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Objective: To compare the incidence of twin-to-twin transfusion syndrome (TTTS) in spontaneous versus IVF-conceived twin pregnancies.Design: Retrospective multicenter study.Setting: University-affiliated tertiary medical centers.Patient(s): Women admitted for 11-14 week's scan between January 1997 and July 2013 who were diagnosed with monochorionic (MC) diamniotic twin pregnancies.Intervention(s): None.Main Outcome Measure(s): Mode of conception, TTTS.Result(s): The study cohort included 327 pregnant women with live MC diamniotic twins. Of them, 284 (86.9%) and 43 (13.1%) were spontaneous and IVF conceived, respectively. The mean maternal age was significantly higher in IVF compared with in spontaneously conceived pregnancies (33.8 ± 5.5 vs. 31.6 ± 5.4, respectively). Thirty-seven twins (11.3%) had TTTS, of whom 36/284 (12.7%) versus 1/43 (2.3%) were spontaneously and IVF conceived, respectively. The mean week of delivery was significantly lower in MC twins diagnosed with TTTS compared with those without TTTS (32.7 ± 3.3 vs. 35.5 ± 2.5, respectively). Furthermore, there was a significantly higher birthweight discordancy in twins diagnosed with TTTS compared with those without (20.6% vs. 11%, respectively).Conclusion(s): The significantly lower proportion of TTTS found in IVF-conceived twins may suggest a different embryological process that lies at the core of IVF conception of monozygotic twinning. [ABSTRACT FROM AUTHOR]

Diethyl dithiocarbamate (DEDTC) has been reported to be a more powerful inhibitor of all-trans-retinoic acid (ATRA) in vitro metabolism than the well-established cytochrome P450 (CYP) inhibitor ketoconazole (KC). In recent years grapefruit juice (GJ) has been shown to be able to increase the oral bioavailability of several drugs by inhibiting intestinal CYP. This study investigated the in vivo effect of these CYP inhibitors on the pharmacokinetics of ATRA. The latter was administered to rats as a constant-rate intravenous (i.v.) infusion (0.48 mg h–1 kg–1) during 10 h and orally (1.6 mg kg–1). DEDTC (320 mg kg–1 × 2 i.v., 6.4 and 32 mg kg–1 per os (p.o.)) did not change the ATRA concentration–time profiles, whereas KC (320 and 32 mg kg–1 p.o.)—with i.v. infused or orally dosed ATRA—increased the mean concentration–time curve value by 160% and 78%, respectively. A high dose of DEDTC (320 mg kg–1 p.o.) caused a marked decrease in plasma levels of ATRA. GJ (6.4 ml kg–1 p.o.) did not affect the plasma levels of ATRA. It is concluded that the in vivo effect of CYP inhibitors (DEDTC and KC) on the elimination rate of ATRA is qualitatively different from that expected from in vitro studies. [Copyright &y& Elsevier]

Background: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy.Objective: The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks.Study Design: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth.Results: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69).Conclusion: In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a major pregnancy complication with adverse short- and long-term implications for both the mother and baby. Screening for preeclampsia at 11-13 weeks' gestation by a combination of maternal demographic characteristics and medical history with measurements of biomarkers can identify about 75% of women who develop preterm preeclampsia with delivery at <37 weeks' gestation and 90% of those with early preeclampsia at <32 weeks, at a screen-positive rate of 10%. A recent trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) has reported that in women identified by first-trimester screening as being at high risk for preeclampsia, use of aspirin (150 mg/d from the first to the third trimester), compared to placebo, reduced the incidence of preterm preeclampsia, which was the primary outcome, by 62% (95% confidence interval, 26-80%) and the incidence of early preeclampsia by 89% (95% confidence interval, 53-97%). The surprising finding of the trial was that despite the reduction in preeclampsia the incidence of admission to the neonatal intensive care unit, which was one of the secondary outcomes, was not significantly affected (odds ratio, 0.93; 95% confidence interval, 0.62-1.40).Objective: We sought to examine the effect of prophylactic use of aspirin during pregnancy in women at high risk of preeclampsia on length of stay in the neonatal intensive care unit.Study Design: This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial to assess evidence of differences in the effect of aspirin on length of stay in neonatal intensive care. Bootstrapping was used for the comparison of mean length of stay between the aspirin and placebo groups. Logistic regression was used to assess treatment effects on stay in the neonatal intensive care unit.Results: In the trial there were 1620 participants and 1571 neonates were liveborn. The total length of stay in neonatal intensive care was substantially longer in the placebo than aspirin group (1696 vs 531 days). This is a reflection of significantly shorter mean lengths of stay in babies admitted to the neonatal intensive care unit from the aspirin than the placebo group (11.1 vs 31.4 days), a reduction of 20.3 days (95% confidence interval, 7.0-38.6; P = .008). Neonatal intensive care of babies born at <32 weeks' gestation contributed 1856 (83.3%) of the total of 2227 days in intensive care across both treatment arms. These occurred in 9 (1.2%) of the 777 livebirths in the aspirin group and in 23 (2.9%) of 794 in the placebo group (odds ratio, 0.42; 95% confidence interval, 0.19-0.93; P = .033). Overall, in the whole population, including 0 lengths of stay for those not admitted to the neonatal intensive care unit, the mean length of stay was longer in the placebo than aspirin group (2.06 vs 0.66 days; reduction of 1.4 days; 95% confidence interval, 0.45-2.81; P = .014). This corresponds to a reduction in length of stay of 68% (95% confidence interval, 20-86%).Conclusion: In pregnancies at high risk of preeclampsia administration of aspirin reduces the length of stay in the neonatal intensive care unit by about 70%. This reduction could essentially be attributed to a decrease in the rate of births at <32 weeks' gestation, mainly because of prevention of early preeclampsia. The findings have implications for both short- and long-term health care costs as well as infant survival and handicap. [ABSTRACT FROM AUTHOR]

Background: Preterm birth is the leading cause of neonatal death and handicap in survivors. Although twins are found in 1.5% of pregnancies they account for about 25% of preterm births. Randomized controlled trials in singleton pregnancies reported that the prophylactic use of progestogens, cervical cerclage and cervical pessary reduce significantly the rate of early preterm birth. In twin pregnancies, progestogens and cervical cerclage have been shown to be ineffective in reducing preterm birth.Objective: The objective of this study was to test the hypothesis that the insertion of a cervical pessary in twin pregnancies would reduce the rate of spontaneous early preterm birth.Study Design: This was a multicenter, randomized controlled trial in unselected twin pregnancies of cervical pessary placement from 20(+0)-24(+6) weeks' gestation until elective removal or delivery vs. expectant management. Primary outcome was spontaneous birth <34 weeks. Secondary outcomes included perinatal death and a composite of adverse neonatal outcomes (intraventricular haemorrhage, respiratory distress syndrome, retinopathy of prematurity or necrotizing enterocolitis) or need for neonatal therapy (ventilation, phototherapy, treatment for proven or suspected sepsis, or blood transfusion). Analysis was by intention to treat. This trial is registered in the ISRCTN registry, number 01096902.Results: A total of 1,180 (56.0%) of the 2,107 eligible women agreed to take part in the trial; 590 received cervical pessary and 590 had expectant management. Two of the former and one of the latter were lost to follow up. There were no significant differences between the pessary and control groups in rates of spontaneous birth <34 weeks (13.6% vs. 12.9%; relative risk 1.054, 95% confidence interval [CI] 0.787-1.413; p=0.722), perinatal death (2.5% vs. 2.7%; relative risk 0.908, 95% CI 0.553-1.491; p=0.702), adverse neonatal outcome (10.0 vs. 9.2%; relative risk 1.094, 95% CI 0.851-1.407; p=0.524) or neonatal therapy (17.9% vs. 17.2%; relative risk 1.040, 95% CI 0.871-1.242; p=0.701). A post hoc subgroup analysis of 214 women with short cervix (≤25 mm) showed no benefit from the insertion of a cervical pessary.Conclusion: In women with twin pregnancy, routine treatment with cervical pessary does not reduce the rate of spontaneous early preterm birth. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI), characterized by a sudden decline in kidney function involving tubular damage and epithelial cell death, can lead to progressive tissue fibrosis and chronic kidney disease due to interstitial fibroblast activation and tissue repair failures that lack direct treatments. After an AKI episode, surviving renal tubular cells undergo cycles of dedifferentiation, proliferation and redifferentiation while fibroblast activity increases and then declines to avoid an exaggerated extracellular matrix deposition. Appropriate tissue recovery versus pathogenic fibrotic progression depends on fine-tuning all these processes. Identifying endogenous factors able to affect any of them may offer new therapeutic opportunities to improve AKI outcomes. Galectin-8 (Gal-8) is an endogenous carbohydrate-binding protein that is secreted through an unconventional mechanism, binds to glycosylated proteins at the cell surface and modifies various cellular activities, including cell proliferation and survival against stress conditions. Here, using a mouse model of AKI induced by folic acid, we show that pre-treatment with Gal-8 protects against cell death, promotes epithelial cell redifferentiation and improves renal function. In addition, Gal-8 decreases fibroblast activation, resulting in less expression of fibrotic genes. Gal-8 added after AKI induction is also effective in maintaining renal function against damage, improving epithelial cell survival. The ability to protect kidneys from injury during both pre- and post-treatments, coupled with its anti-fibrotic effect, highlights Gal-8 as an endogenous factor to be considered in therapeutic strategies aimed at improving renal function and mitigating chronic pathogenic progression. [Display omitted] • Gal-8 preserves kidney function in folic acid-induced AKI. • Gal-8 reduces acute renal cortical damage in folic acid-induced AKI. • Gal-8 has an anti-fibrotic effect in folic acid-induced kidney injury. • Gal-8 decreases fibroblast activation in folic acid-induced kidney injury. [ABSTRACT FROM AUTHOR]

Monocarboxylate transporter 4 (MCT4) is an H+-coupled symporter highly expressed in metastatic tumors and at inflammatory sites undergoing hypoxia or the Warburg effect. At these sites, extracellular lactate contributes to malignancy and immune response evasion. Intriguingly, at 30-40 mM, the reported Km of MCT4 for lactate is more than 1 order of magnitude higher than physiological or even pathological lactate levels. MCT4 is not thought to transport pyruvate. Here we have characterized cell lactate and pyruvate dynamics using the FRET sensors Laconic and Pyronic. Dominant MCT4 permeability was demonstrated in various cell types by pharmacological means and by CRISPR/Cas9-mediated deletion. Respective Km values for lactate uptake were 1.7, 1.2, and 0.7mM in MDA-MB- 231 cells, macrophages, and HEK293 cells expressing recombinant MCT4. In MDA-MB-231 cells MCT4 exhibited a Km for pyruvate of 4.2mM, as opposed to>150mMreported previously. Parallel assays with the pH-sensitive dye 2',7'-bis-(carboxyethyl)- 5-(and-6)-carboxyfluorescein (BCECF) indicated that previous Km estimates based on substrate-induced acidification were severely biased by confounding pH-regulatory mechanisms. Numerical simulation using revised kinetic parameters revealed that MCT4, but not the related transportersMCT1and MCT2, endows cells with the ability to export lactate in highlactate microenvironments. In conclusion, MCT4 is a high-affinity lactate transporter with physiologically relevant affinity for pyruvate. [ABSTRACT FROM AUTHOR]

A total of 123 genetically-unrelated strains of Enterococcus spp. strains (51 Enterococcus faecalis, 57 Enterococcus faecium, 10 Enterococcus gallinarum, and 5 Enterococcus casseliflavus) were phenotypically identified by biochemical profiles and by using an automated method. The strains were also analyzed by a PCR assay to assess the accuracy of the phenotypically-based methods for identification of Enterococcus spp. With this aim, a PCR assay using different cell targets, which allows simultaneous detection of glycopeptide-resistant genotypes as well as identification to the species level by means of different gene targets, was used as the gold standard method. All 51 strains of E. faecalis were correctly identified, whereas 48 of 57 strains (84.2%) of E. faecium, were correctly identified. All of the strains of E. gallinarum and 3 out of 5 strains of E. casseliflavus were also correctly identified. The overall results showed that it is possible to identify Enterococcus spp. at the molecular level in less than 30 hours, compared with the 48–96 hours required for the phenotypically-based methods. The excellent accuracy of the PCR assay in identifying these species, particularly E. faecium, must also be emphasized. These findings may have implications for the routine clinical identification of enterococci species. [Copyright &y& Elsevier]

The glitazones or thiazolidinediones are ligands of the peroxisome proliferator-activated receptor γ(PPARγ). The glitazones are used in the treatment of diabetes, regulate adipogenesis, inflammation, cell proliferation, and induce apoptosis in several l types. High grade astrocytomas are rapidly growing tumors derived from astrocytes, for which new treatments are needed. We determined the effects of two glitazones, ciglitazone and the therapeutic rosiglitazone, on the survival of serum-deprived primary rat astrocytes and glioma cell lines C6 and U251, which were assessed by the methylthiazolyl tetrazolium assay and lactate dehydrogenase release. Rosiglitazone (5–20 μM) decreased survival of glioma cells without affecting primary astrocytes, whereas ciglitazone at 20 μM was toxic for both cell types. Ciglitazone at 10 μM was cytoprotective for primary astrocytes but toxic to glioma cells. Cell death induced by ciglitazone, but not rosiglitazone, presented apoptotic features (Hoechst staining and externalization of phosphatidylserine). Two mechanisms to explain cytotoxicity were investigated: activation of PPARγand production of reactive oxygen species (ROS). PPARγ does not seem to be the main mechanism involved, because the order of efficacy for cytotoxicity, ciglitazone > rosiglitazone, was inverse of their reported affinities for activating PPARγ. In addition, GW9662, an inhibitor of PPARγ, only slightly attenuated cytotoxicity. However, the rapid increase in ROS production and the marked reduction of cell death with the antioxidants ebselen and N-acetylcysteine, indicate that ROS have a key role in glitazone cytotoxicity. Ciglitazone caused a dose-dependent and rapid loss (in minutes) of mitochondrial membrane potential in glioma cells. Therefore, mitochondria are a likely source of ROS and early targets of glitazone cytotoxicity. Our results highlight the potential of rosiglitazone and related compounds for the treatment of astrogliomas. [ABSTRACT FROM AUTHOR]