Mechanism of TLR4 mediated immune effect in transfusion-induced acute lung injury based on Slit2/Robo4 signaling pathway.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is the infusion of blood or blood system. OBJECTIVE: To explore the mechanism of TLR4-mediated T cell immune effect in TRALI. METHODS: In this animal study, a mouse model of LPS-induced TRALI was established. Sixty adult C57/BL6 mice (wild-type, WT) were randomly divided into 5 groups: 1) normal WT type, 2) LPS control group of WT type lipopolysaccharide, 3) WT type TRALI group (LPS + MHC-I mAb), 4) (TLR4 antibody) lipopolysaccharide LPS control group, 5) (TLR4 antibody) TRALI group (LPS + MHC-I mAb). Mice were injected with LPS (0.1 mg/kg) and MHC-I mAb (2 mg/kg) into the tail vein. H&E staining was performed to detect pathological features. The myeloperoxidase (MPO) activity and the level of inflammatory cytokines in lung tissue homogenate supernatant were measured. Blood, spleen single-cell suspension, and bronchoalveolar lavage fluid were collected to detect the ratio of Treg and Th17 cells by flow cytometry. RT-PCR and WB were used to detect mRNA or protein expression. RESULTS: TLR4 mAb treatment alleviated the pathogenesis of LPS-induced TRALI in vivo, the MPO activity, and the level of proinflammatory factors in lung tissues. TLR4 exerted its function by changing of Treg/Th17 ratio via the SLIT2/ROBO4 signaling pathway and downregulating CDH5 and SETSIP. CONCLUSION: TLR4 mediates immune response in the LPS-induced TRALI model through the SLIT2/ROBO4 signaling pathway.

Analysis of the Application Value of X-Ray Digital Tomographic Fusion Technique in Urinary System Diseases.

OBJECTIVE: To explore the application value of the X-ray digital tomographic fusion technique in the diagnosis of urinary system diseases. METHODS: 500 patients with suspected urinary diseases in our hospital were examined by three methods: X-ray digital tomographic fusion imaging (DTS), intravenous pyelography (IVP), and abdominal plain film (KUB), and the image quality before and after tomographic fusion was objectively evaluated. The image quality could be divided into three grades: excellent, good, and poor. RESULTS: The image excellent rate of DTS (88%) was higher than that of IVP (27.5%). The sensitivity of DTS in the diagnosis of renal cyst and space occupying of the bladder was higher than that of IVP (P < 0.05). The accuracy rate of DTS in the diagnosis of urinary calculi was 93.33%, higher than 63.3% of KUB (P < 0.001). The accuracy rate of DTS in the diagnosis of ureteral stricture was 90%, higher than 65% of IVP (P=0.03). The accuracy of DTS in the diagnosis of hydronephrosis was higher than that of IVP and KUB (P < 0.05). CONCLUSION: In the examination of urinary system-related diseases, high-definition images can be obtained by timely using sectional fusion technology. Compared with conventional IVP, space occupying lesions such as the bladder and kidney can be displayed more clearly with the help of the tomographic fusion technique, which is helpful to improve the possibility of finding lesions and is of great significance in clinical application.

Chronic Pelvic Pain in Women: A Review.

IMPORTANCE: Chronic pelvic pain (CPP) is a challenging condition that affects an estimated 26% of the world's female population. Chronic pelvic pain accounts for 40% of laparoscopies and 12% of hysterectomies in the US annually even though the origin of CPP is not gynecologic in 80% of patients. Both patients and clinicians are often frustrated by a perceived lack of treatments. This review summarizes the evaluation and management of CPP using recommendations from consensus guidelines to facilitate clinical evaluation, treatment, improved care, and more positive patient-clinician interactions. OBSERVATIONS: Chronic pelvic pain conditions often overlap with nonpelvic pain disorders (eg, fibromyalgia, migraines) and nonpain comorbidities (eg, sleep, mood, cognitive impairment) to contribute to pain severity and disability. Musculoskeletal pain and dysfunction are found in 50% to 90% of patients with CPP. Traumatic experiences and distress have important roles in pain modulation. Complete assessment of the biopsychosocial factors that contribute to CPP requires obtaining a thorough history, educating the patient about pain mechanisms, and extending visit times. Training in trauma-informed care and pelvic musculoskeletal examination are essential to reduce patient anxiety associated with the examination and to avoid missing the origin of myofascial pain. Recommended treatments are usually multimodal and require an interdisciplinary team of clinicians. A single-organ pathological examination should be avoided. Patient involvement, shared decision-making, functional goal setting, and a discussion of expectations for long-term care are important parts of the evaluation process. CONCLUSIONS AND RELEVANCE: Chronic pelvic pain is like other chronic pain syndromes in that biopsychosocial factors interact to contribute and influence pain. To manage this type of pain, clinicians must consider centrally mediated pain factors as well as pelvic and nonpelvic visceral and somatic structures that can generate or contribute to pain.

Paracervical Block or Uterosacral Ligament Infiltration for Benign Minimally Invasive Hysterectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to estimate the efficacy of preemptive paracervical block or uterosacral ligament infiltration in reducing postoperative pain and opioid consumption after benign minimally invasive hysterectomy. DATA SOURCES: We searched MEDLINE, Cochrane Library, Embase, ClinicalTrials.gov, and Google Scholar from inception until February 2020. METHODS OF STUDY SELECTION: We identified randomized placebo-controlled trials assessing the primary outcome of pain and opioid consumption after paracervical block or uterosacral infiltration in benign laparoscopic, vaginal, or robotic hysterectomy. Two investigators evaluated studies for risk of bias and quality of evidence. TABULATION, INTEGRATION, AND RESULTS: We reviewed 219 abstracts; 6 studies met the inclusion criteria: 3 using paracervical block (2 vaginal and 1 laparoscopic) and 3 using uterosacral ligament infiltration (all vaginal). Two studies were included in the meta-analysis (both vaginal hysterectomy). Because of lack of numerical data, or comparison, the other 4 studies are reported in narrative form. Three controlled trials reported a moderate benefit from paracervical block up to 8 hours after vaginal and 4 hours after laparoscopic surgery. Meta-analysis could not be performed because of the lack of numerical data for pooling results or the lack of a laparoscopic hysterectomy comparison group. Three trials reported that uterosacral infiltration decreases pain up to 6 hours after vaginal hysterectomy, and meta-analysis pooling the results of 2 of these studies demonstrated improvement in pain up to 4 hours on a 0- to 100-mm visual analog scale for pain (-19.97 mm; 95% confidence interval, -29.02 to -10.91; P < 0.000). Five trials reported a moderate reduction in cumulative opioid use within 24 hours after vaginal surgery for both paracervical block and uterosacral infiltration. Meta-analysis was not performed for paracervical block because only 1 trial provided suitable data for pooling. Meta-analysis pooling the results of 2 trials of uterosacral infiltration demonstrated opioid consumption of 20.73 morphine milligram equivalents less compared with controls (95% confidence interval, -23.54 to -17.91; P < 0.000). CONCLUSIONS: There were a total of 6 randomized placebo-controlled studies evaluated in this study. Although a meta-analysis was unable to be performed for all studies because of lack of comparison groups or numerical data, there is evidence that preemptive uterosacral ligament infiltration may reduce postoperative pain and opioid consumption after vaginal hysterectomy. Our study does not allow us to make any substantive conclusions on the use of paracervical block in vaginal hysterectomy or the use of either type of injection in laparoscopic or robotic hysterectomy.

Withdrawal Notice: Molecular Mechanism of TLR4 Mediated T Cell Immune Effect in Transfusion-induced Acute Lung Injury based on Slit2/Robo4 Signaling Pathway

Bentham Science has decided to withdraw this article due to the purposeful breach of COPE guidelines and the copyright agreement by the authors as they had submitted this paper simultaneously to another journal. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policiesmain.php Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Opioid Prescription Usage after Benign Gynecologic Surgery: A Prospective Cohort Study.

STUDY OBJECTIVE: To compare the amount of opioids (tablets and morphine milligram equivalents [MMEs]) prescribed by physicians and used by patients after benign gynecologic surgery. DESIGN: Prospective cohort study. SETTING: Tertiary center: main hospital operating room and outpatient surgery center. PATIENTS: Women undergoing benign gynecologic surgery. INTERVENTIONS: Major and minor gynecologic surgeries. MEASUREMENTS AND MAIN RESULTS: The surgery groups were minor laparoscopy (Minor), major minimally invasive (Major), and laparotomy (Laparotomy). Demographic, medical, and surgical data were abstracted from electronic medical records. On postoperative day (POD) 7, women completed a telephone survey describing pain levels, prescription use, and satisfaction with pain control. Patients who continued to use opioids for pain relief were surveyed on POD 14. If use continued, patients were surveyed again on POD 28. The primary outcome was amount of opioid prescribed compared with opioid used. Of 193 screened participants 172 were enrolled (89%), and data were analyzed for 154 (90%): 59 (38%) Major, 71 (56%) Minor, and 24 (16%) Laparotomy. The median number of tablets and MMEs prescribed was lowest for the Minor group (Minor, 24 tablets; Major, 30 tablets; Laparotomy, 30 tablets [p <.01]; Minor, 150 MMEs; Major, 225 MMEs; Laparotomy, 225 MMEs [p = .01]). We found no difference in the number of tablets (Minor, 8; Major, 8; Laparotomy, 9; p = .77) or MMEs used (Minor, 45 MMEs; Major, 45 MMEs; Laparotomy, 55 MME; p = .81) between the groups. On POD 7 there was no difference in median numerical rating scale pain scores (Minor, 3; Major, 2; Laparotomy, 2; p = .07) or satisfaction with analgesia on POD 7 (p = .44), 14 (p = .87), and 28 (p = .18). Patients with prior chronic pain used more total amounts of opioids (68 MME vs 30 MME, p <.01) and were more likely to require opioid refill (odds ratio, 10.4; 95% confidence interval, 1.3-83.6) compared with those without a similar history. CONCLUSION: In this cohort, gynecologic surgeons prescribed nearly 3 times more opioid tablets and MMEs than was used by patients despite patients reporting similar levels of pain after minor and major surgeries.

Continuous vs. cyclic combined hormonal contraceptives for treatment of dysmenorrhea: a systematic review.

OBJECTIVE: This systematic review aims to evaluate the benefits of oral continuous combined hormonal contraceptives (CHCs) in managing dysmenorrhea by comparing randomized controlled trials (RCTs) evaluating the efficacy of continuous vs. cyclic CHC use for the following outcomes: (a) reducing dysmenorrhea duration and frequency, (b) severity, (c) recurrence and (d) interference with daily activity. STUDY DESIGN: Cochrane, PUBMED and Popline databases were searched from 1934 to 2018 for all relevant studies evaluating CHC for treatment of dysmenorrhea. A study was selected if it (a) compared continuous regimen vs. cyclic regimen of oral CHC, (b) measured dysmenorrhea as a primary or secondary outcome, (c) was an RCT and (d) was published in English. Due to differences in CHC used and outcome measurement, a systematic analysis of individual study results and a limited meta-analysis were conducted. RESULTS: Of 780 studies that were screened by title and abstract, 8 were included in the final analysis; 6 evaluated cyclic vs. continuous CHC, and 2 evaluated cyclic vs. extended/flexible CHC use. Quality of evidence was low for all outcome measures. Overall, compared to cyclic use, flexible/extended CHC resulted in 4 fewer days of dysmenorrhea. Studies revealed conflicting results for interference with daily activity, pain severity and pain recurrence. Side effects were few in both comparison groups. CONCLUSIONS: Continuous or extended/flexible CHC use may reduce dysmenorrhea duration compared to cyclic regimen; however, more rigorous research is needed. IMPLICATIONS: This systematic review shows that continuous CHC use may reduce dysmenorrhea duration compared to cyclic regimen, although the quality of evidence is low. Future double-blinded RCTs with more rigorous study design, consistent outcome measures and comprehensive outcome reporting are needed.

Malignant Endometrial Polyps in Uterine Serous Carcinoma: The Prognostic Value of Polyp Size and Lymphovascular Invasion.

OBJECTIVES: Uterine serous carcinoma (USC) involving an endometrial polyp and concurrent extrauterine disease is associated with poor prognosis. We examined the clinicopathological profiles of patients with stage 1A USC with and without polyp involvement and the role of polyp size and lymphovascular invasion (LVI) as prognostic indicators for extrauterine disease in patients with early USC. METHODS/MATERIALS: From 2002 to 2014, 242 patients with pure USC were identified. Fisher exact test was used for categorical variables. The student t test was used for means. Logistic regression was used to compute the odds ratio for continuous and categorical variables. RESULTS: Among stage 1A patients, the odds ratio of developing extrauterine disease for every 1 cm increase in polyp size is 1.368 (95% confidence interval, 1.034-1.810). Polyp size is only significantly associated with advanced stage disease for patients with myometrial invasion. A higher percent of LVI was found in stage 4 patients (31%). There is no survival or recurrence difference for stage 1 patients regardless of treatment or observation. CONCLUSIONS: Polyp size does not predict extrauterine disease for USC patients with disease in polyp only or disease in polyp and endometrium. Further study is needed to investigate whether presence of LVI is a prognostic factor.

Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress.

Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-ras(G12D) allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras-expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras-driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.

Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma.

NF-kappaB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-kappaB signalling during the past twenty years, the requirement for NF-kappaB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-kappaB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-kappaB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappaB inhibition. Furthermore, the inhibition of NF-kappaB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-kappaB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.

Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis.

Somatic activation of Ras occurs frequently in human cancers, including one-third of lung cancers. Activating Ras mutations also occur in the germline, leading to complex developmental syndromes. The precise mechanism by which Ras activation results in human disease is uncertain. Here we describe the phenotype of a mouse engineered to harbor a germline oncogenic K-rasG12D mutation. This mouse exhibits early embryonic lethality due to a placental trophoblast defect. Reconstitution with a wild-type placenta rescues the early lethality, but mutant embryos still succumb to cardiovascular and hematopoietic defects. In addition, mutant embryos demonstrate a profound defect in lung branching morphogenesis associated with striking up-regulation of the Ras/mitogen-activated protein kinase (MAPK) antagonist Sprouty-2 and abnormal localization of MAPK activity within the lung epithelium. This defect can be significantly suppressed by lentiviral short hairpin RNA (shRNA)-mediated knockdown of Sprouty-2 in vivo. Furthermore, in the context of K-rasG12D-mediated lung tumorigenesis, Sprouty-2 is also up-regulated and functions as a tumor suppressor to limit tumor number and overall tumor burden. These findings indicate that in the lung, Sprouty-2 plays a critical role in the regulation of oncogenic K-ras, and implicate counter-regulatory mechanisms in the pathogenesis of Ras-based disease.