PRA Levels Research Articles

Histocompatibility Testing: A Fundamental Aspect of Renal Transplant Workup

Histocompatibility testing is pivotal in any renal transplantation workup, aimed at enhancing prospective donor recipient compatibility and improving transplant outcomes. The evolution and advancement of histocompatibility testing, particularly HLA typing, have significantly improved its precision. This study outlines the historical progression from serologic to DNA-based HLA typing, emphasizing the role of HLA proteins in immune response. Anti-HLA antibodies, targeting HLA proteins, pose challenges in renal transplantation. Monitoring and managing these antibodies are critical for renal transplant success. Complement-dependent cytotoxicity crossmatch and flow cytometry crossmatch are essential techniques for assessing donor–recipient compatibility. Panel-reactive antibody assesses antibodies against a panel of donor antigens, often HLA. Higher PRA levels (percentage) complicate donor matching, requiring specialized protocols. Virtual crossmatch evaluates recipient anti-HLA antibodies against potential donors through synthetic beads. This approach predicts crossmatch outcomes by comparing antibody profiles, offering a valuable tool for the risk assessment of renal transplantation. Despite advancements, a comprehensive understanding of alloreactive immune responses requires a combination of assays, emphasizing the importance of a multifaceted approach in histocompatibility testing. This is an attempt to compile the relevant information, providing a basis for comparison in a clear and foundational format for histocompatibility testing laboratories.

DONOR-SPECIFIC ANTIBODIES AS A PREDICTOR OF GRAFT REJECTION AFTER LIVER TRANSPLANTATION

The main reason for graft loss is the rejection of the donor organ, which may occur at different time after transplantation and may be caused by the recipient’s organism reaction against donor’s human leukocyte antigen (HLA) proteins. Donor-specific antibodies (DSA) are produced in patient’s organism as a response to foreign HLA antigens. Aim. The purpose of our study was to evaluate the effects of already existed and/or de novo generated DSAs in liver transplantation as predictors of graft rejection and to establish an interconnection between blood biochemical parameters (Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin level) with the level of DSA in patients with liver transplant. Methods. xMAP-Luminex next generation flow cytometry technology and LABScreen Single antigen beads reagent (Onelambda, USA) were used for antiHLA determination. Total bilirubin level was detected photometrically. The activity of ALT and AST was determined spectrophotometrically on the automatic analyzer COBAS C 111 (Roche, Switzerland) in accordance with the manufacture’s instruction. Results. Detection of DSA and PRA was important at the same level as measurement of classical biochemical parameters of liver function (ALT, AST etc.) for monitoring of graft status and prevention of acute or chronical rejection and choosing correct immunosuppression protocol. Conclusions. The DSA and PRA levels as well as total bilirubin and ALT and AST activity corresponded to each other and could be used for comprehensive both pre- and post-transplantation screening of patients requiring liver transplantation or re-transplantation. Detection of DSA and PRA was important at the same level as measurement of classical biochemical parameters of liver function (ALT, AST etc.) for monitoring of graft status and prevention of acute or chronical rejection and choosing correct immunosuppression protocol.

Abstract 3584: Context matters: Genomic profiling of PR isoform-specific actions in breast cancer stem cells reveals novel therapeutic insights for ER+ breast cancer

Abstract Exposure to progesterone is a recognized risk factor for breast cancer, and PGR polymorphisms are associated with various malignancies. The two progesterone receptor (PR) isoforms, full length PR-B and truncated PR-A, are expressed from the PGR gene in breast tissue and play crucial roles in normal physiology. An imbalance in the expression ratio of these isoforms, favoring increased levels of PR-A, is common in breast cancer and is associated with resistance to tamoxifen in Luminal A-type tumors. Notably, PRs have recently been implicated in promoting endocrine resistance and driving the expansion of cancer stem-like cell (CSC) populations implicated in early dissemination and maintenance of metastatic populations. Because prior gene expression studies were primarily conducted in 2D culture conditions, the isoform-specific molecular and epigenetic mechanisms underlying PR actions in advanced ER+ breast cancer remain elusive. Our goal was to define progesterone-driven gene expression in CSC cells by employing transcriptomic profiling of T47D cells cultivated in spheroid-culture conditions (3D) expressing exclusively PR-A or PR-B. Utilizing CUT&RUN, we have mapped the genomic binding sites unique to each PR isoform and identified shared sites. This genomic data has been integrated with phenotypic studies in cells expressing a single PR isoform. Our findings indicate that PR-A acts as a regulator of the cell cycle and senescence, while PR-B plays a pivotal role in cell metabolism and intracellular signaling. We find little overlap between PR-regulated gene sets derived from the same hormone-treated cells harvested from 2D relative to 3D conditions. Our genomic profiling of PRs in this 3D model system has unveiled novel strategies to combat CSC outgrowth and late recurrence in luminal breast cancer patients. This work has shifted our prior understanding of the role of PRs in gene regulation within the CSC population, and offers potential insights for therapeutic interventions in ER+ breast cancer. Citation Format: Noelle E. Gillis, Thu H. Truong, Jessica Finlay-Schultz, Carol A. Sartorius, Carol A. Lange. Context matters: Genomic profiling of PR isoform-specific actions in breast cancer stem cells reveals novel therapeutic insights for ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3584.

Plasma aldosterone concentration / plasma renin activity ratio in patients with essential hypertension before treatment

Abstract Background The renin–angiotensin–aldosterone-sodium system, an important player in maintaining blood pressure, is influenced by antihypertensive drugs. However, the analysis of the renin-aldosterone-sodium system in hypertensive patients without adrenal adenoma without antihypertensive drugs is not still enough. Purpose We analyzed plasma aldosterone level, renin activity, serum potassium level, and serum sodium level in hypertensive patients without adrenal adenoma before treatment. Methods We measured plasma aldosterone concentration (PAC; pg/mL), plasma renin activity (PRA; ng/mL/h), serum potassium and sodium levels (mEq/L) in 456 consecutive new hypertensive patients untreated with antihypertensive drugs. We sampled all blood after 30 minutes bedrest. We excluded 28 cases with blood pressures less than 135/85 mmHg at rest, 4 patients with adrenal adenoma, and 3 patients with renovascular hypertension. We analyzed 421 patients with essential hypertension before treatment (232 males, mean age 56.5±12.8 years, and 189 females, mean age 61.0±13.5 years). Results There was a significant positive correlation between PRA and PAC (ρ=0.2445, p<0.001). There was a significant positive correlation between PAC/PRA ratio and serum sodium levels (ρ=0.1604, p=0.0027); however, no correlation was observed between PAC/PRA ratio and serum potassium levels. There were significant negative correlations between PRA and serum sodium levels (ρ=-0.1925, p<0.001). However, there was no correlation between PAC and serum sodium levels. On univariate analyses, a high PAC/PRA ratio (>200) was significantly associated with female (p<0.001), high serum sodium level (p=0.003), and low pulse rate (p=0.02). Multiple logistic analyses revealed that the most predictive independent factor for high PAC/PRA was female (p<0.001). On analyses of gender differences, the incidence rates of high PAC/PRA (>200) were 33.9% in females and 16.4% in males. There was a significant positive correlation between PRA and PAC in both genders (males: ρ=0.2731, p<0.001; females: ρ=0.1976, p=0.0064). In females, there was a significant positive correlation between PAC/PRA and serum sodium levels (ρ=0.2221, p=0.0043); however, there were no significant correlations between PAC/PRA and serum sodium levels in males. In females, there was a significant negative correlation between PRA and serum sodium levels (ρ=-0.2668, p<0.001); however, there were no significant correlations between PRA and serum sodium levels in males. Serum sodium levels were significantly higher in females than in males (p=0.02). Conclusion We revealed gender differences in the renin-aldosterone-sodium system in patients with essential hypertension before treatment.

Ureum and Creatinine Levels of Kidney Failure Patients Pra and Post Hemodialysis in Jayapura General Hospital Papua

Kidney failure is a worldwide health problem seen from the increase in incidence, prevalence, and the level of morbidity. Indonesia is one country with high rates of kidney failure. The purpose of this research was to determine the description of the results of urea and creatinine levels in patients with kidney failure before and after hemodialysis. The population used in this study was all renal failure patients who would carry out hemodialysis at the Jayapura Regional General Hospital (RSUD). The number of samples in this research is 30. The method of examining urea and creatinine used is the photometry method. This research was conducted from 10 May to 10 June 2018. To determine the levels of urea and creatinine before and after hemodialysis, the average value of the results of the examination was calculated and the results of the average urea level before hemodialysis 53.37 mg/dl and the average yield were obtained. Average after hemodialysis 18.83 mg/dl. The results of the average creatinine level of patients before 12.25 mg/dl and the average results after hemodialysis were 43.63 mg/dl. The results of the examination showed that there were no significant differences and that the results remained high. This research concluded that there was no significant difference between the examination of urea and creatinine levels before hemodialysis and after hemodialysis.

Plasma renin activity variation following admission predicts patient outcome in acute decompensated heart failure with reduced and mildly reduced ejection fraction

BackgroundPlasma renin activity (PRA) level at admission is reported to be a prognostic predictor of acute decompensated heart failure (ADHF) patients. Although PRA is affected during hospitalization by several factors including fluid volume and drug titration, whether the changes in PRA levels during hospitalization (ΔPRA) are associated with prognosis of ADHF patients are largely unknown. Purpose: Investigate the predictive impact of ΔPRA on the prognosis of ADHF patients with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF). Methods: Retrospectively analyzed consecutive 116 HFrEF and HFmrEF patients admitted for ADHF. PRA measurements were acquired at admission and at discharge. The primary outcome was a composite of cardiovascular death and HF re-hospitalization. Results: Out of 116 patients, 85 had PRA measurements both at admission and at discharge. Compared to admission, PRA level was significantly higher at discharge (0.8 (IQR 0.3–2.2) to 2.8 (IQR 1.0–7.2), p < 0.001). Tertiary groups ranked by PRA level on admission showed trend of poor prognosis in order of high, mid, and low PRA level (p = 0.07). On the contrary, PRA level at discharge significantly differentiated the prognosis and was poor in order of high, low, and mid (p = 0.026). Next, when the participants were divided into tertiary groups ranked by ΔPRA, prognosis worsened in the order of “minimal”, “decreasing”, and the “increasing” tier. Cubic splines analysis also indicate a similar tendency. Conclusions: In ADHF patients with HFrEF and HFmrEF, patients with minimal ΔPRA showed the better prognosis over the those with either increasing or decreasing.

Preserved oxytocin-induced myometrium contraction and sensitivity to progesterone inhibition following rat uterus thermal insult. Impact on fertility

Women seeking improved fertility often undergo diagnostic hysteroscopy that could cause uterine thermal injury with unclear impact on uterine contraction, embryo implantation and fertility. We tested whether uterine thermal insult adversely affects myometrium function and contraction related receptors, channels, junctional proteins and remodeling enzymes. Female Sprague-Dawley rats were anesthetized, the left uterine horn was infused with 85 ℃ hot saline (thermal Insult) and the right horn was infused with 25℃ warm saline (control) for 3 min. After 7-days recovery, uterine strips were prepared for tissue histology and measurement of contraction, and mRNA and protein levels of oxytocin receptor, progesterone (P4) receptor A (PR-A), membrane K+ channel TREK-1, junctional protein connexin-43 (CX-43) and matrix metalloproteinases MMP-2 and MMP-9. Uterine tissue histology showed cellular swelling and inflammatory cell infiltration immediately following thermal insult, and recovery with no difference from control 7-days later. KCl (96 mM) and oxytocin (10-13-10-7 M) caused significant contraction that was not different in thermal insult vs control uterine strips. Pretreatment with P4 (10-5 M) for 1 h caused marked inhibition of KCl and oxytocin contraction that was insignificantly greater in thermal vs control uterus. RT-PCR showed decreases in oxytocin receptor, PR-A, TREK-1, CX-43, MMP-2 and MMP-9 mRNA in thermal vs control uterus. Western blots showed decreases in oxytocin receptor, no change in TREK-1 and increased PRA, CX-43, MMP-2, and MMP-9 protein levels in thermal vs control uterus. To assess the impact on fertility, female rats were housed with male rats, and on gestational day 19, the litter size, pup weight and crown-rump length, and placenta weight were not different in thermal vs control uterus. Thus, after thermal insult-induced immediate inflammation and reduced heat-sensitive mRNA expression, the uterus undergoes a recovery and adaptation process involving preserved oxytocin-induced contraction, P4 inhibition and TREK-1 channels. The uterus self-healing process appears to require improved PR-A signaling, intercellular communication via CX-43 and tissue remodeling by MMP-2 and MMP-9. The uterine thermal recovery processes could be essential for maintaining fertility and future pregnancy outcome.

Does Open Chest After LVAD Surgery Affect Blood Transfusion Rates and PRA

<h3>Purpose</h3> Patients undergoing LVAD placement may experience right ventricular failure (RVF). Treatment strategies for RVF include medications, mechanical support, and inhaled agents. Some centers leave the chest open for first 24 to 48 hrs as a strategy to treat RVF. Open chest however has potential to increase blood transfusion rates. The aim of this study was to understand if open chest after LVAD affects blood transfusion rates and PRA levels at 3 months post implant. <h3>Methods</h3> Patients undergoing primary sternotomy with LVAD implantation between January 2017 and December 2020 were included in the study. 66 patients met those criteria. 45 patients had open chest and 21 had chest closed at the time of LVAD implantation. The Wilcoxon signed-rank test was utilized to find any deference in any blood product utilization and PRA pre and post implant. <h3>Results</h3> Patient baseline characteristics were similar between the two groups. Both groups had similar coagulation parameters, MELD scores and pre implant PRA. The overall amount of blood product utilization perioperatively was similar in the two groups. There was also no difference in PRA pre and post LVAD implant. 2 (4.4%) patients in the open chest group required RVAD implantation whereas 1(4.7%) patient in the closed chest group needed RVAD placement. There was no incidence of mediastinal infection or sternal infections in either of the two groups. <h3>Conclusion</h3> Open chest can be used as an effective treatment option for RVF and does not increase blood transfusion rates or elevated PRA post LVAD at 3 months. Bigger and multicenter studies are needed to better understand the effects of peri-operative blood transfusion on the PRA.

T-Cadherin, E-Cadherin, PR-A, and ER-α Levels in Deep Infiltrating Endometriosis.

The goal of this study was to compare the T-cadherin, E-cadherin, progesterone receptor (PR), and estrogen receptor (ER) staining levels of deep infiltrating endometriosis (DIE) tissue, ovarian endometriomas and normal endometrial tissues in the same individuals. The tissue sections of both DIE nodule(s) and endometrioma(s) of 15 cases were examined. As a control group, normal endometrial tissue sections of 23 cases were examined. T-cadherin, E-cadherin, ER-α, and PR-A staining levels of DIE, endometrioma tissues, and endometrial tissues were compared immunohistochemically. H -score was calculated to compare the expression of T-cadherin, E-cadherin, ER-α, and PR-A in immunohistochemical staining based on the percentage of cells stained at each intensity level. T-cadherin, E-cadherin, ER, and PR H -score were lowest in DIE tissue and highest in endometrial tissue ( P <0.0001, <0.0001, <0.0001, and <0.0001, respectively). In correlation analysis, a positive correlation was found between T-cadherin, E-cadherin, PR, and ER H -score ( P <0.0001 for each). T-cadherin, E-cadherin, ER, and PR H -score were lowest in DIE tissue and highest in endometrium tissue. We think that examination of DIE tissue and endometrioma tissue from the same individual excludes the possibility of an effect due to different genetic and environmental factors from different individuals. With the help of this exclusion we showed that DIE and endometrioma have different biological properties.

High plasma renin activity associates with obesity-related diabetes and arterial hypertension, and predicts persistent hypertension after bariatric surgery

BackgroundInformation about the renin–angiotensin–aldosterone system (RAAS) in obese individuals before and after bariatric surgery is scarce. Aim of this study was to analyze the RAAS in severely obese subjects, in relation to anthropometric and metabolic variables, with special reference to glucose tolerance.Methods239 subjects were evaluated at baseline, and 181 one year after bariatric surgery [laparoscopic gastric banding (LAGB)].ResultsAt baseline, renin (plasma renin activity, PRA) was increased from normal to glucose tolerance and more in diabetes, also correlating with ferritin. After LAGB, the decrease of PRA and aldosterone was significant in hypertensive, but not in normotensive subjects, and correlatied with decrease of ferritin. PRA and glucose levels were predictive of persistent hypertension 1 year after LAGB.ConclusionsThese data support the role of RAAS in the pathophysiology of glucose homeostasis, and in the regulation of blood pressure in obesity. Ferritin, as a proxy of subclinical inflammation, could be another factor contributing to the cross-talk between RAAS and glucose metabolism.

Classic CAH Presenting in Adulthood: Experience From a Tertiary Care Hospital in Eastern India

Abstract Classic CAH presenting in adulthood: Experience from a tertiary care hospital in Eastern India: Congenital adrenal hyperplasia(CAH) is one of the most common genetic disorders transmitted as an autosomal recessive trait. Of the various forms CAH due to 21-hydroxylase deficiency is most common. Based on the clinical phenotype CAH can be classified as classic and non-classic form. It is very rare for classic CAH to present in adulthood. We describe 3 patients with classic CAH presenting in adulthood. Case 1: 21 year old female presented with complaint of not attaining menarche. She had features of virilisation t with a modified Ferriman Gallwey(FG) score of 18/36, pubic hair stage 4 and atrophied breasts. Genital examination revealed clitoromegaly (CI-100 mm2) with Prader stage 2. Biochemical evaluation revealed elevated levels of serum testosterone (257.2 ng/dl), 17-hydroxy progesterone(332 ng/ml), DHEAS(417 µg/dl) and PRA of 34ng/ml/hr. Case 2: 30 year old female presented with complaint of primary infertility for 5 years. She had history of delayed menarche at 20 years and oligomenorrheic cycles since last 10 years. On examination there was hirsutism with a modified FG score of 15/36, pubic hair stage 5 with atrophied breasts. Genital examination revealed symmetrical genitalia with nonpalpable gonads, clitiromegaly(CI=135mm2) and a single urogenital opening (Prader stage 3). Biochemical evaluation revealed elevated levels of serum testosterone (812ng/dl), 17-hydroxy progesterone (164.8 ng/ml), DHEAS (503 µg/dl) and PRA of 42ng/ml/hr. Case 3: 26 year old female presented with complaint of noticing excessive hair growth in androgen dependent areas. On examination there was short stature,modified FG score 16/36, pubic hair stage 5 with atrophied breasts. Genital examination revealed clitoromegaly (CI=75mm2) with Prader stage 2. Biochemical evaluation revealed elevated levels of serum testosterone (254.2 ng/dl), 17-hydroxy progesterone (351.8 ng/ml), DHEAS (296.2 µg/dl) and PRA of 30ng/ml/hr. Karyotype in all the three patients was 46,XX. All our patients had serum testosterone values in tumorous range, however imaging studies didnot reveal any evidence of malignancy in the adrenals except for occurrence of a single right adrenal nodule of size 2×2.1cm with precontrast HU of &amp;lt;10 and absolute contrast washout of &amp;gt;60% in case 2. Based on clinical and biochemical findings a diagnosis of classic CAH was made. They were started on corticosteroid and mineralocorticoid replacement. In all of the above three patients none of them had been evaluated for the presenting complaints prior to visiting our centre. Failure of implementation of neonatal screening for CAH in many centres in India and the social stigma associated with genital ambiguity are contributory to the delay in diagnosis of CAH.

The Influence Mechanism of Abnormal Immunophilin FKBP52 on the Expression Levels of PR-A and PR-B in Endometriosis Based on Endometrial Stromal Cell Model in Vitro

ABSTRACT As a chaperone protein of progesterone receptor (PR), FK-506 Binding Protein 52 (FKBP52) can enhance the activity of PR, but the mechanism of FKBP52 affecting PR expression levels is difficult to clarify. Here, we report a novel in vitro model of ectopic endometrial stromal cells (ESCM) established through the primary culture method of endometrial stromal cells, which is used to study the details of relationship between FKBP52 abnormality and PR expression level in endometriosis (Ems). At the same time, the clinical study of the relationship between FKBP52 and PR expression levels in endometriosis patients was used to verify our conclusions. The results showed that the expression levels of PR-A mRNA and protein in endometriosis are positively correlated with FKBP52 and the abnormality of FKBP52 leads to the decrease of PR-B mRNA and protein expression. When FKBP52 was deleted or reduced, the expression levels of m RNA and protein of PR-A and PR-B have decreased leading to the proliferation of ectopic endometrium cells (ESC) and the occurrence of endometriosis, which is consistent with the expression levels of clinical endometriosis patients and fully confirms our conclusions and reliability of the model, and has great guiding significance for the research of Ems disease occurrence mechanism and clinical treatment.

Time to second kidney transplantation in young adults after failed pediatric kidney transplant.

Under the current kidney allocation system, pediatric candidates listed prior to age 18 receive priority for high-quality deceased donor organs. This has resulted in a decline in living donor transplantation in pediatrics, despite superior outcomes of living donor transplantation. Due to a young age at transplantation, most pediatric kidney transplant recipients require re-transplantation. The effects of a previously failed deceased donor vs a previously failed living donor on re-transplant candidates are unknown. Using the United Network for Organ Sharing database, we examined 2772 re-transplant recipients aged 18-30years at time of relisting for second KT from 2000 to 2018 with history of prior pediatric KT (age≤18years). PFLDKT recipients compared to those with PFDDKT had shorter median waiting times and dialysis time regardless of their second donor type (14.0 vs 20.3months, and 19.1 vs 34.5months, respectively). PFLDKT recipients had higher re-transplant rates (adjusted HR 1.17, 95% CI 1.09-1.27, and adjusted HR 1.05, 95% CI 0.95-1.15 when calculating from time of relisting and time of returning to dialysis, respectively). PFDDKT recipients were more likely to have higher median PRA levels (90% vs 73%). Re-transplant candidates who received a previous deceased donor as a child had a higher level of sensitization, longer waiting time, and dialysis exposure compared to those with PFLDKT. Among primary pediatric kidney transplant candidates, consideration should be considered for living donor transplantation, despite the priority for deceased donor organs, to avoid increased sensitization and longer waiting times for with re-transplantation.

Clinical efficacy, safety and tolerability of Aliskiren Monotherapy (AM): an umbrella review of systematic reviews

BackgroundAliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial.ObjectiveTo evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM).MethodsAn umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author.ResultsEventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, − 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, − 0.21 to − 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, − 0.8 to − 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16).ConclusionWe found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant.Trial registrationStudy has been registered in PROSPERO (CRD42019142141).

Application value of sufentanil combined with propofol anesthesia in basal ganglia intracerebral hemorrhage

Objective To investigate the clinical value of sufentanil combined with propofol anesthesia in cerebral hemorrhage in basal ganglia. Methods From November 2015 to June 2018, 100 patients with cerebral hemorrhage in the basal ganglia of the People's Hospital of Shanxi Province were enrolled and randomly divided into two groups according to the digital table, with 50 cases in each group.The control group received fentanyl+ propofol, and the study group received sufentanil + propofol.At T0 (before induction of anesthesia), T1 (after anesthesia induction), T2 (after tracheal intubation), T3 (surgery), the hemodynamic parameters[mean arterial pressure (MAP), heart rate (HR)] level, postoperative recovery time (recovery of spontaneous breathing, recovery time and extubation time), preoperative and postoperative 6 h serum angiotensin Ⅱ (Ang Ⅱ), renin activity (PRA), neuron specific enolase (NSE) ), glial fibrillary acidic protein (GFAP) levels, the incidence of adverse reactions of the two groups were counted. Results (1)Hemodynamics: MAP and HR levels in the two groups were higher in T1, T2 and T3 than those in T0(all P<0.05), and HR and MAP in the study group were lower than those in the control group (all P<0.05). (2)Postoperative recovery: the time of extubation, recovery time and spontaneous breathing time of the study group were (12.42±3.27)min, (9.10±1.95)min, (7.32±2.23)min, respectively, which were shorter than those of the control group[(15.30±3.35)min, (12.67±2.18)min, (8.96±2.48)min] (t=4.350, 8.631, 3.477, all P<0.05). (3)Serum Ang Ⅱ and PRA: the serum Ang Ⅱ and PRA levels in the two groups at 6 h after surgery were higher than those before surgery(all P<0.05), and Ang Ⅱ, PRA levels of the study group were lower than those of the control group (t=4.350, 8.631, 3.477, all P<0.05). (4) Serum NSE and GFAP: the serum NSE and GFAP levels in the two groups at 6 h after surgery were higher than those before surgery(all P<0.05), and NSE, GFAP levels of the study group were lower than those of the control group (all P<0.05). (5) Adverse reactions: the incidence of adverse reactions in the study group [12.0%(6/50)] was lower than that in the control group [28.0%(14/50)] (χ2=4.000, P<0.05). Conclusion Sufentanil combined with propofol anesthesia in patients with cerebral hemorrhage in the basal ganglia can promote hemodynamic fluctuations, inhibit the increase of Ang Ⅱ and PRA, NSE and GFAP, and has less adverse reactions and high security. Key words: Cerebral hemorrhage; Anesthesia; Blood pressure; Heart rate; Hemodynamics; Sufentanil; Propofol

Differential quantitative proteomics reveals key proteins related to phenotypic changes of breast cancer cells expressing progesterone receptor A

Progesterone receptor isoforms A and B exert different biological effects in breast cancer cells. Alteration of PRA/PRB ratio is often observed during breast cancer progression. High PRA/PRB ratios in breast cancer patients are associated with resistance to chemotherapy and poor prognosis. While it is well accepted that PRA and PRB regulate different sets of genes, how the expression of PRA and PRB alters breast cancer proteomes has not been fully investigated. To directly investigate the effects of PR isoform expression on the breast cancer proteome, both in the presence and absence of progestin, PRA and PRB were independently stably expressed in T47DC42 PR-null breast cancer cells using a doxycycline (Dox)-regulated promoter. Dox induction dose-dependently increased PRA and PRB expression. Dox-induced PRA and PRB showed normal receptor localization and were transcriptionally active. Differential quantitative proteomic analysis by stable isotope dimethyl labeling was performed to quantitatively examine how PR isoforms altered global breast cancer proteomes. Cells expressing PRA in the absence of progestin were enriched in proteins involved in the TCA cycle and enriched in proteins involved in glycolysis in the presence of progestin, whilst cells expressing PRB in the absence and presence progestin were significantly enriched in proteins involved in the cell cycle and cell apoptosis pathways. This proteomic data revealed a link between PR isoform expression and alteration in cell metabolism, cell proliferation, and apoptosis. The enrichment of proteins involved in the glycolytic pathway in breast cancer cells expressing PRA is consistent with stem cell-like properties, previously reported in PRA-rich breast cancer cells. Moreover, compared to liganded PRB, liganded PRA differentially upregulated proteins involved in chromatin remodeling, such as linker histone H1.2. Silencing H1.2 gene expression suppressed PRA-mediated cell proliferation and promoted G2/M and S phase entry of the cell cycle. Additionally, liganded PRA upregulated the expression of cathepsin D (CTSD) protease, whose expression is associated with poor prognosis in breast cancer patients. Together, our data demonstrated that the expression of PRA or PRB dramatically and differentially altered breast cancer cell proteomes. These isoform-specific changes in the breast cancer proteome will help to explain the distinct phenotypic properties of breast cancer cells expressing different levels of PRA and PRB.

Effect of combined spinal epidural anesthesia with different doses of ropivacaine on maternal and child RAAS system in cesarean section

Objective To investigate the impact of different doses of ropivacaine combined with spinal epidural anesthesia for maternal and neonatal renin activity, angiotensin II and aldosterone in the cesarean section system. Methods From June 2015 to April 2017, 140 parturients undergoing cesarean section in the Maternal and Child Health Hospital of Anji County were selected in the research.Combined spinal-epidural ropivacaine were used in all patients during cesarean section anesthesia, and according to different dose of ropivacaine, the patients were divided into A group (8mg), B group(10mg), C group(12mg), D group(15mg), with 35 cases in each group.The analgesic effects of four groups and the changes of each index in the RAAS system of mother and baby in each time period were compared. Results All fetuses were delivered smoothly.Compared the analgesic effect of four groups, the analgesic effect of IV grade in A group was the lowest percentage [17.14%(6/35)], B, C group had similar proportions [42.86%(15/35), 45.71%(16/35)], D group had the highest proportion [71.42%(25/35)], the maternal proportion of anesthesia effect of IV grade in D group was significantly better than those in A, B, C group, and the differences were statistically significant(χ2=20.90, 5.83, 4.77, all P<0.05). There was no significant change in the level of PRA in each period of A group.The PRA levels in B, C and D group at T1-T3 time were significantly lower than T0(t=14.64, 37.04, 3.97; 15.34, 29.93, 4.73; 25.83, 33, 5.23; 12.47, 8.94, 5.96, all P< 0.05). AT-II in A group at T1-T3 time was decreased, but there was no statistically significant difference compared with T0.AT-II levels in B, C, D group at T1-T3 time were significantly lower than that of T0(t=5.95, 5.98, 3.19; 5.86, 5.54, 4.77; 7.96, 5.47, 6.13; all P<0.05). No significant changes in ALD level of A group in every period of time; ALD levels in B, C, D group at T1-T3 time period were significantly lower than that of T0(t=3.75, 4.92, 2.47; 4.08, 5.77, 2.05; 3.94, 6.13, 3.55, all P<0.05). The fetal umbilical artery and vein of PRA, AT-II and ALD concentration were measured in maternal value range. Conclusion When combined with 10-15 mg ropivacaine for combined spinal epidural anesthesia, the RAAS system of mother and baby is more stable, and the effect of anesthesia and analgesia is better. Key words: Cesarean section; Ropivacaine; Renin-angiotensin system; Aldosterone; Anaesthesia, union

The Effect of Imbalanced Progesterone Receptor-A/-B Ratio on Gelatinase Expressions in Endometriosis.

BackgroundGelatinases degrade extracellular matrix (ECM) components to allow for physiological remodeling and contribute to pathological tissue destruction in endometriosis. It is known that the function of gelatinases is resistant to suppression by progesterone in endometriosis. The ability of progesterone to impact gene expression depends on the progesterone receptor-A/-B (PR-A/PR-B) ratio. An imbalanced PR-A/PR-B ratio in endometriotic tissue may be the result of the differential expression of MMP-2 and MMP-9, which could be important in the etiology and pathogenesis of the disease. Hence, we decided to study the association of PR-A/PR-B ratio and gelatinases expression in endometriosis.Materials and MethodsIn this prospective case-control study, we enrolled 40 women, 20 in the case group who were diagnosed with stage III/IV endometriosis and 20 normal subjects without endometriosis (controls) who referred to Royan Institute, Tehran, Iran during 2013-2014. We obtained 60 tissue samples [ectopic (n=20), eutopic (n=20), and normal endometrium (n=20)]. RNA was extracted from the tissue samples in order to analyze PR-A, PR-B, MMP-2, and MMP-9 mRNA levels through real-time polymerase chain reaction (PCR).ResultsThere was significantly lower expression of the PR-B isoform in ectopic tissues compared to the control (P=0.002) and eutopic endometrium (P=0.006) tissues. PR-A expression was higher, but not significantly so, in the same ectopic and eutopic endometrium tissues compared to the control tissues (P=0.643). There was significant over- expression of MMP-9 in ectopic samples compared to control (P=0.014) and eutopic endometrium (P=0.012) samples. The PR-A/PR-B ratio was not significantly higher in either eutopic or ectopic samples compared to the control samples (P=0.305).ConclusionOur findings support an altered PR-B expression in endometriosis, which may be associated with MMP-9 overexpression. This finding can be important for disease pathogenesis.

The toxicity and efficacy evaluation of different fractions of Kansui fry-baked with vinegar on Walker-256 tumor-bearing malignant ascites effusion rats and normal rats

Ethnopharmacological relevanceKansui, the root of Euphorbia kansui S.L.Liou ex S.B.Ho (E.kansui), is a classical traditional Chinese medicine (TCM) with certain toxicity. According to the theory of TCM, kansui fry-baked wtith vinegar (VEK) possesses low toxicity and mild diuretic and purgative efficacy. In clinical practice, it is commonly used for the treatmtablent of ascites and oliguria. The present study aimed to evaluate the toxicity and efficacy of different fractions of VEK and reveal the underlying material basis by employing an animal model of malignant ascites effusion (MAE) in rats. Materials and methodstaThe MAE rats as the model were constructed in SPF male wistar rats by intraperitoneal injection of Walker-256 tumor cells. The MAE rats were used and randomly divided into the control group (normal rats), control groups with different fractions (VEKA, VEKB, VEKC and VEKD), model group (MAE rats), positive control group (model group with furosemide), model groups with different fractions (VEKA, VEKB, VEKC and VEKD). Histopathological observation was used to confirm Walker-256 tumor-bearing organ injuries in rats. For the efficacy evaluation, the ascites and urine volumes, the urinary electrolyte concentrations (Na+, K+ and Cl-) and pH, the ascites levels of pro-inflammatory cytokines (IL-2, IL-6, TNF-α, IFN-γ and VEGF), PRA, the serum levels of Ang II, ALD and ADH, as well as AQP8 protein expression in the gastrointestinal tract were detected. Furthermore, different levels of indicators were measured in the toxicity evaluation of different fractions both on normal and model rats, including serum liver enzymes (AST and ALT), serum oxidative damage parameters (GSH, MDA, LDH and SOD), expressions of inflammatory parameters (NF-κB, ICAM-1 and E-cadherin) and apoptosis signals (caspase-3, −8, −9, Bcl-2 and Bax) in the liver and gastrointestinal tract. ResultsWalker-256 tumor-bearing malignant ascites effusion rats showed obvious hepatic and gastrointestinal injuries by histopathological observation. In the efficacy evaluation, model rats treated with VEKB and VEKC showed significant urine increase (VEKB, P < 0.01; VEKC, P < 0.01) and ascites reduction (VEKB, P < 0.01; VEKC, P < 0.01). These two fractions also balanced the concentrations of Na+, K+ and Cl- in urine (VEKB, all P < 0.05; VEKC, all P < 0.05), remarkably decreased urinary pH (VEKB, P < 0.01; VEKC, P < 0.01), and reduced the ascites levels of IL-2, IL-6, TNF-α, IFN-γ and VEGF (VEKB, all P < 0.01; VEKC, all P < 0.01) in the model rats. Moreover, levels of PRA, the serum Ang II, ALD and ADH of model rats were decreased after treated by VEKB and VEKC (VEKB, all P < 0.05; VEKC, all P < 0.05). Meanwhile, the expression of gastrointestinal AQP8 of the model rats was also enhanced after treated by VEKB and VEKC (VEKB, P < 0.01; VEKC, P < 0.01). In the toxicity evaluation, although VEKB and VEKC caused toxic indexes moved to the worse aspects in normal rats, nearly all of these indicators notably improved in the model rats. Additionally, VEKA showed no effect on the indicators, either in the efficacy evaluation or in the toxicity evaluation. And VEKD could significantly improve some indicators (urine volume, concentration of K+ in urine, serum MDA, AI and caspase-9) in MAE rats. ConclusionsVEKB and VEKC were demonstrated a significant efficacy in treating malignant ascites effusion, which could reduce hepatic and gastrointestinal damage on the model rats but cause the same damage to the normal. These data embody the traditional Chinese medicine application principle: You Gu Wu Yun. And these results will provide reference for the safer and better clinical utilization of kansui.

Control of Progesterone Receptor-A Transrepressive Activity in Myometrial Cells: Implications for the Control of Human Parturition.

Uterine quiescence during pregnancy is maintained by progesterone primarily via signaling mediated by the type-B progesterone receptor (PR-B) in myometrial cells. Withdrawal of PR-B-mediated progesterone activity is a principal trigger for labor. One mechanism for PR-B withdrawal is by inhibition of its activity by the type-A PR (PR-A) isoform in myometrial cells. We hypothesized that human parturition involves hormonal interactions that induce the capacity for PR-A to inhibit PR-B in myometrial cells and that pro-inflammatory cytokines are major regulators of this process. We tested this hypothesis in an immortalized human myometrial cell line, hTERT-HMA/B, in which levels of PR-A and PR-B can be experimentally controlled. We found that the capacity for PR-A to repress PR-B, assessed by activity of a transiently transfected reporter DNA controlled by the progesterone response element, and expression of FK506 binding protein 5 ( FKBP5) an endogenous PR-B responsive gene, was increased by serum supplementation and interleukin-1β. In pregnant uterus, FKBP5 was detected exclusively in myometrial cells and its expression decreased with advancing gestation and in association with the onset of labor at term. These findings suggest that in myometrial cells the repressive activity of PR-A on PR-B increases with advancing gestation and is induced by pro-inflammatory cytokines. This may be a key mechanism linking inflammation with the onset of labor.