112,428 research outputs found
Antibiotic prophylaxis for term or near-term premature rupture of membranes: Metaanalysis of randomized trials
No full textOBJECTIVE:
The objective of the study was to evaluate the efficacy of antibiotic prophylaxis in women with term or near-term premature rupture of membranes.
STUDY DESIGN:
Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, ScienceDirect.com, MEDSCAPE, and the Cochrane Central Register of Controlled Trials with the use of a combination of key words and text words related to antibiotics, premature rupture of membranes, term, and trials from inception of each database to September 2014. We included all randomized trials of singleton gestations with premature rupture of membranes at 36 weeks or more, who were randomized to antibiotic prophylaxis or control (either placebo or no treatment). The primary outcomes included maternal chorioamnionitis and neonatal sepsis. A subgroup analysis on studies with latency more than 12 hours was planned. Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration number CRD42014013928). The metaanalysis was performed following the Preferred Reporting Item for Systematic Reviews and Meta-analyses statement.
RESULTS:
Women who received antibiotics had the same rate of chorioamnionitis (2.7% vs 3.7%; relative risk [RR], 0.73, 95% confidence interval [CI], 0.48-1.12), endometritis (0.4% vs 0.9%; RR, 0.44, 95% CI, 0.18-1.10), maternal infection (3.1% vs 4.6%; RR, 0.48, 95% CI, 0.19-1.21), and neonatal sepsis (1.0% vs 1.4%; RR, 0.69, 95% CI, 0.34-1.39). In the planned subgroup analysis, women with latency longer than 12 hours, who received antibiotics, had a lower rate of chorioamnionitis (2.9% vs 6.1%; RR, 0.49, 95% CI, 0.27-0.91) and endometritis (0% vs 2.2%; RR, 0.12, 95% CI, 0.02-0.62) compared with the control group.
CONCLUSION:
Antibiotic prophylaxis for term or near-term premature rupture of membranes is not associated with any benefits in either maternal or neonatal outcomes. In women with latency longer than 12 hours, prophylactic antibiotics are associated with significantly lower rates of chorioamnionitis by 51% and endometritis by 88%
Cervical assessment by ultrasound for preventing preterm delivery
No full textBACKGROUND:
Measurement of cervical length by ultrasound is predictive of preterm birth (PTB). There are three methods of ultrasound cervical assessment: transvaginal (TVU), transabdominal (TAU), and transperineal (TPU, also called translabial). Cervical length measured by TVU is a relatively new screening test, and has been associated with better prediction of PTB than previously available tests. It is unclear if cervical length measured by ultrasound is effective for preventing PTB. This is an update of a review last published in 2013.
OBJECTIVES:
To assess the effectiveness of antenatal management based on transvaginal, transabdominal, and transperineal (also called translabial) ultrasound screening of cervical length for preventing preterm birth.
SEARCH METHODS:
For this update, we searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) to 30 August 2018; reviewed the reference lists of all articles, and contacted experts in the field for additional and ongoing trials.
SELECTION CRITERIA:
We included published and unpublished randomised controlled trials (RCT) including pregnant women between the gestational ages of 14 to 32 weeks, for whom the cervical length was screened for risk of PTB with TVU, TAU, or TPU. This review focused on studies based on knowledge versus no knowledge of cervical length results, or ultrasound versus no ultrasound for cervical length. We excluded studies based on interventions (e.g. progesterone, cerclage) for short cervical length.
DATA COLLECTION AND ANALYSIS:
We followed standard Cochrane methods.
MAIN RESULTS:
We included seven RCTs (N = 923): one examined asymptomatic women with twin pregnancies; four included women with singleton pregnancies and symptoms of preterm labour (PTL); one included women with singleton pregnancies and symptoms of preterm premature rupture of membranes (PPROM); and one included asymptomatic singletons. All trials used TVU for screening.We assessed the risk of bias of the included studies as mixed, and the quality of the evidence for primary outcomes as very low for all populations.For asymptomatic women with twin pregnancies, it is uncertain whether knowledge of TVU-measured cervical length compared to no knowledge reduces PTB at less than 34 weeks (risk ratio (RR) 0.62, 95% confidence intervals (CI) 0.30 to 1.25; 1 study, 125 participants) because the quality of the evidence is very low. The results were also inconclusive for preterm birth at 36, 32, or 30 weeks; gestational age at birth, and other maternal and perinatal outcomes.Four trials examined knowledge of TVU-measured cervical length of singletons with symptoms of PTL versus no knowledge. We are uncertain of the effects because of inconclusive results and very low-quality evidence for: preterm births at less than 37 weeks (average RR 0.59, 95% CI 0.26 to 1.32; 2 studies, 242 participants; I2 = 66%; Tau2 = 0.23). Birth occurred about four days later in the knowledge groups (mean difference (MD) 0.64 weeks, 95% CI 0.03 to 1.25; 3 trials, 290 women). The results were inconclusive for the other outcomes for which there were available data: PTB at less than 34 or 28 weeks; birthweight less than 2500 g; perinatal death; maternal hospitalisation; tocolysis; and steroids for fetal lung maturity.The trial of singletons with PPROM (N = 92) evaluated safety of using TVU to measure cervical length in this population as its primary outcome, not its effect on management. The results were inconclusive for incidence of maternal and neonatal infections between the TVU and no ultrasound groups.In the trial of asymptomatic singletons (N = 296), in which women either received TVU or not, the results were inconclusive for preterm birth at less than 37 weeks (RR 1.27, 95% CI 0.61 to 2.61; I2 = 0%), gestational age at birth, and other perinatal and maternal outcomes.We downgraded evidence for limitations in study design, inconsistency between the trials, and imprecision, due to small sample size and wide confidence intervals crossing the line of no effect.No trial compared the effect of knowledge of the CL with no knowledge of CL in other populations, such as asymptomatic women with singleton pregnancies, or symptomatic women with twin pregnancies.
AUTHORS' CONCLUSIONS:
There are limited data on the effects of knowing the cervical length, measured by ultrasound, for preventing preterm births, which preclude us from drawing any conclusions for women with asymptomatic twin or singleton pregnancies, singleton pregnancies with PPROM, or other populations and clinical scenarios.Limited evidence suggests that knowledge of transvaginal ultrasound-measured cervical length, used to inform the management of women with singleton pregnancies and symptoms of preterm labour, appears to prolong pregnancy by about four days over women in the no knowledge groups.Future studies could look at specific populations separately (e.g. singleton versus twins; symptoms versus no symptoms of PTL), report on all pertinent maternal and perinatal outcomes, and include cost-effectiveness analyses. Most importantly, future studies should include a clear protocol for management of women based on TVU-measured cervical length
Fetal fibronectin testing for reducing the risk of preterm birth
No full textBACKGROUND:
Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where it is concentrated in this area between decidua and trophoblast. In normal conditions, FFN is found at very low levels in cervicovaginal secretions. Levels greater than or equal to 50 ng/mL at or after 22 weeks have been associated with an increased risk of spontaneous preterm birth. In fact, FFN is one of the best predictors of preterm birth in all populations studied so far, and can help in selecting which women are at significant risk for preterm birth. This is an update of a review first published in 2008.
OBJECTIVES:
To assess the effectiveness of management based on knowledge of FFN testing results for preventing preterm birth.
SEARCH METHODS:
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (7 September 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 September 2018), and reference lists of retrieved studies.
SELECTION CRITERIA:
Randomized controlled trials of pregnant women screened with FFN for risk of preterm birth. Studies included are based exclusively on knowledge of FFN results versus no such knowledge, and we have excluded studies including women with only positive or only negative FFN results.
DATA COLLECTION AND ANALYSIS:
Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.
MAIN RESULTS:
We identified 16 trials, of which six were eligible for inclusion. The six included studies randomized 546 women with singleton gestations and threatened preterm labor (PTL) at 23 0/7 to 34 6/7 weeks. A total of 277 women were randomized to knowledge and 269 to no knowledge of FFN. No trials were identified on asymptomatic women or multiple gestations.The risk of bias of included studies was mixed. For selected important outcomes, preterm birth before 37, 34, and 32 weeks, and maternal hospitalization, we graded the quality of the evidence and created a 'Summary of findings' table. For these outcomes, the evidence was graded as mainly low quality due to the imprecision of effect estimates.Management based on knowledge of FFN results may reduce preterm birth before 37 weeks (21.6%) versus controls without such knowledge (29.2%) (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.52 to 1.01; 4 trials; 357 women; low-quality evidence). However, management based on knowledge of FFN results may make little or no difference to preterm birth before 34 (RR 1.09, 95% CI 0.54 to 2.18; 4 trials; 357 women; low-quality evidence) or maternal hospitalization (RR 1.06, 95% CI 0.79 to 1.43; 5 trials; 441 women; low-quality evidence). The evidence for preterm birth before 32 weeks is uncertain because the quality was found to be very low (average RR 0.79, 95% CI 0.16 to 3.96; 4 trials; 357 women; very low-quality evidence).For all other outcomes, for which there were available data (preterm birth less than 28 weeks; gestational age at delivery (weeks); birthweight less than 2500 g; perinatal death; tocolysis; steroids for fetal lung maturity; time to evaluate; respiratory distress syndrome; neonatal intensive care unit (NICU) admission; and NICU days), knowledge of FFN results may make little or no difference to the outcomes.
AUTHORS' CONCLUSIONS:
The evidence from this review suggests that management based on knowledge of FFN results may reduce preterm birth before 37 weeks. However, our confidence in this result is limited as the evidence was found to be of low quality. Effects on other substantive outcomes are uncertain due to serious concerns in study design, inconsistency, and imprecision of effect estimates. No trials were identified on asymptomatic women, or multiple gestations.Future studies are needed that include specific populations (e.g. singleton gestations with symptoms of preterm labor), a study group managed with a protocol based on the FFN results, and that report not only maternal but also important perinatal outcomes. Cost-effectiveness analyses are also needed
HDAC inhibitors for muscular dystrophies: progress and prospects
No full textHDAC inhibitors for muscular dystrophies: progress and prospects
Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy (MD) that affects 1 in 3500–6000 live male births. This lethal X-linked genetic disease is caused by muta- tions in dystrophin gene that leads to a complete absence of the protein, thereby compromising the structural and functional integrity of the dystrophin- associated protein complex (DAPC).[1] The DAPC links the actin cytoskeleton to the extracellular matrix and has an essential role in stabilizing the sarcolemma during repeated cycles of contraction.[2] As such, dystrophin-deficient muscles are vulnerable to mechanical damage and develop progressive muscu- lar weakness, as a consequence of muscle degenera- tion, leading to loss of myofibers, which are ultimately replaced by fibrotic scars and fat deposition.[3] There is still no available cure for DMD, but only palliative treatments that aim to counter muscle loss, thereby extending patient mobility and delaying the onset of respiratory and cardiac problems.[4]
The progression of DMD is highly influenced by the ability of dystrophin-deficient muscles to counter mus- cle loss by a regenerative response, which typically defines a clinical latency observed during the early stages of the disease. The gradual exhaustion of such compensatory response coincides with changes in the muscle tissue composition, leading to the progressive formation of fibrotic and adipose tissue in place of contractile fibers. This ‘restriction point’ in the natural history of DMD is due to alterations in the interactions between the cell types that contribute to promote regeneration, eventually culminating with a switch of muscle repair toward fibrotic and fat deposition.[5] In particular, studies in the last decade have revealed the importance of changes in the identity and functional properties of the cellular components of the muscle stem (satellite) cell (MuSC) niche. For instance, the inter- actions between inflammatory cells (e.g. macrophages), interstitial ‘support’ cells (e.g. fibro-adipogenic progeni- tors – FAPs) and MuSCs appear a key determinant to drive the skeletal muscle toward a regeneration or degeneration process.[6,7] This notion has inspired a number of current pharmacological strategies aimed at targeting these cells and the functional networks they establish,[8,9] as an alternative to gene replace- ment and cell-based strategies.
Among the pharmacological interventions that aim to slow down the disease progression by targeting key events downstream of the genetic defect, the histone deacetylase inhibitors (HDACi) have recently been translated into a clinical trial, based on the encouraging preclincial data generated in the mouse model of DMD – the mdx mice.[10,11]
In principle, the rationale for the use of HDACi in the treatment of DMD was provided by the finding that dystrophin-deficient muscles display an aberrant, con- stitutive activation of HDAC2, as a consequence of reduced nitric oxide (NO)-mediated NO-dependent S-nitrosylation in myofibers.[12] Moreover, recent stu- dies have revealed complex epigenetic networks tar- geted by HDACi in MuSCs and FAPs.[13,14] In particular, studies from Saccone et al. have identified an HDAC-regulated network that controls the func- tional phenotype of FAPs from dystrophic muscles. Treatment with HDACi promotes the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60c [15] and upregulates three myogenic microRNA involved into muscle differ- entiation (myomiRs; miR-1.2, miR-133 and miR-206) in FAPs. MyomiRs in turn target two alternative BAF60 variants – BAF60 A and B – that when incorporated into the Switch/Sucrose NonFermentable (SWI/SNF) chromatin-remodeling complex would otherwise pro- mote the activation of the fibro-adipogenic program. [14] Thus, HDACi-mediated selection of BAF60 C-based SWI/SNF complex appears to mediate a therapeutic switch of FAP phenotype from pro-fibroadipogenic to pro-myogenic one. Interestingly, FAPs from dystrophic muscles at advanced stage of disease are resistant to the beneficial effects of HDACi, accounting for the stage-specific effect of HDACi previously observed by Mozzetta et al.[9] Genome-wide studies of chromatin accessibility showed that at early stages of the disease, HDACi promote an extensive chromatin remodeling, which was not observed at late stage of the disease. [14] This finding indicates that pharmacological inter- ventions that target FAPs could be used to promote compensatory regeneration, while preventing fibro- adipogenic degeneration of DMD muscles. It also sug- gests that FAPs of dystrophic muscles at late stages of DMD progression might acquire a chromatin conforma- tion that confers resistance to treatments that are
© 2015 Taylor & Francis
126 M. SANDONÁ ET AL.
otherwise effective at early stages of disease. Understanding the molecular basis of such resistance could reveal novel targets for interventions aimed at restoring the ability of FAPs to support muscle regen- eration rather than fibrosis and fat infiltration in a larger population of patients.
Conclusion
As preclinical evidence supported the rationale for the use of HDACi in the treatment of DMD, the HDACi Givinostat has been launched as the first epigenetic drug tested in a Phase I/II clinical trial on DMD boys between 8 and 10 years of age that is currently under investigation. Given the potential of HDACi to promote regeneration at the expense of fibro-adipogenic degen- eration, one predicted effect of Givinostat on DMD muscles is to extend the compensatory regeneration and delay the disease progression in patients at early stages of disease progression, Future research should evaluate the efficacy of Givinostat in a larger population of DMD patients and identify molecular criteria and noninvasive biomarkers that define patient responsive- ness and eventually inspire further interventions that sensitize to HDACi unresponsive patients.
Expert opinion
Three fundamental aspects for the future development of HDACi-based therapies concern a) the identification of biomarkers that help selecting patients for clinical studies and monitoring their responsiveness to the treatments, b) the discovery of complementary approaches that synergize with HDACi to provide an optimal combined therapeutic intervention and c) the potential extension of HDACi-based treatments to other forms of muscular dystrophies.
While the analysis of muscle biopsies is currently regarded as the most reliable readout of the histologi- cal effects of HDACi, this procedure is invasive, is lim- ited to one specific muscle and cannot be repeated multiple times during the course of clinical trials. As such, it is currently missing an effective readout of the efficacy of treatment with HDACi or similar pharmaco- logical approaches. Identification of circulating biomar- kers and/or setting noninvasive or semi-invasive procedures for the evaluation of the effects of pharma- cological interventions is clearly a fundamental step to further move forward pro-clinical and clinical research on DMD.
Moreover, beyond the beneficial effects on muscle histology, the clinical efficacy of HDACi treatment needs to be correlated with functional tests. Studies with
HDACi in mdx mice demonstrated that the morpholo- gical recovery is accompanied by increased muscle strength and exercise performance.[10,11] Thus, match- ing functional tests, such as 6 Minute Walk Test (6MWT) and North Star Ambulatory Assessment, with the histo- logical evaluation of treated muscles, will be mandatory to reveal the efficacy of HDACi and other pharmacolo- gical interventions in DMD patients.
Regarding the identification of complementary approaches that synergize with HDACi, the most urgent questions relate to the functional interactions between HDACi and steroids – the standard treatment currently used in the treatment of DMD. In this case, it is inter- esting to note that steroids are typically acting through a nuclear receptor – the glucocorticoid receptor (GR) – whose activity is negatively regulated by an HDAC- containing repressive complex. Moreover, the possibi- lity to combine HDACi-based treatment with emerging strategies toward re-introducing functional dystrophin in DMD muscles (i.e. exon skipping or future CRISPR- based interventions) is supported by a strong rationale consisting of the necessity to protect the newly formed myofibers, induced by HDACi-promoted regeneration, from contraction-mediated regeneration, via dystrophin re-expression.
Finally, future research should determine the poten- tial efficacy of HDACi on other forms of muscular dys- trophies that share pathogenic events with DMD, e.g. the shift from compensatory regeneration to fibrosis and fat deposition.
Declaration of interest
Funding has been received from AFM Telethon and Duchenne Parent Project (DPP-NL). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock owner- ship or options, expert testimony, grants or patents received or pending, or royalties.
References
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
1. Dalkilic I, Kunkel LM. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev. 2003;13(3):231–238. 2. Petrof BJ, Shrager JB, Stedman HH, et al. Dystrophin protects the sarcolemma from stresses developed during muscle
contraction. Proc Natl Acad Sci USA. 1993;90(8):3710–3714. 3. Straub V, Campbell KP. Muscular dystrophies and the dystrophin-glycoprotein complex. Curr Opin Neurol.
1997;10(2):168–175.
4. Mercuri E, Muntoni F. Muscular dystrophy: new chal-
lenges and review of the current clinical trials. Curr
Opin Pediatr. 2013;25(6):701–707. DOI:10.1097/
MOP.0b013e328365ace5.
5. Serrano AL, Mann CJ, Vidal B, et al. Cellular and molecular
mechanisms regulating fibrosis in skeletal muscle repair and disease. Curr Top Dev Biol. 2011;96:167–201. DOI:10.1016/B978-0-12-385940-2.00007-3.
6. Farup J, Madaro L, Puri PL, et al. Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease. Cell Death Dis. 2015;6:e1830. DOI:10.1038/ cddis.2015.198.
7. Judson RN, Zhang RH, Rossi FM. Tissue-resident mesenchymal stem/progenitor cells in skeletal muscle: collaborators or saboteurs? Febs J. 2013;280 (17):4100–4108. DOI:10.1111/febs.12370.
8. Lemos DR, Babaeijandaghi F, Low M, et al. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med. 2015;21(7):786–794. DOI:10.1038/nm.3869.
9. Mozzetta C, Consalvi S, Saccone V, et al. Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice. EMBO Mol Med. 2013;5 (4):626–639. DOI:10.1002/emmm.201202096.
• Exciting paper studying the fibroadipogenic pro- genitors (FAPs) as cellular determinants of the ben- eficial effects of HDAC inhibitors. FAPs mediate HDACi effects promoting muscles regeneration in a stage-specific manner.
10. Minetti GC, Colussi C, Adami R, et al. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med. 2006;12 (10):1147–1150.
• Interesting paper describing the functional and mor- phological effects of HDAC inhibitors treatments. HDAC inhibitors increase myofiber size and counter the functional decline of dystrophic muscles
11. Consalvi S, Mozzetta C, Bettica P, et al. Preclinical studies in the mdx mouse model of Duchenne muscular dystro- phy with the histone deacetylase inhibitor Givinostat. Mol Med. 2013;19:79–87. DOI:10.2119/molmed.2013.00011.
•• Excellentpaperdemonstratingtheeffectivenessofa long-term treatment with Givinostat. The findings of this paper provide preclinical basis for a translation on DMD patients.
12. Colussi C, Mozzetta C, Gurtner A, et al. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals
a common target in Duchenne muscular dystrophy treatment. Proc Natl Acad Sci USA. 2008;105 (49):19183–19187. DOI:10.1073/pnas.0805514105.
13. Cacchiarelli D, Martone J, Girardi E, et al. MicroRNAs involved in molecular circuitries relevant for the Duchenne muscular dystrophy pathogenesis are controlled by the dystrophin/nNOS pathway. Cell Metab. 2010;12(4):341–351. DOI:10.1016/j. cmet.2010.07.008.
14. Saccone V, Consalvi S, Giordani L, et al. HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes Dev. 2014;28(8):841–857. DOI:10.1101/gad.234468.113.
• Fascinating paper determines the molecular mechan- ism that controls the FAPs switch from a fibroadipo- genic to a myogenic phenotype after HDACi treatment.
15. Forcales SV, Albini S, Giordani L, et al. Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. Embo J. 2012;31(2):301–316. DOI:10.1038/emboj. 2011.391.
M. Sandoná
IRCCS Fondazione Santa Lucia, Rome, Italy DAHFMO, Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
S. Consalvi
IRCCS Fondazione Santa Lucia, Rome, Italy
L. Tucciarone
IRCCS Fondazione Santa Lucia, Rome, Italy
P. L. Puri
IRCCS Fondazione Santa Lucia, Rome, Italy Muscle Development and Regeneration Program, Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
V. Saccone
IRCCS Fondazione Santa Lucia, Rome, Ital
Quaderni di Meykhane V (2015)
No full textRivista bilingue (persiano e italiano), attiva dal 2011 e a uscita annuale, con comitato scientifico internazionale e peer review. Trattasi della prima, e finora unica, rivista italiana dedicata esclusivamente all'iranistica e in particolare alla letteratura persiana classica e moderna. E' inserita in un progetto più ampio che comprende l'archivio online "Meykhane. Voci e memorie persiane", con cui condivide il sito web
Rivista di Studi Indo-Mediterranei V (2015)
No full textRivista elettronica plurilingue, con comitato scientifico internazionale e peer review, a uscita annuale, dedicata a studi letterari, religiosi e storici con un taglio prevalentemente comparativo e interculturale, e focalizzata sugli scambi tra le culture mediterranee e dell'Asia Centrale/Meridional
- …
