluid microenvironment. The cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel widely distributed at the apical membrane of epithelial cells, plays a crucial role in mediating the secretion of Cl− and HCO3−. In this study, we investigated the effect of T. vaginalis on vaginal epithelial ion transport elicited by prostaglandin E2 (PGE2), a major prostaglandin in the semen. Luminal administration of PGE2 triggered a remarkable and sustained increase of short-circuit current (ISC) in rat vaginal epithelium, which was mainly due to Cl− and HCO3− secretion mediated by the cAMP-activated CFTR. However, T. vaginalis infection significantly abrogated the ISC response evoked by PGE2, indicating impaired transepithelial anion transport via CFTR. Using a primary cell culture system of rat vaginal epithelium and a human vaginal epithelial cell line, we demonstrated that the expression of CFTR was significantly down-regulated after T. vaginalis infection. In addition, defective Cl− transport function of CFTR was observed in T. vaginalis-infected cells by measuring intracellular Cl− signals. Conclusively, T. vaginalis restrained exogenous PGE2-induced anion secretion through down-regulation of CFTR in vaginal epithelium. These results provide novel insights into the intervention of reproductive complications associated with T. vaginalis infection such as infertility and disequilibrium in vaginal fluid microenvironment.

Frequency and anatomic distribution of arterial obstructions in patients with vasculogenic erectile dysfunction not responding to intracavernous prostaglandin.

Background: The extent of arterial disease in patients with erectile dysfunction (ED) non-responsive to intracavernosal injection of Alprostadil is of importance for therapeutic options. However, published evidence, in particular angiographically validated is scarce. Here we investigated arterial lesion patterns in this specific patient cohort by selective angiography. Patients and methods: A cohort of 239 patients received a clinical and duplex-sonographic workup for ED of suspected vascular origin. Duplex ultrasound of the cavernosal arteries was performed after intracavernosal injection of 10μg Alprostadil. Consequently, standardized workup included grading of the erectile and determination of peak systolic velocity (PSV) and end-diastolic velocity (EDV) in both cavernosal arteries. PSV-values below 30cm/sec indicated reduced arterial flow, whereas EDV-values above 15cm/sec indicated a venous leak of the pudendal veins. All patients with suspected arterial ED based on duplex sonography underwent contrast-enhanced computed tomography. Endovascular therapy was carried out in ED patients not responsive or with significant side effects to PDE-5-inhibitors or Alprostadil by selective angiographic depiction of erection-related arteries. Results: 54 patients with a mean age of 61.2 (±9.8) years underwent angioplasty of erectionr elated arteries. Out of these 48/54 (89%) patients presented with an erection considered insufficient for penetration (E0-E3) subsequent to intracavernous application of 10μg Alprostadil. 14/48 (29%) patients had bilateral arterial obstructions and 34/48 (71%) had unilateral disease. Commonly affected was the internal pudendal artery (n=31, 65%), followed closely by the common penile artery (n=30, 64%). The least affected arteries were the dorsal penile (n=6, 13%), hypogastric (n=4, 8%), common iliac (n=4, 8%), cavernosal (n=4, 8%), and inferior gluteal (n=1, 2%) arteries. Conclusions: Arterial obstructions amenable to endovascular revascularization are frequent in patients non-responsive to intracavernosal prostaglandin administration. Therapeutic strategies in ED patients non-responsive to conservative measures should therefore consider endovascular treatment opportunities.

485 Efficacy of early versus late intrauterine balloon tamponade in the management of severe postpartum hemorrhage

Intrauterine balloon tamponade (IUBT) is used to achieve hemostasis in refractory postpartum hemorrhage (PPH) unresponsive to uterotonic therapy. Its optimal timing is unknown: as final first-line therapy, with prostaglandin administration, or as initial second-line therapy after prostaglandin treatment has failed. This open multicenter randomized trial included women aged ≥18 years, with a vaginal delivery ≥35 weeks and PPH unresponsive to oxytocin. Exclusion criteria were PPH due to cervicovaginal lacerations without uterine hemorrhage, uterine rupture, or placenta accreta. Women were randomized into: A study group: IV infusion of sulprostone (prostaglandin) started simultaneously with IUBT (ebb®, Clinical Innovation). If bleeding persisted 30 minutes afterwards, an invasive emergency procedure was performed. A control group: IV sulprostone infusion only. If bleeding persisted ≥30 minutes, IUBT was performed. If bleeding persisted 30 minutes after IUBT, an invasive emergency procedure took place. The primary binary composite outcome was calculated peripartum blood loss >1000 mL and/or transfusion of at least 3 RBC units (ClinicalTrials.gov NCT02226731). Between February 2017 and December 2019, 403 women were included. After exclusion of 11 (6 secondarily ineligible, 5 withdrew consent), the intention-to-treat analysis included 392 women, and the per protocol group 331. The groups were similar for women's baseline characteristics, except the rate of women with an estimated blood loss > 1000 mL when sulprostone administration began was higher in the study group (Table 1). After adjustment for this characteristic, the primary outcome was significantly lower in the study group: 67.2% vs 74.3%, aRR (95% CI), 0.87 (0.77-0.99); number needed to treat (95%CI):13.95 (6.22-52.25). Secondary outcomes did not differ between the groups. Per protocol results were similar (Table 2). Early IUBT used as final first-line therapy, together with prostaglandin administration, reduced the risk of severe PPH, compared with later placement.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

A multi-centre case series of alectinib-related erythrocyte membrane changes and associated haemolysis

Alectinib is an orally bioavailable anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK mutated non-small cell lung cancer (NSCLC). This case series documents the development of significant erythrocyte membrane changes associated with alectinib use in six patients. Morphological findings found on blood film examination include moderate-marked acanthocytes, spheroacanthocytes, and one case demonstrated moderate schistocytes. Two patients in this multi-centre case series developed grade 1 anaemia, and four patients developed grade 2 anaemia. Two patients suffered significant non-immune-related haemolysis. One patient had a co-existing β thalassaemia trait and required treatment cessation due to severe haemolysis. Low-grade anaemia was seen in 22% of patients using alectinib in the ALEX trial and 5% developed ≥ grade 3 anaemia. Alterations in erythrocyte morphology and membrane structure have not been reported in the safety data and clinical trials to date. Drug-induced acanthocytosis is a rare phenomenon and has previously been reported with high-dose prostaglandin administration only. This case series highlights this important laboratory finding with alectinib use and associated clinical sequelae. Alectinib-associated acanthocytosis is likely to be more prevalent than previously recognised. We also highlight the need for vigilance in haematopathology departments for unexpected laboratory findings associated with novel therapies. These findings can be detected in the post-marketing surveillance phase and may have serious clinical implications for patients.

Outpatient Induction of Labor - Are Balloon Catheters an Appropriate Method?

As the number of labor inductions in high-income countries has steadily risen, hospital costs and the additional burden on obstetric staff have also increased. Outpatient induction of labor is therefore becoming increasingly important. It has been estimated that 20 – 50% of all pregnant women requiring induction would be eligible for outpatient induction. The use of balloon catheters in patients with an unripe cervix has been shown to be an effective and safe method of cervical priming. Balloon catheters are as effective as the vaginal administration of prostaglandin E 2 or oral misoprostol. The advantage of using a balloon catheter is that it avoids uterine hyperstimulation and monitoring is less expensive. This makes balloon catheters a suitable option for outpatient cervical ripening. Admittedly, intravenous administration of oxytocin to induce or augment labor is required in approximately 75% of cases. Balloon catheters are not associated with a higher risk of maternal and neonatal infection compared to vaginal PGE 2 . Low-risk pregnancies (e.g., post-term pregnancies, gestational diabetes) are suitable for outpatient cervical ripening with a balloon catheter. The data for high-risk pregnancies are still insufficient. The following conditions are recommended when considering an outpatient approach: strict selection of appropriate patients (singleton pregnancy, cephalic presentation, intact membranes), CTG monitoring for 20 – 40 minutes after balloon placement, the patient must be given detailed instructions about the indications for immediate readmission to hospital, and 24-hour phone access to the hospital must be ensured. According to reviewed studies, the balloon catheter remained in place between 12 hours (“overnight”) and 24 hours. The most common reason for readmission to hospital was expulsion of the balloon catheter. The advantages of outpatient versus inpatient induction of cervical ripening with a balloon catheter were the significantly shorter hospital stay, the lower costs, and higher patient satisfaction, with both procedures having been shown to be equally effective. Complication rates (e.g., vaginal bleeding, severe pain, uterine hyperstimulation syndrome) during the cervical ripening phase are low (0.3 – 1.5%); severe adverse outcomes (e.g., placental abruption) have not been reported. Compared to inpatient induction of labor using vaginal PGE 2 , outpatient cervical ripening using a balloon catheter had a lower rate of deliveries/24 hours and a significantly higher need for oxytocin; however, hospital stay was significantly shorter, frequency of pain during the cervical ripening phase was significantly lower, and patientsʼ duration of sleep was longer. A randomized controlled study comparing outpatient cervical priming with a balloon catheter with outpatient or inpatient induction of labor with oral misoprostol would be of clinical interest.

EFECTO DE LA APLICACIÓN DE ESTRADIOL Y PROSTAGLANDINA DURANTE EL POST PARTO SOBRE EL DESEMPEÑO REPRODUCTIVO EN VACAS HOLSTEIN BAJO CRIANZA INTENSIVA

After delivery, the process of uterine involution begins, in which a series of changes in the anatomy and histology of the uterus take place and there is a return to cyclical activity of the ovary. The objective was to evaluate the effect of the application of estradiol benzoate and prostaglandin F2α (PGF2α) in the postpartum period on reproductive performance in dairy cows. Six experimental groups were formed in a 2 x 3 factorial arrangement, where a factor determined the administration of estradiol (E2): a) without E2 or b) with E2 (10 mg of estradiol benzoate was applied at 14 days postpartum) ; and another factor determined the administration of PGF2α: a) without PGF2α, b) administration of PGF2α in early postpartum (application of 25 mg of dinoprost at 28 days repeated 14 days later) or c) administration of PGF2α in late postpartum (application of 25 mg dinoprost at 42 days repeated 14 days later). 96 intensively reared Holstein cows were used for the experiment. The variables of interest evaluated were the cumulative pregnancy percentage (PA), the pregnancy rate (TP), the conception rate (TC), the service rate (TS), the first service delivery interval (IP1S) and the interval conception delivery (CPI). For the statistical analysis, the generalized linear model was used. As independent variables in the model, the administration of estradiol, the administration of prostaglandin and the interaction of both factors were analyzed. No significant effect (p> 0.05) of the application of E2 and PGF2α was found on TS, TC, TP and BP. However, a significant effect (p <0.05) of the application of prostaglandin on IP1S and IPC was observed, finding that the administration of PGF2α in the early or late postpartum significantly decreased IP1S. While the CPI was significantly better with the application of PGF2α in the late postpartum period. In conclusion, the application of prostaglandins from day 42 post parturition repeated 14 days later significantly improves the IP1S and IPC in dairy cows.

Synergistic action of estradiol and PGE2 on endometrial transcriptome in vivo resembles pregnancy effects better than estradiol alone†.

Successful pregnancy establishment in mammals depends on numerous interactions between embryos and the maternal organism. Estradiol-17β (E2) is the primary embryonic signal in the pig, and its importance has been questioned recently. However, E2 is not the only molecule of embryonic origin. In pigs, prostaglandin E2 (PGE2) is abundantly synthesized and secreted by conceptuses and endometrium. The present study aimed to determine the role of PGE2 and its simultaneous action with E2 in changes in porcine endometrial transcriptome during pregnancy establishment. The effects of PGE2 and PGE2 acting with E2 were studied using an in vivo model of intrauterine hormone infusions, and were compared to the effects of E2 alone and conceptuses' presence on day 12 of pregnancy. The endometrial transcriptome was profiled using gene expression microarrays followed by statistical analyses. Downstream analyses were performed using bioinformatics tools. Differential expression of selected genes was verified by quantitative polymerase chain reaction. Microarray analysis revealed 2413 differentially expressed genes (DEGs) in the endometrium treated simultaneously with PGE2 and E2 (P<0.01). No significant effect of PGE2 administered alone on endometrial transcriptome was detected. Gene ontology annotations enriched for DEGs were related to multiple processes such as: focal adhesion, vascularization, cell migration and proliferation, glucose metabolism, tissue remodeling, and activation of immune response. Simultaneous administration of E2 and PGE2 induced more changes within endometrial transcriptome characteristic to pregnancy than infusion of E2 alone. The present findings suggest that synergistic action of estradiol-17β and PGE2 resembles the effects of pregnancy on endometrial transcriptome better than E2 alone.

Effect of intramuscular and intravaginal PGE-2 treatment compared to intramuscular oxytocin treatment in eutocic sows on the farrowing performance in a free farrowing system

A duration of parturition beyond 300 min negatively impacts the health of the sow and the survival of piglets during parturition. Hence, oxytocin is widely used to speed up the parturition. However, oxytocin’s negative side effects raise the need of finding alternative treatments such as those already implemented in human medicine. The aim of this study was to evaluate the efficacy of Prostaglandin E2 (PGE2) applied intravaginally (PGE2-V) (1.0 mg) or intramuscularly (PGE2-M) (2.5 mg) to improve the parturition process after expulsion of the fourth piglet compared to a placebo (P–V), which was sterile intravaginal gel or intramuscular oxytocin application (OXY-M) (20 iu) in free farrowing systems.In total, 201 eutocic sows were examined after stratification by parity and random allocation into groups: 54 (P–V), 48 (OXY-M), 50 (PGE2-V), 49 (PGE2-M). Farrowing duration (time between first piglet and last piglet), piglet interval and placenta expulsion duration (time between first and last placenta) were recorded, and each piglet was scored for meconium staining and vitality. Furthermore, stillborn piglets were categorized into ante-partum and intra-partum deaths.Under the present conditions, neither administration of PGE2 nor oxytocin revealed a significant effect on the farrowing process or the vitality of the piglets when compared to untreated sows. Nonetheless, significant differences could be detected between PGE-2 and oxytocin treatments. The duration of farrowing was significantly shorter in oxytocin-treated sows (156 min) compared to sows treated intramuscularly with PGE2 (238 min). Furthermore, the placenta expulsion duration in the OXY-M group (130 min) significantly differed from PGE2-V (198 min) and PGE2-M group (218 min). Although these accelerations of parturition might be considered as a beneficial effect, routine treatment with uterotonic agents after birth of the fourth piglet in free farrowing eutocic sows cannot be recommended, because an overall benefit when compared to untreated sows was not approved.

Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat

TACAN (Tmem120A), a mechanotransducing ion channel highly expressed in a subset of nociceptors, has recently been shown to contribute to detection of noxious mechanical stimulation. In the present study we evaluated its role in sensitization to mechanical stimuli associated with preclinical models of inflammatory and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to TACAN mRNA attenuated TACAN protein expression in rat dorsal root ganglia (DRG). While TACAN AS-ODN produced only a modest increase in mechanical nociceptive threshold, it markedly reduced mechanical hyperalgesia produced by intradermal administration of prostaglandin E2, tumor necrosis factor alpha, and low molecular weight hyaluronan, and systemic administration of lipopolysaccharide, compatible with a prominent role of TACAN in mechanical hyperalgesia produced by inflammation. In contrast, TACAN AS-ODN had no effect on mechanical hyperalgesia associated with CIPN produced by oxaliplatin or paclitaxel. Our results provide evidence that TACAN plays a role in mechanical hyperalgesia induced by pronociceptive inflammatory mediators, but not CIPN, compatible with multiple mechanisms mediating mechanical nociception, and sensitization to mechanical stimuli in preclinical models of inflammatory versus CIPN. PerspectiveWe evaluated the role of TACAN, a mechanotransducing ion channel in nociceptors, in preclinical models of inflammatory and CIPN. Attenuation of TACAN expression reduced hyperalgesia produced by inflammatory mediators but had not chemotherapeutic agents. Our findings support the presence of multiple mechanotransducers in nociceptors.

Phlebitis Induced by Intravenous Prostaglandin E1 in Patients with Malignancy Following Flap Reconstruction: A Case Series Study

Background: Prostaglandin E1 (PGE1) is a vasodilator and smooth-muscle relaxant commonly used in patients with free flap reconstruction to increase the survival rate of the flap. However, phlebitis is the most common adverse event in patients who receive an intravenous solution of PGE1, and it will lead to more medical treatment. Objective: The incidence of PGE1-induced phlebitis has not been well examined. This study aimed to determine which patient characteristics increase the risk of PGE1-induced phlebitis. Methods: We retrospectively reviewed the medical records of patients with phlebitis caused by PGE1 in our hospital from May 2018 to May 2019. Among the records, we focused on patients with head and neck malignancy who received free flap reconstruction. Results: In total, 1026 patients were prescribed PGE1, and 13 patients developed PGE1-induced phlebitis. Among 78 patients with head and neck cancer, the incidence rate of phlebitis was 15.4% (12 patients). These patients’ mean age was 56 ± 9 years, and all were men. Their mean body weight, estimated glomerular filtration rate, serum creatinine level, white blood cell count, and neutrophil count were 69.6±12.6kg, 81± 18 mL/min/1.73 m2, 0.97 ± 0.19 mg/dL, 10.3 ± 4.4 103/μL, and 75% ± 12%, respectively, before PGE1 administration. The white blood cell count before PGE1 administration was significantly higher (p&lt;0.05) in patients with phlebitis than in those without phlebitis. Conclusion: Prescribers of PGE1 should be aware that patients with head and neck malignancy who receive flap reconstruction may have an increased risk of phlebitis. These patients should be monitored upon admission to prevent PGE1-induced phlebitis.

The effect of prostaglandin and gonadotrophins (GnRH and hCG) injection combined with the ram effect on progesterone concentrations and reproductive performance of Karakul ewes during the non-breeding season.

The effect of prostaglandin and gonadotrophins (GnRH and hCG) combined with the ram effect on the progesterone (P4) concentrations and reproductive performance of Karakul ewes was investigated during non‐breeding season. Ewes (n = 93) received a male effect and were divided into two treatment groups including GnRH ‐ hCG (hCG, n = 32), GnRH ‐ GnRH (GnRH, n = 30) and a control (n = 31) group. This study was carried out from April (hormonal injection) to October (lambing). The first doses of GnRH (4.2 μg, Buserelin) were injected at the beginning of the study in treatment groups. These ewes were treated with hCG (250 IU) or the second GnRH dose five days later. All animals received two injections (ten days apart) of 150 μg PGF2α five days after the hCG or the second GnRH injection. Mating was initiated two days after the second prostaglandin injection and lasted for 34 days. Blood samples were collected by jugular venipuncture on days −10, −5, 0 (first PGF2α injection), 17 and 30 during the study. Pregnancy diagnosis was performed through transabdominal ultrasonography on day 40 after the removing of ram. Conception rate was 93.8, 90 and 87.1% in the hCG, GnRH and control groups, respectively. Lambing rate tended to increase in the hCG group compared with the control group (87.1 versus 58.1%; p < .1). There was no significant difference in P4 concentrations among studied groups in identical sampling times (p > .05). In conclusion, the administration of prostaglandin and hCG in combination with the ram effect tended to decrease lambing period. In other words this protocol tended to increase lambing rate at the first cycle. Treatment with hCG or GnRH did not increase serum P4 concentrations of treated Karakul ewes during the non‐breeding season.

Improving diagnostic accuracy in neonates with left heart obstruction in a transport setting

Differentiating left heart obstruction (LHO) from other severe illness in the neonatal period is challenging, and important for guiding clinical management. The aim of this study was to identify factors distinguishing LHO from non-LHO in neonates. A retrospective, cohort study of neonates referred to the Newborn and Paediatric Emergency Transport Service, New South Wales, with suspected LHO during the epoch 1996-2016. A total of 273 neonates were included; 240 with confirmed LHO. Administration of prostaglandin E1 to infants with a structurally normal heart was not associated with impaired acid-base or oxygenation status. Pre-transport diagnostic accuracy of LHO was 74.4%; sensitivity 84.5%, positive predictive value 86.0%. On multivariable logistic regression, hepatomegaly (odds ratio 2.54; 95% confidence interval 1.05-6.16) was associated with confirmed LHO. A low threshold for prostaglandin E1 infusion should be maintained in infants with suspected LHO. Hepatomegaly is associated with a diagnosis of LHO and may be more useful than other parameters in predicting the condition.

Successful Urgent Living Donor Liver Transplantation for Massive Liver Necrosis Accompanied by Nonocclusive Mesenteric Ischemia in a Biliary Atresia Infant: A Case Report

BackgroundTreatment options for patients presenting with life-threatening splanchnic ischemia, including that of the intestine and liver, could previously only receive salvage surgery and attempted medical revascularization. We propose that urgent liver transplantation (LT) for acute liver failure (ALF) due to massive liver necrosis should be considered as a life-saving treatment. We successfully performed urgent living donor LT for nonocclusive hepatic ischemia accompanied by nonocclusive mesenteric ischemia (NOMI). CaseAn 11-month-old boy with biliary atresia whose jaundice was re-elevated after Kasai portoenterostomy underwent cysto-jejunostomy. Three hours after the uneventful operation, tachycardia, hypotension, and unconsciousness suddenly occurred. Computed tomography revealed whole-liver and massive splenic and focal intestinal ischemia without any vessel occlusion. Urgent LT was performed on postoperative day 3 because intensive therapies, including prostaglandin E1 administration, blood transfusion, and continuous hemodiafiltration, were not effective and the patient had developed life-threatening bradycardia and hypotension. Intraoperative findings included whole-liver necrosis and splenic ischemia and segmental ileal necrosis without any vessel thrombus. LT and necrotic intestinal resections by end-to-end anastomosis were performed. Massive liver necrosis with Gram-positive cocci was histopathologically identified, indicating bacterial translocation due to NOMI. The post-LT course was uneventful, and the neurologic outcomes were uncomplicated. ConclusionsUrgent LT was successfully completed for ALF with NOMI. LT is the sole treatment for the refractory ALF, and undelayed determination is important to rescue.

Dysregulation of HULC promotes contrast-induced nephropathy (CIN) via regulating signaling pathway of miRNA-512 and prostaglandin E1 (PGE1)

It has been shown that contrast-induced nephropathy (CIN) can be attenuated by the administration of PGE1. As an enzyme responsible for the production of PGE1, PTGS1 was confirmed in this study as a miR-512 target. Meanwhile, HULC has been identified as a competing endogenous RNA of miR-512. Therefore, in this study, we tested the diagnostic value of HULC and miR-512 in subjects with or without CIN. In addition, we evaluated the regulatory relationship among HULC, miR-512, PTGS1 and PGE1 in vitro. We enrolled 320 patients with coronary heart disease and divided them into a CIN group and a non-CIN group. Subsequently, we detected the differential expression of miR-512, HULC and PGE1 in the two groups. We also used a dual luciferase reporter assay to evaluate the regulatory relationship among HULC, miR-512, PTGS1 and PGE1 in THP-1 cells. In patients with CIN, the expression levels of HULC and PGE1 were lower, but the expression level of miR-512 was higher. MiR-512 could directly bind to and negatively regulate the expression of PTGS1 and HULC. The expression of HULC was positively correlated with the expression of PTGS1 and PGE1, while negatively correlated with the expression of miR-512. The findings of this study demonstrated that deregulation of lncRNA-HULC/miR-512/PTGS1/PGE1 might be involved in the pathogenesis of CIN.