Fluid retention-associated adverse events in patients treated with BCR::ABL1 inhibitors based on FDA Adverse Event Reporting System (FAERS): a retrospective pharmacovigilance study.

OBJECTIVES: This study aimed to conduct a thorough analysis of fluid retention-associated adverse events (AEs) associated with BCR::ABL inhibitors. DESIGN: A retrospective pharmacovigilance study. SETTING: Food and Drug Administration Adverse Event Reporting System (FAERS) database for BCR::ABL inhibitors was searched from 1 January 2004 to 30 September 2021. MAIN OUTCOME MEASURES: Reporting OR (ROR) and 95% CI were used to detect the signals. ROR was calculated by dividing the odds of fluid retention event reporting for the target drug by the odds of fluid retention event reporting for all other drugs. The signal was considered positive if the lower limit of 95% CI of ROR was >1. The analysis was run only considering coupled fluid retention events/BCR::ABL inhibitors with at least three cases. RESULTS: A total of 97 823 reports were identified in FAERS. Imatinib had the most fluid retention signals, followed by dasatinib and nilotinib, while bosutinib and ponatinib had fewer signals. Periorbital oedema (ROR=24.931, 95% CI 22.404 to 27.743), chylothorax (ROR=161.427, 95% CI 125.835 to 207.085), nipple swelling (ROR=48.796, 95% CI 26.270 to 90.636), chylothorax (ROR=35.798, 95% CI 14.791 to 86.642) and gallbladder oedema (ROR=77.996, 95% CI 38.286 to 158.893) were the strongest signals detected for imatinib, dasatinib, nilotinib, bosutinib and ponatinib, respectively. Pleural effusion, pericardial effusion and pulmonary oedema were detected for all BCR::ABL inhibitors, with dasatinib having the highest RORs for pleural effusion (ROR=37.424, 95% CI 35.715 to 39.216), pericardial effusion (ROR=14.146, 95% CI 12.649 to 15.819) and pulmonary oedema (ROR=11.217, 95% CI 10.303 to 12.213). Patients aged ≥65 years using dasatinib, imatinib, nilotinib or bosutinib had higher RORs for pleural effusion, pericardial effusion and pulmonary oedema. Patients aged ≥65 years and females using imatinib had higher RORs for periorbital oedema, generalised oedema and face oedema. CONCLUSIONS: This pharmacovigilance study serves as a clinical reminder to physicians to be more vigilant for fluid retention-associated AEs with BCR::ABL inhibitors.

Microbiota from healthy mice alleviates cognitive decline via reshaping the gut-brain metabolic axis in diabetic mice.

Diabetic cognitive decline has been associated with the gut microbial disorders, but its potential gut-brain axis mechanisms remain unclear. Herein we transplanted the gut microbiota from healthy mice into type 1 diabetic (T1D) mice and then investigated the effect of fecal microbiota transplantation (FMT) on cognitive function and the gut-brain metabolic axis. The results demonstrate that FMT from healthy mice effectively improved the learning and memory abilities in T1D mice, and significantly reduced neuroinflammation and neuron injury in the cortex and hippocampus. Moreover, FMT partly reversed the gut microbiota and gut-brain metabolic disorders, particularly glutamate metabolism. In vitro study, we found that glutamate notably decreased microglia activation and the expression levels of proinflammatory factor. Hence, our study suggests that glutamate serves as a key signal metabolite connecting the gut to brain and affects cognitive functions.

Retrospective study to assess the effect of epidural analgesia on labor progress and women's pelvic floor muscle from the perspective of electromyography.

OBJECTIVE: Epidural analgesia has been widely used as a form of pain relief during labor and its safety has been gradually recognized. However, few studies of the effect of epidural analgesia on the pelvic floor are known. Thus, we aim to analyze the effect of epidural analgesia on labor progress and women's pelvic floor muscle from the perspective of electromyography systematically. In addition, obstetric risk factors for dysfunction of pelvic floor muscle after vaginal delivery were also evaluated. METHODS: Childbirth data of 124 primiparas who gave first birth vaginally in our hospital and their pelvic floor function assessment results at postpartum 7 weeks were retrospectively collected. Pelvic floor muscle electromyogram screenings were performed by a biofeedback electro-stimulant therapy instrument. RESULTS: There was no significant difference in the percentage of episiotomy, forceps, artificial rupturing membrane, and the application of oxytocin, except perineal laceration. Woman who implemented epidural analgesia experienced a longer stage of labor. Statistically, there was no significant difference in the total score and pelvic floor muscle strength. The risk factors for the value of the pre-rest phase include the age of pregnant women, the fetal weight, and the length of the second stage while the value of the post-rest phase was only associated with the fetal weight and the length of the second stage. In addition, the value of type I muscles was associated with the gravida and fetal weight while the value of type II muscles was only associated with forceps. The sustained contraction was correlated with the gravida and the total scores had a significant correlation with forceps. CONCLUSION: Epidural analgesia during labor is approved to be a safe and effective procedure to relieve pain with very low side effects on the mode of labor and pelvic floor muscle. The assessment of pelvic floor muscle before pregnancy is beneficial in guiding the better protection of pelvic floor muscle function. According to the evaluation results, the doctors can control the associated risk factors as much as possible to reduce the injury of pregnancy and parturition to the pelvic floor.

Effects of lauromacrogol injection under contrast-enhanced ultrasound guidance on cesarean scar pregnancy: a prospective cohort study.

Background: Compared with the current commonly used pretreatment approaches, the therapeutic effect of contrast-enhanced ultrasound-guided sclerotherapy with lauromacrogol injection (CEUSL) on cesarean scar pregnancy (CSP) is not clear. This study aimed to investigate the clinical efficacy and safety of CEUSL compared with gelatin sponge uterine artery embolization (UAE) and UAE combined with methotrexate (UAEM) in the pretreatment of CSP to prevent massive bleeding during subsequent curettage. Methods: Sixty-four patients were divided into the CEUSL (n=20), UAE (n=22), and UAEM (n=22) groups. All patients with CSP underwent curettage and hysteroscopy after CEUSL, UAE, or UAEM pretreatment. The efficacy and safety indicators after pretreatment were analyzed. Results: Time for pretreatment [95% confidence interval (CI): 31.92-39.28] and hospitalization cost (95% CI: 7,852.32-9,063.23) were significantly decreased in the CEUSL group compared with that in the UAE (95% CI: 53.55-59.99% and 95% CI: 12,901.42-15,166.63, respectively) and the UAEM group (95% CI: 52.90-58.83 and 95% CI: 11,324.66-13,302.69, respectively; P<0.001). The beta human chorionic gonadotropin (ß-hCG) percentage decrease 24 hours later and the hospital stay were significantly decreased in the CEUSL group (95% CI: 0.65-0.70 and 95% CI: 3.32-4.58 days, respectively) compared with those in the UAE (95% CI: 0.67-0.74 and 95% CI: 4.06-5.84, respectively) or UAEM (95% CI: 0.62-0.68 and 95% CI: 4.12-5.88, respectively) groups (P<0.05). After pretreatment, there were significantly fewer patients (P<0.05) with fever (95% CI: -0.52 to -0.093), pelvic pain (95% CI: -0.427 to -0.018), increased white blood cell count (95% CI: -0.359 to 0.040), and hypersensitive C-reactive protein (hs-CRP) elevation (95% CI: -0.572 to -0.118) in the CEUSL group than in the UAE or UAEM groups. At follow-up, all patients resumed normal menstruation, with no residual gestational sac on ultrasound imaging or sequel. Conclusions: The pretreatment procedures were all technically successful, with good outcomes in different pretreatment procedures. Compared with UAE with or without methotrexate, CEUSL may be as effective and safe for pretreatment of CSP, with fewer adverse effects and shorter pretreatment time and hospital stay.

New-onset Systemic Lupus Erythematosus in a Woman with Previous Lymphoma during Late Pregnancy: a case report and literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) is most likely to occur during the first and second trimesters of pregnancy. There were few studies focused on the new-onset SLE during the late pregnancy or puerperium. SLE has been considered an important cause of thrombocytopenia. However, lymphoma may also be a cause of thrombocytopenia. Here, we reported a challenging case of new-onset SLE occurred at the gestational age of 33 weeks, and the pregnant woman suffered lymphoma before. CASE PRESENTATION: A 25-year-old primigravid Chinese woman with a medical history of non-Hodgkin lymphoma (NHL) suffered thrombocytopenia at 30+5 weeks of gestation. Her skin rashes occurred one week later. Her platelet count was decreased progressively. She had been misdiagnosed with the recrudescence of NHL. The final diagnosis of new-onset SLE was confirmed and a cesarean section was performed at the 34th week of pregnancy. Both the pregnant woman and the newborn were cured with good prognosis. CONCLUSION: SLE should be considered in a pregnant woman with a medical history of malignancy to rule out other diseases, especially the rheumatic immune diseases.

Depletion of acetate-producing bacteria from the gut microbiota facilitates cognitive impairment through the gut-brain neural mechanism in diabetic mice.

BACKGROUND: Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also have an effect on cognitive functions in T1D. Herein we used a non-absorbable antibiotic vancomycin to modify the gut microbiota in streptozotocin (STZ)-induced T1D mice and studied the impact of microbial changes on cognitive performances in T1D mice and its potential gut-brain neural mechanism. RESULTS: We found that vancomycin exposure disrupted the gut microbiome, altered host metabolic phenotypes, and facilitated cognitive impairment in T1D mice. Long-term acetate deficiency due to depletion of acetate-producing bacteria resulted in the reduction of synaptophysin (SYP) in the hippocampus as well as learning and memory impairments. Exogenous acetate supplement or fecal microbiota transplant recovered hippocampal SYP level in vancomycin-treated T1D mice, and this effect was attenuated by vagal inhibition or vagotomy. CONCLUSIONS: Our results demonstrate the protective role of microbiota metabolite acetate in cognitive functions and suggest long-term acetate deficiency as a risk factor of cognitive decline. Video Abstract.

Region-specific metabolic characterization of the type 1 diabetic brain in mice with and without cognitive impairment.

Type 1 diabetes (T1D) has been reported to cause cognitive decline, but brain metabolic changes during this process are still far from being fully understood. Here, we found that streptozotocin (STZ)-induced T1D mice exhibited impaired learning and memory at 11 weeks after STZ treatment but not at 3 weeks. Therefore, we studied metabolic alterations in six different brain regions of T1D mice with and without cognitive decline, and attempted to identify key metabolic pathways related to diabetic cognitive dysfunction. The results demonstrate that lactate had already increased in all brain regions of T1D mice prior to cognitive decline, but a decreased TCA cycle was only observed in hippocampus, cortex and striatum of T1D mice with cognitive impairment. Reduced N-acetylaspartate and choline were found in all brain regions of T1D mice, irrespective of cognitive decline. In addition, disrupted neurotransmitter metabolism was noted to occur in T1D mice before cognitive deficit. Of note, we found that the level of uridine was significantly reduced in cerebellum, cortex, hypothalamus and midbrain of T1D mice when cognitive decline was presented. Therefore, brain region-specific metabolic alterations may comprise possible biomarkers for the early-diagnosis and monitoring of diabetic cognitive decline. Moreover, down-regulated TCA cycle and pyrimidine metabolism could be closely related to T1D-associated cognitive impairment.

Expression of cellular adherent and invasive molecules in recurrent ovarian endometriosis.

OBJECTIVE: This study aimed to examine expression of cellular adhesion molecules and metalloproteinases of the extracellular matrix in ectopic endometrium for evaluating their roles in recurrence of endometriosis. METHODS: This study retrospectively analyzed 49 female patients (mean age: 30.1±5.5 years) with endometriomas who had undergone two separate operations. After a maximum follow-up of 80 months, all participants were divided into the recurrent group or nonrecurrent (control) group. Samples were immunostained for epithelial cadherin (E-cadherin), ß-catenin, urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-2, and extracellular matrix metalloproteinase inducer (EMMPRIN). RESULTS: In the recurrent group, E-cadherin concentrations in the membrane and cytoplasm of ectopic endometrial glandular cells were significantly reduced, while those of MMP-9 and EMMPRIN were higher than those in the control group. Additionally, uPA concentrations in the membrane and cytoplasm of ectopic endometrial glandular, stromal, and vascular endothelial cells were significantly higher in the recurrent group than in the control group. Tissue inhibitor of matrix metalloproteinase-2 and ß-catenin concentrations were similar between the groups. CONCLUSION: E-cadherin, MMP-9, and associated factors may contribute to development of endometriosis. E-cadherin, MMP-9, and uPA may act as potential markers for detection of recurrence of endometriosis.

Sex-specific metabolic alterations in the type 1 diabetic brain of mice revealed by an integrated method of metabolomics and mixed-model.

Type 1 diabetes (T1D) can cause brain region-specific metabolic disorders, but whether gender influences T1D-related brain metabolic changes is rarely reported. Therefore, here we examined metabolic changes in six different brain regions of male and female mice under normal and T1D conditions using an integrated method of NMR-based metabolomics and linear mixed-model, and aimed to explore sex-specific metabolic changes from normal to T1D. The results demonstrate that metabolic differences occurred in all brain regions between two genders, while the hippocampal metabolism is more likely to be affected by T1D. At the 4th week after streptozotocin treatment, brain metabolic disorders mainly occurred in the cortex and hippocampus in female T1D mice, but the striatum and hippocampus in male T1D mice. In addition, anaerobic glycolysis was significantly altered in male mice, mainly in the striatum, midbrain, hypothalamus and hippocampus, but not in female mice. We also found that female mice exhibited a hypometabolism status relative to male mice from normal to T1D. Collectively, this study suggests that T1D affected brain region-specific metabolic alterations in a sex-specific manner, and may provide a metabolic view on diabetic brain diseases between genders.

NMR-based metabolomics analysis identifies discriminatory metabolic disturbances in tissue and biofluid samples for progressive prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in men, but its metabolic characteristics during tumor progression are still far from being fully understood. METHODS: The metabolic profiles of matched tissue, serum and urine samples from the same patients were analyzed using a 1H NMR-based metabolomics approach. We identified several important metabolites that significantly altered at different stages of PCa, including benign prostatic hyperplasia (BPH), early PCa (EPC), advanced PCa (APC), metastatic PCa (MPC) and castration-resistant PCa (CRPC). Metabolic correlation networks among tissue, serum and urine samples were examined using Pearson's correlation. RESULTS: The changes in metabolic phenotypes during the progression of PCa were more noticeable in tissue samples when compared with serum and urine samples. Herein we identified a series of important metabolic disturbances, including decreased trends of citrate, creatinine, acetate, leucine, valine, glycine, lysine, histidine, glutamine and choline as well as increased trends of uridine and formate. These metabolites are mainly implicated in energy metabolism, amino acid metabolism, choline and fatty acid metabolism as well as uridine metabolism. We also found that energy metabolism in tumor tissues was positively associated with amino acid metabolism in serum and urine. Additionally, CRPC patients had a peculiar metabolic phenotype, especially decreased amino acid metabolism in serum. CONCLUSIONS: The present study characterizes metabolic disturbances in both tissue and biofluid samples during PCa progression and provides potential diagnostic biomarkers and therapeutic targets for PCa.

Antibiotic Exposure Disturbs the Gut Microbiota and Its Metabolic Phenotype Differently in Rats with Advanced-Stage Type 1 Diabetes and Age-Matched Controls.

Antibiotic-induced microbial perturbations alter host metabolism and affect host physiology. In this study, we aimed to investigate the effects of vancomycin (Vanc) and ciprofloxacin/metronidazole (CiMe) exposures on the gut microbiome and metabolome in the colonic content and tissue samples from advanced-stage type 1 diabetic (AST1D) rats and age-matched controls (AMCs) using 16S ribosomal RNA gene sequencing and nuclear magnetic resonance-based metabolomics. The results show that antibiotic effects on the gut microbiota were stronger in AMC rats relative to AST1D rats. These microbial alterations were accompanied by a series of metabolic changes, including energy metabolism, short-chain fatty acid metabolism, and amino acid metabolism. We found that AMC rats had a more notable metabolic response to antibiotic exposure than AST1D rats. Additionally, Vanc had a stronger impact on the gut microbiota and host metabolic phenotype versus CiMe. Therefore, our results reveal that antibiotic-induced shifts in the gut microbiome and metabolome are different between AST1D and AMC rats. If confirmed in human studies, these findings suggest that diabetic patients may need a specific strategy for antibiotic use in clinical practice.

Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus.

Cognitive decline is a common symptom at advanced stage of type 1 diabetes (T1D), but its potential pathogenesis remains unclear. In this study, therefore, we investigated changes in the gut microbiome and metabolome in serum and hippocampus between advanced-stage T1D (AST1D) rats with cognitive decline and age-matched controls (AMC), and explored the possible mechanism of the gut-microbiota-metabolite axis in T1D-induced cognitive dysfunction. The results demonstrated that AST1D rats possessed peculiar metabolic phenotypes in serum and hippocampus relative to AMC rats, as characterized by decreases in tricarboxylic acid (TCA) cycle and amino acid and choline metabolism as well as disturbances in glutamate/GABA-glutamine cycle and astrocyte-neuron metabolism. We also found that AST1D rats had higher relative abundances of Prevotella_9, Bacteroides and Lachnospiraceae_NK4A136_group as well as lower relative abundances of Clostridium_sensu_stricto_1, Romboutsia and Turicibacter than AMC rats. Microbiota-host metabolic correlation analysis suggests that metabolic alterations in serum and hippocampus may be modulated by the gut microbiota, especially Clostridium_sensu_stricto_1, Romboutsia and Turicibacter. Therefore, our study implies that the modification of host metabolism by targeting the gut microbiota may be a novel avenue for prevention and treatment of diabetic encephalopathy in the future.

Role of laparoscopy as a minimally invasive procedure in treatment of ruptured uterine scar during second-trimester induction of abortion.

Uterine rupture is an uncommon complication following termination of pregnancy and is usually accompanied by severe lower abdominal pain and shock caused by intra-abdominal hemorrhage. Laparotomy should be carried out promptly in order to repair the uterus or even to resect the uterus. Here we present a case of uterine rupture of a scarred uterus, which occurred during a second-trimester induced abortion. The patient was successfully treated by laparoscopy with the help of laparoscopic ultrasound. This case suggests an alternative, effective approach to the diagnosis and treatment of uterine rupture.

Uterine rupture disguised by urinary retention following a second trimester induced abortion: a case report.

BACKGROUND: Uterine rupture classically presents with severe abdominal pain, loss of fetal station, vaginal bleeding, and shock. CASE PRESENTATION: We present a case of uterine rupture presenting as significant urinary retention that occurred following a second trimester abortion induced with mifepristone and misoprostol. Uterine rupture was discovered unexpectedly on diagnostic laparoscopy. The uterine rupture was contained by dense adhesions between the omentum and bladder with the previous uterine cesarean hysterotomy scar. CONCLUSION: This case highlights the difficulties in diagnosis of abnormal placentation and an unusual presentation of uterine rupture. This case was managed successfully laparoscopically.

A multiple perspectives on atypical polypoid adenomyoma of uterus.

Atypical polypoid adenomyoma (APA) is a rare benign uterine tumor, with less than 200 cases have been reported in English literature. Although, it is considered as a benign lesion and treated conservatively previously, more and more cases show that APA has a high rate of recurrence or residual, and is found to precede the development of carcinoma. Given the data from present research on APA, the therapy of APA becomes more complex and must be cautious, especially for the nulliparous and premenopausal patients. In addition, because of the low incidence, studies on this disease are less, and the etiology and pathogenesis of APA is still unclear. In this review, we aim to summarize recent researches concerning APA from multiple perspectives, including clinical presentation, histogenesis, immunohistochemistry and molecular features, diagnosis and differential diagnosis, treatment opinion and prognosis, which may provide theory and clinical basis for the future clinical treatment and research of this rare disease.

RNAi-mediated blocking of ezrin reduces migration of ectopic endometrial cells in endometriosis.

Ezrin is a member of the ezrin-radixin-moesin (ERM) family of membrane-cytoskeletal linkage proteins. It is important for maintenance of cell shape, adhesion, migration and division. The overexpression of ezrin in some tumours is associated with increased cell migration that is mediated by the Rho/ROCK family of small GTPases. To investigate the role of ezrin in the migration of ectopic endometrial cells in endometriosis, we conducted real-time quantitative RT-PCR analysis of the eutopic and ectopic endometrium from women with endometriosis compared with those without the disease. RNAi, wound healing assays and western blot analysis of endometriotic cells were also included in this research. We found significantly higher levels of mRNA expression of ezrin (0.42 versus 0.27, P < 0.05), RhoA (0.99 versus 0.74, P < 0.05), RhoC (0.79 versus 0.43, P < 0.005) and ROCK1 (0.68 versus 0.38, P < 0.005) in the ectopic endometrial cells compared with the eutopic endometrial cells in endometriosis. Blocking ezrin with small-interfering RNA reduced the migration of ectopic endometrial cells with decreased expression of RhoA (42.68%), RhoC (58.42%) and ROCK1 (59.88%). Our results indicate that the over-expression of ezrin in endometriosis may play a significant role in the migration of endometrial cells of endometriosis, and the RhoC/Rock pathway may provide a promising treatment target.

Growth mechanisms of endometriotic cells in implanted places: a review.

Endometriosis is a common gynecological disease defined by extrauterine growth of endometrial glands and stroma. A variety of theories have been proposed to account for the pathogenesis of this disease, including retrograde transplantation theory, metaplasia of coelomic epithelium, hematogenic and lymphogenic spread, and remnants of the Mullerian duct. However, the etiopathology of endometriosis is still obscure. In this article, we aim to summarize recent researches concerning the growth mechanisms of endometriotic cells in implanted sites systematically, including the adhesion, invasion, angiogenesis, proliferation, apoptosis of endometriotic cells, variations of the immune molecules and endometriotic cells themselves, which may provide clues for future researches in the pathogenesis of endometriosis.