miR-125b reverses cisplatin resistance by regulating autophagy via targeting RORA/BNIP3L axis in lung adenocarcinoma.

The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma (LUAD), and chemoresistance, however, usually results in treatment failure and limits its application in the clinic. It has been shown that microRNAs (miRNAs) play a significant role in tumor chemoresistance. In this study, miR-125b was identified as a specific cisplatin (DDP)-resistant gene in LUAD, as indicated by the bioinformatics analysis and the real-time quantitative PCR assay. The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time. MiR-125b decreased the A549/DDP proliferation, and the multiple drug resistance- and autophagy-related protein expression levels, which were all reversed by the inhibition of miR-125b. In addition, xenografts of human tumors in nude mice were suppressed by miR-125b, demonstrating that through autophagy regulation, miR-125b could reverse the DDP resistance in LUAD cells, both in vitro and in vivo. Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L, which in turn inhibited autophagy and reversed chemoresistance. Based on these findings, miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.

A retrospective cohort study of the anesthetic management of postpartum tubal ligation.

BACKGROUND: Neuraxial anesthesia with reactivation of a labor epidural catheter is commonly utilized for postpartum tubal ligations (PPTL), although the optimal anesthetic approach is unknown. We assessed institutional anesthesia practices for PPTL, and evaluated the failure rates of reactivation of labor epidural catheters, de novo spinal anesthesia, and spinal anesthesia after failed blocks. METHODS: We conducted a single-center retrospective cohort analysis of 300 consecutive patients who underwent a PPTL and 100 having spinal anesthesia for cesarean delivery. Anesthetic management data (existing labor epidural catheter reactivation, de novo spinal anesthesia or general anesthesia) were collected from electronic medical records. Anesthetic block failure rates were determined for each anesthetic technique. RESULTS: The failure rate was 15% for de novo spinal anesthesia and 23% after failed reactivation of a labor epidural catheter or spinal anesthesia. The epidural catheter reactivation failure rate was 35%. The failure rate of spinal anesthesia for cesarean delivery was 4%. Drug dosage, epidural catheter use in labor, time since epidural catheter placement or delivery, labor neuraxial technique (combined spinal-epidural, epidural), supplemental top-up doses during labor, and anesthesiologist experience did not predict neuraxial anesthesia failures. CONCLUSIONS: Our analysis revealed an unexpectedly high neuraxial anesthesia failure rate even when de novo spinal anesthesia was used for PPTL. The results are consistent with other institutions' recent findings, and are higher than spinal anesthesia failure rates associated with cesarean delivery. Further studies are required to determine optimal anesthesia dosing strategies, and to understand the mechanisms behind high neuraxial anesthesia failures for PPTL.

Ethnicity, socio-economic deprivation and postpartum outcomes following caesarean delivery: a multicentre cohort study.

Disparities relating to postpartum recovery outcomes in different socio-economic and racial ethnic groups are underexplored. We conducted a planned analysis of a large prospective caesarean delivery cohort to explore the relationship between ethnicity, socio-economic status and postpartum recovery. Eligible patients were enrolled and baseline demographic, obstetric and medical history data were collected 18 h and 30 h following delivery. Patients completed postpartum quality of life and recovery measures in person on day 1 (EuroQoL EQ-5D-5L, including global health visual analogue scale; Obstetric Quality of Recovery-10 item score; and pain scores) and by telephone between day 28 and day 32 postpartum (EQ-5D-5L and pain scores). Socio-economic group was determined according to the Index of Multiple Deprivation quintile of each patient's usual place of residence. Data from 1000 patients who underwent caesarean delivery were included. There were more patients of Asian, Black and mixed ethnicity in the more deprived quintiles. Patients of White ethnicities had shorter postpartum duration of hospital stay compared with patients of Asian and Black ethnicities (35 (28-56 [18-513]) h vs. 44 (31-71 [19-465]) h vs. 49 (33-75 [23-189]) h, respectively. In adjusted models at day 30, patients of Asian ethnicity had a significantly greater risk of moderate to severe pain (numerical rating scale ≥ 4) at rest and on movement (odds ratio (95%CI) 2.42 (1.24-4.74) and 2.32 (1.40-3.87)), respectively). There were no differences in readmission rates or incidence of complications between groups. Patients from White ethnic backgrounds experience shorter postpartum duration of stay compared with patients from Asian and Black ethnic groups. Ethnic background impacts pain scores and recovery at day 1 postpartum and following hospital discharge, even after adjusting for socio-economic group. Further work is required to understand the underlying factors driving differences in pain and recovery and to develop strategies to reduce disparities in obstetric patients.

Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond.

Interest in vertebrate cardiac regeneration has exploded over the past two decades since the discovery that adult zebrafish are capable of complete heart regeneration, contrasting the limited regenerative potential typically observed in adult mammalian hearts. Undercovering the mechanisms that both support and limit cardiac regeneration across the animal kingdom may provide unique insights in how we may unlock this capacity in adult humans. In this review, we discuss key discoveries in the heart regeneration field over the last 20 years. Initially, seminal findings revealed that pre-existing cardiomyocytes are the major source of regenerated cardiac muscle, drawing interest into the intrinsic mechanisms regulating cardiomyocyte proliferation. Moreover, recent studies have identified the importance of intercellular interactions and physiological adaptations, which highlight the vast complexity of the cardiac regenerative process. Finally, we compare strategies that have been tested to increase the regenerative capacity of the adult mammalian heart. This article is categorized under: Cardiovascular Diseases > Stem Cells and Development.

Quantitative Three-dimensional Label-free Digital Holographic Imaging of Cardiomyocyte Size, Ploidy, and Cell Division.

Cardiac regeneration in newborn rodents depends on the ability of pre-existing cardiomyocytes to proliferate and divide. This capacity is lost within the first week of postnatal development when these cells rapidly switch from hyperplasia to hypertrophy, withdraw from the cell cycle, become binucleated, and increase in size. How these dynamic changes in size and ploidy impact cardiomyocyte proliferative potential is not well understood. In this study, we innovate the application of a commercially available digital holographic imaging microscope, the Holomonitor M4, to evaluate the proliferative responses of mononucleated diploid and binucleated tetraploid cardiomyocytes. This instrument coupled with the powerful Holomonitor App Suite software enables long-term label-free quantitative three-dimensional tracking of primary cardiomyocyte dynamics in real-time with single-cell resolution. Our digital holographic imaging results provide direct evidence that mononucleated cardiomyocytes retain significant proliferative potential as most can successfully divide with high frequency. In contrast, binucleated cardiomyocytes exhibit a blunted response to a proliferative stimulus with the majority not attempting to divide at all. Nevertheless, some binucleated cardiomyocytes were capable of complete division, suggesting that these cells still do retain limited proliferative capacity. By quantitatively tracking cardiomyocyte volume dynamics during these proliferative responses, we reveal that both mononucleated and binucleated cells reach a unique size threshold prior to attempted cell division. The absolute threshold is increased by binucleation, which may limit the ability of binucleated cardiomyocytes to divide. By defining the interrelationship between cardiomyocyte size, ploidy, and cell cycle control, we will better understand the cellular mechanisms that drive the loss of mammalian cardiac regenerative capacity after birth.

An injury-responsive mmp14b enhancer is required for heart regeneration.

Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent mmp14b endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of mmp14b. Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.

Retraction Note: Lixisenatide protects doxorubicin-induced renal fibrosis by activating wNF-κB/TNF-α and TGF-ß/Smad pathways.

The article "Lixisenatide protects doxorubicin-induced renal fibrosis by activating wNF-κB/TNF-α and TGF-ß/Smad pathways", by N.-F. Guo, Y.-J. Cao, X. Chen, Y. Zhang, Y.-P. Fan, J. Liu, X.-L. Chen published in Eur Rev Med Pharmacol Sci 2019; 23 (9): 4017-4026. DOI: 10.26355/eurrev_201905_17832-PMID: 31115031 has been retracted by the Editor in Chief for the following reasons: This paper has been questioned on PubPeer (https://pubpeer.com/publications/983F02C9C18817139AE18497C359FA). In particular, concerns were raised about Figures 2A and 5A as the figures result to overlap with previously published papers. The Editorial Office has contacted the corresponding author of the article to provide a reply to the comments on PubPeer and check the raw data. Still, the journal has yet to receive a reply. Therefore, considering the comments released on PubPeer and the lack of response from authors, the Editor in Chief no longer relies on the data presented and decided to withdraw the manuscript. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/17832.

Quality of recovery following childbirth: a prospective, multicentre cohort study.

To better understand outcomes in postpartum patients who receive peripartum anaesthetic interventions, we aimed to assess quality of recovery metrics following childbirth in a UK-based multicentre cohort study. This study was performed during a 2-week period in October 2021 to assess in- and outpatient post-delivery recovery at 1 and 30 days postpartum. The following outcomes were reported: obstetric quality of recovery 10-item measure (ObsQoR-10); EuroQoL (EQ-5D-5L) survey; global health visual analogue scale; postpartum pain scores at rest and movement; length of hospital stay; readmission rates; and self-reported complications. In total, 1638 patients were recruited and responses analysed from 1631 (99.6%) and 1282 patients (80%) at one and 30 days postpartum, respectively. Median (IQR [range]) length of stay postpartum was 39.3 (28.5-61.0 [17.7-513.4]), 40.3 (28.5-59.1 [17.8-220.9]), and 35.9 (27.1-54.1 [17.9-188.4]) h following caesarean, instrumental and vaginal deliveries, respectively. Median (IQR [range]) ObsQoR-10 score was 75 ([62-86] 4-100) on day 1, with the lowest ObsQoR-10 scores (worst recovery) reported by patients undergoing caesarean delivery. Of the 1282 patients, complications within the first 30 days postpartum were reported by 252 (19.7%) of all patients. Readmission to hospital within 30 days of discharge occurred in 69 patients (5.4%), with 49 (3%) for maternal reasons. These data can be used to inform patients regarding expected recovery trajectories; facilitate optimal discharge planning; and identify populations that may benefit most from targeted interventions to improve postpartum recovery experience.

Unlocking cardiomyocyte renewal potential for myocardial regeneration therapy.

Cardiovascular disease remains the leading cause of mortality worldwide. Cardiomyocytes are irreversibly lost due to cardiac ischemia secondary to disease. This leads to increased cardiac fibrosis, poor contractility, cardiac hypertrophy, and subsequent life-threatening heart failure. Adult mammalian hearts exhibit notoriously low regenerative potential, further compounding the calamities described above. Neonatal mammalian hearts, on the other hand, display robust regenerative capacities. Lower vertebrates such as zebrafish and salamanders retain the ability to replenish lost cardiomyocytes throughout life. It is critical to understand the varying mechanisms that are responsible for these differences in cardiac regeneration across phylogeny and ontogeny. Adult mammalian cardiomyocyte cell cycle arrest and polyploidization have been proposed as major barriers to heart regeneration. Here we review current models about why adult mammalian cardiac regenerative potential is lost including changes in environmental oxygen levels, acquisition of endothermy, complex immune system development, and possible cancer risk tradeoffs. We also discuss recent progress and highlight conflicting reports pertaining to extrinsic and intrinsic signaling pathways that control cardiomyocyte proliferation and polyploidization in growth and regeneration. Uncovering the physiological brakes of cardiac regeneration could illuminate novel molecular targets and offer promising therapeutic strategies to treat heart failure.

Prevalence and predictors for postpartum sleep disorders: a nationwide analysis.

OBJECTIVE: To describe the prevalence and predictors of postpartum sleep disorders. DESIGN: A retrospective cohort study. SETTING: Postpartum. POPULATION: Commercially insured women delivering in California (USA) between 2011 and 2014. METHODS: Using the Optum Clinformatics Datamart Database. MAIN OUTCOME MEASURES: Prevalence of a postpartum sleep disorder diagnosis with and without a depression diagnosis up to 12 months following hospital discharge for inpatient delivery. We also identified predictors of a postpartum sleep disorder diagnosis using multivariable logistic regression. RESULTS: We identified 3535 (1.9%) women with a postpartum sleep disorder diagnosis. The prevalence of sleep disorder diagnoses was insomnia (1.3%), sleep apnea (0.25%), and other sleep disorder (0.25%). The odds of a postpartum sleep disorder were highest among women with a history of drug abuse (adjusted odds ratio (aOR): 2.70, 95% confidence interval (CI): 1.79-4.09); a stillbirth delivery (aOR: 2.15, 95% CI: 1.53-3.01); and chronic hypertension (aOR: 1.82; 95% CI: 1.57-2.11). A comorbid diagnosis of a postpartum sleep disorder and depression occurred in 1182 women (0.6%). These women accounted for 33.4% of all women with a postpartum sleep disorder. The strongest predictors of a comorbid diagnosis were a history of drug abuse (aOR: 4.13; 95% CI: 2.37-7.21) and a stillbirth delivery (aOR: 2.93; 95% CI: 1.74-4.92). CONCLUSIONS: Postpartum sleep disorders are underdiagnosed conditions, with only 2% of postpartum women in this cohort receiving a sleep diagnosis using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Insomnia was the most common disorder and one-third of women diagnosed with a postpartum sleep disorder had a co-morbid diagnosis of depression. Future studies are needed to improve the screening and diagnostic accuracy of postpartum sleep disorders.

Obstetric services in the UK during the COVID-19 pandemic: A national survey.

BACKGROUND: The management of obstetric patients with coronavirus disease 2019 (COVID-19) due to human-to-human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires unique considerations. Many aspects of labour and delivery practice required adaptation in response to the global pandemic and were supported by guidelines from the Royal College of Obstetrics and Gynaecologists. The adoption and adherence to these guidelines is unknown. METHODS: Participating centres in "Quality of Recovery in Obstetric Anaesthesia study-a multicentre study" (ObsQoR) completed an electronic survey based on the provision of services and care related to COVID-19 in October 2021. The survey was designed against the Royal College of Obstetricians and Gynaecologists COVID-19 guidelines. RESULTS: One hundred and five of the 107 participating centres completed the survey (98% response rate representing 54% of all UK obstetric units). The median [IQR] annual number of deliveries among the included sites was 4389 [3000-5325]. Ninety-nine of the 103 (94.3%) sites had guidelines for the management of peripartum women with COVID-19. Sixty-one of 105 (58.1%) sites had specific guidance for venous thromboembolism (VTE) prophylaxis. Thirty-seven of 104 (35.6%) centres restricted parturient birthing plans if a positive diagnosis of COVID-19 was made. A COVID-19 vaccination referral pathway encouraging full vaccination for all pregnant women was present in 63/103 centres (61.2%). CONCLUSION: We found variability in care delivered and adherence to guidelines related to COVID-19. The clinical implications for this related to quality of peripartum care is unclear, however there remains scope to improve pathways for immunisation, birth plans and VTE prophylaxis.

Visualization of regenerating and repairing hearts.

With heart failure continuing to become more prevalent, investigating the mechanisms of heart injury and repair holds much incentive. In contrast with adult mammals, other organisms such as teleost fish, urodele amphibians, and even neonatal mammals are capable of robust cardiac regeneration to replenish lost or damaged myocardial tissue. Long-term high-resolution intravital imaging of the behaviors and interactions of different cardiac cell types in their native environment could yield unprecedented insights into heart regeneration and repair. However, this task remains challenging for the heart due to its rhythmic contraction and anatomical location. Here, we summarize recent advances in live imaging of heart regeneration and repair, discuss the advantages and limitations of current systems, and suggest future directions for novel imaging technology development.

Quantitative blood loss after vaginal delivery: a retrospective analysis of 104 079 measurements at 41 institutions.

BACKGROUND: Peripartum quantitative blood loss (QBL) measurement is recommended over visual estimation. However, QBL measurement after vaginal delivery has been inadequately evaluated. The primary aim of this study was to determine the characteristics of QBL measurements from a large, multicenter cohort of patients having vaginal deliveries. We also determined the incidence of postpartum hemorrhage (PPH) and the relationship between gravimetric QBL from weighed sponges vs. volumetric QBL from liquid drape or suction cannister contents. METHODS: Data were collected from 41 institutions in the United States of America that use an automated QBL device after vaginal delivery as part of routine care. The QBL device tracks cumulative blood loss based on gravimetry and volumetric V-drape assessment, automatically subtracting the dry weights of all blood-containing sponges, towels, pads and other supplies as well as the amniotic fluid volume. RESULTS: Between January 2017 and April 2020, 104 079 QBL values were obtained from patients having vaginal deliveries. Total median [IQR] QBL was 171 [61-362] mL. The PPH incidence, stratified by QBL, was 15.2% (>500 mL), 3.4% (>1000 mL), and 1.0% (>1500 mL). The contribution of QBL from V-drapes was 60.6±26.3% of total QBL. CONCLUSION: Results from this large set of QBL measurements and the PPH incidence provide normative "real-world" clinical care values that can be expected as hospitals transition from estimated blood loss to QBL to assess the blood loss at vaginal delivery.

Mending a broken heart with novel cardiogenic small molecules.

Adult mammalian cardiomyocytes are unable to proliferate to regenerate lost tissue after heart injury. Du et al., reporting in Cell Stem Cell, employ a FUCCI- and MADM-based system to screen for small molecules combinations that produced a collaborative effect on cardiomyocyte cycling and cytokinesis. The authors generate a cocktail of five small molecules that increase cardiomyocyte proliferation and regeneration in vitro and in vivo with high efficiency, and explore its potential in cardiac regenerative repair after myocardial infarction through a new potential pathway for cardiomyocyte cell-cycle re-entry.

Development and validation of a Portuguese version of Obstetric Quality of Recovery-10 (ObsQoR-10-Portuguese).

BACKGROUND: We aimed to develop and validate a Portuguese version of the Obstetric Quality of Recovery-10 (ObsQoR-10-Portuguese) patient-reported outcome measure and evaluate its psychometric properties. METHODS: After ethical approval, we recruited term pregnant women undergoing uncomplicated elective cesarean delivery in a single Brazilian institution. Women were invited to complete the translated ObsQoR-10-Portuguese and EuroQoL (EQ-5D) questionnaires (including a global health visual analog scale [GHVAS]) at 24 h (±6 h) following delivery, and a subset of women an hour later. We assessed validity and reliability of ObsQoR-10-Portuguese. RESULTS: One hundred thirteen enrolled women completed the surveys at 24 h and 29 women at 25 h (100% response rate). VALIDITY: (i) convergent validity: ObsQoR-10-Portuguese correlated moderately with EuroQoL score (r = -0.587) and GHVAS score (r = 0.568) at 24 h. (ii) Discriminant validity: ObsQoR-10 discriminated well between good versus poor recovery (GHVAS score ≥ 70 versus < 70; difference in mean scores 14.2; p < 0.001). (iii) Hypothesis testing: 24-h ObsQoR-10-Portuguese scores correlated with gestational age (r = 0.191; p = 0.043). (iv) Cross-cultural validity: differential item functioning analysis suggested bias in 2 items. Reliability: (i) internal consistency was good (Cronbach's alpha = 0.82 and inter-item correlation = 0.31). (ii) Split-half reliability was very good (Spearman-Brown Prophesy Reliability Estimate = 0.80). (iii) Test re-test reliability was excellent (intra-class correlation coefficient = 0.87). (iv) Floor and ceiling effects: < 5% women scored either 0 or 100 (lowest and highest scores, respectively). CONCLUSION: ObsQoR-10-Portuguese is valid and reliable, and should be considered for use in Portuguese-speaking women to assess their quality of inpatient recovery following cesarean delivery.

Accuracy of visual estimation of blood loss in obstetrics using clinical reconstructions: an observational simulation cohort study.

INTRODUCTION: Postpartum hemorrhage is the leading cause of maternal mortality worldwide, and optimal management requires accurate blood loss estimations. The aim of this study was to assess whether differences exist between visually estimated blood loss vs. actual blood loss based on delivery mode, blood volume or distribution/location and knowledge of patient's current cardiovascular status. METHODS: For this observational cohort study, photographs were taken of 18 blood loss scenarios for vaginal delivery and cesarean delivery, and six photographs were duplicated and annotated with maternal vital signs. Scenarios were categorized into 50% (500 mL), 100% (1000 mL) and 200% (2000 mL) of the defined blood loss volume for postpartum hemorrhage and the photographs were shown to participants to visually estimate blood loss volumes. RESULTS: The mean ±â€¯standard deviation estimates of actual 500 mL, 1000 mL and 2000 mL blood loss volumes were 1208 ±â€¯438 mL, 1676 ±â€¯630 mL and 2637 ±â€¯1123 mL, respectively (P <0.001 among groups). The difference was significantly greater in vaginal delivery than cesarean delivery scenarios (1064 ±â€¯849 mL vs. 284 ±â€¯456 mL; P <0.001). Estimated blood loss volume was not influenced by blood loss distribution/location, or by provider group or experience. The cardiovascular status of the patient impacted estimations only if tachycardia and hypotension were present. CONCLUSIONS: Most providers significantly overestimated blood loss volumes (by nearly 700 mL). Provider and scenario factors that impact inaccuracies in visual estimated blood loss identified in this study can be used to guide education and training.

Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration.

During the past two decades, the field of mammalian myocardial regeneration has grown dramatically, and with this expanded interest comes increasing claims of experimental manipulations that mediate bona fide proliferation of cardiomyocytes. Too often, however, insufficient evidence or improper controls are provided to support claims that cardiomyocytes have definitively proliferated, a process that should be strictly defined as the generation of two de novo functional cardiomyocytes from one original cardiomyocyte. Throughout the literature, one finds inconsistent levels of experimental rigor applied, and frequently the specific data supplied as evidence of cardiomyocyte proliferation simply indicate cell-cycle activation or DNA synthesis, which do not necessarily lead to the generation of new cardiomyocytes. In this review, we highlight potential problems and limitations faced when characterizing cardiomyocyte proliferation in the mammalian heart, and summarize tools and experimental standards, which should be used to support claims of proliferation-based remuscularization. In the end, definitive establishment of de novo cardiomyogenesis can be difficult to prove; therefore, rigorous experimental strategies should be used for such claims.

Thyroid hormone-dependent regulation of metabolism and heart regeneration.

While adult zebrafish and newborn mice possess a robust capacity to regenerate their hearts, this ability is generally lost in adult mammals. The logic behind the diversity of cardiac regenerative capacity across the animal kingdom is not well understood. We have recently reported that animal metabolism is inversely correlated to the abundance of mononucleated diploid cardiomyocytes in the heart, which retain proliferative and regenerative potential. Thyroid hormones are classical regulators of animal metabolism, mitochondrial function, and thermogenesis, and a growing body of scientific evidence demonstrates that these hormonal regulators also have direct effects on cardiomyocyte proliferation and maturation. We propose that thyroid hormones dually control animal metabolism and cardiac regenerative potential through distinct mechanisms, which may represent an evolutionary tradeoff for the acquisition of endothermy and loss of heart regenerative capacity. In this review, we describe the effects of thyroid hormones on animal metabolism and cardiomyocyte regeneration and highlight recent reports linking the loss of mammalian cardiac regenerative capacity to metabolic shifts occurring after birth.

[Studies on resistance of Schistosoma to praziquantel XVIII Sensitivity to praziquantel in filial generations of praziquantel-resistant and -sensitive Schistosoma japonicum mixed infections].

OBJECTIVE: To investigate the sensitivity of adult worms of filial generations from praziquantel-resistant and -sensitive Schistosoma japonicum mixed infections to praziquantel. METHODS: Mice were infected with the cercariae of an experimentally generated praziquantel-resistant S. japonicum isolate [median effective dose (ED50) = 277.4 mg/kg] and a laboratory-maintained praziquantel-sensitive S. japonicum isolate (ED50 = 99.6 mg/kg) at a mixture ratio of 1:1 and 2:1, which was maintained in the laboratory via the mouse-snail cycle for 8 generations. Then, mice were infected with the cercariae of the 8th filial-generation parasite, and grouped 35 days post-infection. Mice in the 5 treatment groups were given praziquantel treatment by gavage at a single oral dose of 37.5, 75, 150, 300 mg/kg and 600 mg/kg, while animals in the control group was administered orally with 2.5% cremophor EL. All mice were sacrificed 14 days post-treatment and adult worms were collected by perfusion of the portal vein. The worm burden reductions and praziquantel ED50 values were calculated. The praziquantel-resistant S. japonicum isolate generated from experimental induction with 12 rounds of praziquantel treatment with sub-curative doses was maintained in the laboratory via the mouse-snail cycle, and mice were infected with the cercariae of the 8th filial-generation parasite. The praziquantel ED50 value against the 8th filial-generation adults was measured. RESULTS: After mice were infected with the mixture of cercariae of PZQ-resistant and -sensitive S. japonicum isolates at a ratio of 1:1, the praziquantel ED50 was 135.2 mg/kg against the adults of the 8th filial-generation parasite. After mice were infected with the mixture of cercariae of PZQ-resistant and -sensitive S. japonicum isolates at a ratio of 2:1, the praziquantel ED50 was 129.2 mg/kg against the adults of the 8th filial-generation parasite. In addition, the praziquantel ED50 was 208.4 mg/kg against the adults of the 8th filial-generation S. japonicum without the selection pressure of praziquantel. CONCLUSIONS: Compared with the experimentally induced praziquantel-resistant S. japonicum isolate, the adult worms of the filial-generation S. japonicum show a reduced sensitivity to praziquantel in the same host following infection with the mixture of cercariae of praziquantel-resistant and -sensitive S. japonicum isolates. The adult worms of the filial generation of the praziquantel-resistant S. japonicum isolate without the selection pressure of praziquantel may still maintain the resistance to praziquantel.