Oxidative stress biomarkers (OSBs) may be strongly associated with disease progression and recurrent pregnancy loss (RPL). However, the research on associations of most OSBs (e.g., 8-nitroguanine ...8-NO
Gua and 4-hydroxy-2-nonenal-mercapturic acid HNE-MA) with RPL is limited. Therefore, we aimed to investigate the effect of OSBs exposure on RPL risk by performing a case-control study.
We use our established dataset, Taiwan Recurrent Pregnancy Loss and Environmental Study (TREPLES), which included 514 Taiwanese reproductive age women (aged 20-50 years; 397 cases and 117 controls) from National Cheng Kung University Hospital. RPL is clinically defined by a history of two or more consecutive miscarriages, where a miscarriage is defined as the termination of pregnancy before 20 weeks of gestation. The urinary levels of several OSBs (e.g., 8-hydroxy-2'-deoxyguanosine 8-OHdG, 8-NO
Gua, 8-isoprostaglandin F
8-isoPGF2
, and HNE-MA) and malondialdehyde (MDA) were measured using isotope dilution liquid chromatography-tandem mass spectrometry and thiobarbituric acid reactive substances, respectively.
The median levels of 8-NO
Gua (6.15 vs. 3.76 ng/mL) and HNE-MA (30.12 and 21.54 ng/mL) were significantly higher in the RPL group than in the control group. By categorizing the OSBs data into tertiles, after we adjusted for age and urine creatinine levels discovered that the RPL risk associated with 8-NO
Gua and HNE-MA levels in the third tertile were approximately 2 times higher than those in the first tertile (8-NO
Gua, adjusted OR = 3.27, 95 % CI = 1.66-6.43; HNE-MA, adjusted OR = 1.96, 95 % CI = 1.05-3.64; p < 0.05). These findings suggest that the oxidative stress biomarkers of 8-NO
Gua and HNE-MA are risk factors for RPL.
Our findings indicate that specific OSBs are associated with an increased RPL risk, suggesting that reducing OSB levels can improve RPL risk. Nevertheless, more studies on preventive medicine are required to understand the exposure sources and adverse outcome pathways of OSBs associated with RPL.
OBJECTIVE:Recent studies suggested that prophylactic aspirin prior to 16 weeks of gestation in high-risk patients may reduce the risk of developing preeclampsia; however, the exact mechanism of ...aspirinʼs effect on the pathophysiology of preeclampsia is not clear. This study was designed to investigate the effect of aspirin on trophoblast cell function and its effect on soluble fms-like tyrosine kinase 1 (sFlt-1) production to elucidate the preventive mechanisms for preeclampsia.
METHODS AND RESULTS:We used two human trophoblastic cell lines (HTR-8/SVneo and JAR) and freshly isolated cytotrophoblasts from normal and preeclamptic placenta at term to determine the effect of aspirin on trophoblast cell function. Trophoblasts were pretreated with aspirin, and then cell functions and sFlt-1 expression were assessed. Our results showed that aspirin promoted trophoblast invasion not only in HTR-8/SVneo and JAR cells, but also in isolated cytotrophoblasts. sFlt-1 production was repressed by aspirin in a dose-dependent manner. By adding Flt-1 recombinant protein, the trophoblast invasion ability was inhibited in HTR-8/SVneo cells, which was reversed by Flt-1 small interfering ribonucleic acid knockdown. In addition, metalloproteinase 2/9 expression and activity were activated by aspirin but inhibited by sFlt-1. Aspirin also downregulated Akt phosphorylation, and trophoblast invasiveness was facilitated under Akt inhibitor treatment.
CONCLUSION:Aspirin enhances cell invasiveness and inhibits sFlt-1 production in trophoblasts. Moreover, sFlt-1 itself also inhibits trophoblast invasion. Our novel findings suggest that the preeclampsia prevention effect of aspirin may be exerted through these two mechanisms.
Septins play important roles in regulating development and differentiation. Septin 7 (SEPT7) is a crucial component in orchestrating the septin core complex into highly ordered filamentous ...structures. Here, we showed that genetic depletion of SEPT7 or treatment with forchlorfenuron (FCF; a compound known to affect septin filament assembly) led to reduced the S phase entry in cell models and zebrafish embryos. In addition to colocalizing with actin filaments, SEPT7 resided in the centrosome, and SEPT7 depletion led to aberrant mitotic spindle pole formation. This mitotic defect was rescued in SEPT7‐deficient cells by wild‐type SEPT7, suggesting that SEPT7 maintained mitotic spindle poles. In addition, we observed disorganized microtubule nucleation and reduced cell migration with SEPT7 depletion. Furthermore, SEPT7 formed a complex with and maintained the abundance of p150glued, the component of centriole subdistal appendages. Depletion of p150glued resulted in a phenotype reminiscent of SEPT7‐deficient cells, and overexpression of p150glued reversed the defective phenotypes. Thus, SEPT7 is a centrosomal protein that maintains proper cell proliferation and microtubule array formation via maintaining the abundance of p150glued.
By interacting with and maintaining the abundance of p150glued, SEPT7 controlled the S phase entry and orchestrated microtubule nucleation arrays in vitro and in vivo. Thus, our study demonstrates that SEPT7 regulates cell cycle progression and microtubule nucleation via p150glued.
IMPORTANCE: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role ...in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. OBJECTIVE: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. INTERVENTIONS: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. RESULTS: In the FAS, 236 eligible patients (175 men 74.2%; mean SD age, 57.0 10.9 years; mean SD glycated hemoglobin level, 8.1% 1.6%) with DFUs classified as Wagner grade 1 or 2 (mean SD ulcer area, 4.8 4.4 cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. CONCLUSIONS AND RELEVANCE: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01898923
The optimal type of dressing in the setting of total joint arthroplasty (TJA) remains uncertain. The aim of this network meta-analysis was to compare various wound dressings and identify the optimal ...type of dressings for blister reduction and prevention of periprosthetic joint infection (PJI) in patients after TJA.
Studies comparing 2 or more dressing groups after TJA (hip or knee) were systematically searched on PubMed, Embase, and Scopus. Two authors performed the study selection, risk of bias assessment, and data extraction. Both outcomes were assessed using odds ratios (OR) with 95% confidence intervals (CI) and were ranked using surface under the cumulative ranking curve (SUCRA) probabilities to determine a hierarchy of dressings. A sensitivity analysis was performed to reduce the effect of intransitivity between studies.
A total of 21 studies, consisting of 12 dressing types in 7293 TJAs, were included in the final analysis. The highest incidence of blisters occurred when using negative-pressure wound therapy (OR 9.33, 95% CI 3.51-24.83, vs gauze). All dressings ranked better than gauze in infection rate except for hydrofiber (OR 1.46, 95% CI 0.02-112.53) and fabric dressings (OR 1.46, 95% CI 0.24-9.02). For blister reduction, alginate (SUCRA = 87.7%) and hydrofiber with hydrocolloid (SUCRA = 92.3%) were ranked as the optimal dressings before and after a sensitivity analysis, respectively. Antimicrobial dressing (SUCRA = 83.7%) demonstrated the most efficacy for preventing PJI.
Based on the evidence from our analysis, an antimicrobial dressing is the optimal dressing to prevent PJI. If negative-pressure wound therapy is used, surgeons should be aware of an increased incidence of blister formation. Further studies should focus on the alginate versus hydrofiber and hydrocolloid dressing to determine the optimal dressing to reduce blisters.
Pressure sore reconstruction remains a significant challenge for plastic surgeons due to its high postoperative complication and recurrence rates. Free-style perforator flap, fasciocutaeous flap, and ...musculocutaneous flap are the most common options in pressure sore reconstructions. Our study compared the postoperative complications among these three flaps at Kaohsiung Chang Gung Memorial Hospital.
From 2003 to 2012, 99 patients (54 men and 45 women) with grade III or IV pressure sores received regional flap reconstruction, consisting of three cohorts: group A, 35 free-style perforator-based flaps; group B, 37 gluteal rotation fasciocutaneous flaps; and group C, 27 musculocutaneous or muscle combined with fasciocutaneous flap. Wound complications such as wound infection, dehiscence, seroma formation of the donor site, partial or complete flap loss, and recurrence were reviewed.
The mean follow-up period for group A was 24.2 months, 20.8 months in group B, and 19.0 months for group C. The overall complication rate was 22.9%, 32.4%, and 22.2% in groups A, B, and C, respectively. The flap necrosis rate was 11.4%, 13.5%, and 0% in groups A, B, and C, respectively. There was no statistical significance regarding complication rate and flap necrosis rate among different groups.
In our study, the differences of complication rates and flap necrosis rate between these groups were not statistically significant. Further investigations should be conducted.
This updated network meta-analysis aims at exploring whether the concurrent use of midazolam or antiemetics may enhance the efficacy of other pharmacological regimens for delirium prophylaxis in ...pediatric population after general anesthesia (GA).
Network meta-analysis (PROSPERO registration: CRD42020179483).
Postoperative recovery area.
Pediatric patients undergoing GA with sevoflurane.
Pharmacological interventions applied during GA with sevoflurane.
This network meta-analysis of randomized controlled trials (RCTs) was conducted with a frequentist model. PubMed, Embase, ProQuest, ScienceDirect, Cochrane CENTRAL, ClinicalKey, Web of Science, and ClinicalTrials.gov were searched from their inception dates to April 12, 2020, for RCTs of either placebo-controlled or active-controlled design containing information on the incidence of emergence delirium in pediatric patients undergoing sevoflurane anesthesia.
Seventy studies comprising 6904 participants were included for the analysis of 30 pharmacological interventions. Based on surface under the cumulative ranking curve (SUCRA) analysis, midazolam was ranked the lowest in therapeutic effect (SUCRA: 20%), while antiemetics as a monotherapy had no effect on delirium prophylaxis. However, there was a trend that most combination therapies with midazolam or antiemetics were superior to monotherapies for delirium prophylaxis. Subgroup analyses based on age (i.e., ≤7 years) and a validated scoring system (i.e., the Pediatric Anesthesia Emergence Delirium scale) for delirium also suggested a better efficacy of combination therapies than monotherapies. Overall, combination therapies with midazolam or antiemetics did not have a negative impact on the incidence of postoperative nausea and vomiting, length of stay in the postanesthesia care unit, or time to extubation. The dexmedetomidine-midazolam-antiemetic combination was the most effective strategy for the prevention of emergence delirium.
This network meta-analysis suggested that the incorporation of midazolam or antiemetics as adjuncts for combination therapies may have synergistic effects against pediatric postoperative emergence delirium. Future large-scale placebo-controlled RCTs are warranted to validate our findings.
•Most combined regimens were better than monotherapies against emergence delirium.•Triple therapies were more effective than dual therapies, followed by monotherapies.•Dexmedetomidine-midazolam-antiemetic combination had the best prophylactic effect.
Nucleotide-binding oligomerization domain (NACHT), leucine rich repeat (LRR) and pyrin domain (PYD) 7 containing protein, NLRP7, is a member of the NLR family which serves as innate immune sensors. ...Mutations and genetic variants of NLRP7 have been found in women with infertility associated conditions, such as recurrent hydatidiform mole, recurrent miscarriage, and preeclampsia. Decidualization of endometrial stromal cells is a hallmark of tissue remodeling to support embryo implantation and proper placental development. Given defective decidualization has been implicated in miscarriage as well as preeclampsia, we aimed to explore the link between the NLRP7 gene and decidualization.
Endometrial samples obtained from pregnant women in the first trimester and non-pregnant women were used to study NLRP7 expression pattern. The human telomerase reverse transcriptase (hTERT)-immortalized human endometrial stromal cells (T-HESCs) were used to study the effect of NLRP7 on decidualization. Decidualization of T-HESCs was induced with 1 μM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). siRNA was used to knock down NLRP7 while lentiviral vectors were used to overexpress NLRP7 in cells. NLRP7 expression was detected by immunofluorescence, qRT-PCR, and Western blotting. Decidualization markers, Insulin-like growth factor-binding protein 1 (IGFBP-1) and prolactin (PRL), were detected by qRT-PCR and ELISA. Nuclear translocation of NLRP7 was detected by the subcellular fractionation and confocal microscopy. The effect of NLRP7 on progesterone receptor (PR) activity was evaluated by a reporter system.
NLRP7 was up-regulated in the decidual stromal cells of human first-trimester endometrium. After in vitro decidualization, T-HESCs presented with the swollen phenotype and increased expressions of IGFBP-1 and PRL. Knockdown or over-expression of NLRP7 reduced or enhanced the decidualization, respectively, according to the expression level of IGFBP-1. NLRP7 was found to translocate in the nucleus of decidualized T-HESCs and able to promote PR activity.
NLRP7 was upregulated and translocated to the nucleus of the endometrial stromal cells in an in vitro decidualization model. Overexpressed NLRP7 promoted the IGFBP-1 expression and PR reporter activation. IGFBP-1 expression decreased with the knockdown of NLRP7. Therefore, we suggest that NLRP7 contributes to in vitro decidualization of endometrial stromal cells.
Male infertility has become a worldwide health problem, but the etiologies of most cases are still unknown. SEPT12, a GTP-binding protein, is involved in male fertility. Two SEPT12 mutations ...(SEPT12(T89M) and SEPT12(D197N)) have been identified in infertile men who have a defective sperm annulus with a bent tail. The function of SEPT12 in the sperm annulus is still unclear. Here, we found that SEPT12 formed a filamentous structure with SEPT7, SEPT 6, SEPT2 and SEPT4 at the sperm annulus. The SEPT12-based septin core complex was assembled as octameric filaments comprising the SEPT proteins 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12. In addition, the GTP-binding domain of SEPT12 was crucial for its interaction with SEPT7, and the N- and C-termini of SEPT12 were required for the interaction of SEPT12 with itself to polymerize octamers into filaments. Mutant mice carrying the SEPT12(D197N) mutation, which disrupts SEPT12 filament formation, showed a disorganized sperm annulus, bent tail, reduced motility and loss of the SEPT ring structure at the sperm annulus. These phenotypes were also observed in an infertile man carrying SEPT12(D197N). Taken together, our results demonstrate the molecular architecture of SEPT12 filaments at the sperm annulus, their mechanical support of sperm motility, and their correlation with male infertility.
Cystic hygromas are frequently encountered in fetus with Turner syndrome (TS). Nevertheless, identification of genetic loci responsible for the cystic hygroma has been problematic. Here, we tried to ...elucidate the candidate gene for cystic hygroma through a rare case of complex Y chromosomal rearrangements involving duplication of partial Yq and monosomy of partial Yp.
A 30-year-old woman, gravida 1 para 0, was diagnosed with fetal cystic hygroma at 12 weeks of gestation. The genetic analysis of the product of conception revealed complex rearrangement of Y chromosome: microdeletion in Yp11.2p11.31 and microduplicatin in Yq11.223q11.23. The deleted region spans about 6.25 Mb and includes 76 genes, including SRY. The duplicated region spans about 4.76 Mb and includes 145 genes.
From this rare case with non-mosaic complex Y-chromosome rearrangements, we could narrow down Turner stigmata critical region to Yp11.2～p11.3. We also propose RPS4Y1 as lymphedema candidate gene.
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