Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates.
To investigate whether prophylactic rhEPO administration in very preterm infants ...improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs).
Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources.
RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age.
Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment.
Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81),
< .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome.
Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.
Background
We discuss the challenges of multiple pregnancy at very advanced reproductive age.
Case presentation
We present the case of a quadruplet pregnancy at the maternal age of 65 following
...in-vitro
fertilization (IVF) with donor eggs and sperm, involving cross-border reproductive care. All children born were at 25 weeks’ gestation and survived; however, poor neurodevelopmental outcome remains a major concern in one child.
Conclusions
The use of reproductive technology to achieve a multiple pregnancy at such an advanced post-menopausal age generated a debate on ethical, psychosocial and medical questions. We share this debate and highlight the need to reconsider international guidelines for women of advanced reproductive age.
The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs) suggests that many regulatory mechanisms contribute to the transcriptional output of the ...circadian clock. We aim to predict these mechanisms using a large scale promoter analysis of CCGs.Our study is based on a meta-analysis of DNA-array data from rodent tissues. We searched in the promoter regions of 2065 CCGs for highly overrepresented transcription factor binding sites. In order to compensate the relatively high GC-content of CCG promoters, a novel background model to avoid a bias towards GC-rich motifs was employed. We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCKratioBMAL1, DBP, HLF, E4BP4, CREB, RORalpha and the recently described regulators HSF1, STAT3, SP1 and HNF-4alpha. As additional promising candidates of circadian transcriptional regulators PAX-4, C/EBP, EVI-1, IRF, E2F, AP-1, HIF-1 and NF-Y were identified. Moreover, GC-rich motifs (SP1, EGR, ZF5, AP-2, WT1, NRF-1) and AT-rich motifs (MEF-2, HMGIY, HNF-1, OCT-1) are significantly overrepresented in promoter regions of CCGs. Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found. The regulation of the erythropoietin (Epo) gene was analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulated expression in the adult murine kidney. Basing on a comprehensive literature search we integrate our predictions into a regulatory network of core clock and clock-controlled genes. Our large scale analysis of the CCG promoters reveals the complexity and extensiveness of the circadian regulation in mammals. Results of this study point to connections of the circadian clock to other functional systems including metabolism, endocrine regulation and pharmacokinetics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Neonatal thrombocytopenia is widespread in preterm and term neonates admitted to neonatal intensive care units, with up to one-third of infants demonstrating platelet counts <150 × 109 /L. ...Thrombocytopenia may arise from maternal, placental or fetal/neonatal origins featuring decreased platelet production, increased consumption, or both mechanisms. Over the past years, innovations in managing neonatal thrombocytopenia were achieved from prospectively obtained clinical data on thrombocytopenia and bleeding events, animal studies on platelet life span and production rate and clinical use of fully automated measurement of reticulated platelets (immature platelet fraction). This review summarizes the pathophysiology of neonatal thrombocytopenia, current management including platelet transfusion thresholds and recent developments in megakaryopoietic agents. Furthermore, we propose a novel index score for bleeding risk in thrombocytopenic neonates to facilitate clinician's decision-making when to transfuse platelets.
Objective To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection ...to very preterm infants. Study design Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. Results There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. Conclusions Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. Trial registration ClinicalTrials.gov : NCT00413946.
Long-lived plasma cells in the bone marrow produce memory antibodies that provide immune protection persisting for decades after infection or vaccination but can also contribute to autoimmune and ...allergic diseases. However, the composition of the microenvironmental niches that are important for the generation and maintenance of these cells is only poorly understood. Here, we demonstrate that, within the bone marrow, plasma cells interact with the platelet precursors (megakaryocytes), which produce the prominent plasma cell survival factors APRIL (a proliferation-inducing ligand) and IL-6 (interleukin-6). Accordingly, reduced numbers of immature and mature plasma cells are found in the bone marrow of mice deficient for the thrombopoietin receptor (c-mpl) that show impaired megakaryopoiesis. After immunization, accumulation of antigen-specific plasma cells in the bone marrow is disturbed in these mice. Vice versa, injection of thrombopoietin allows the accumulation and persistence of a larger number of plasma cells generated in the course of a specific immune response in wild-type mice. These results demonstrate that megakaryocytes constitute an important component of the niche for long-lived plasma cells in the bone marrow.
Summary
This review summarizes current data on the pathomechanisms and clinical aspects of primary and secondary thrombocytosis in childhood. Primary thrombocytosis is extremely rare in childhood, ...mostly diagnosed at the beginning of the second decade of life. As in adults, the criteria of the Polycythemia Vera Group are appropriate to diagnose primary thrombocytosis. The pathomechansims of non‐familial forms are complex and include spontaneous formation of megakaryopoietic progenitors and increased sensitivity to thrombopoietin (Tpo). Familial forms can be caused by mutations in Tpo or Tpo receptor (c‐mpl) genes. These mutations result in overexpression of Tpo, sustained intracellular signalling or disturbed regulation of circulating Tpo. Treatment of primary thrombocytosis is not recommended if platelet counts are <1500/nl and bleeding or thrombosis did not occur in patient's history. In severe cases, decision on treatment should weigh potential risks of treatment options (hydroxyurea, anagrelide) against expected benefits for preventing thrombosis or haemorrhage. Secondary thrombocytosis is frequent in children, in particular in the first decade of life. Hepatic Tpo production is stimulated in acute response reaction to a variety of disorders. Thrombosis prophylaxis is not required, even at platelet counts >1000/nl, except for cases with additional prothrombotic risk factors.
Gonad morphogenesis relies on the correct spatiotemporal expression of a number of genes that together fulfill the differentiation of the bipotential gonad into testes or ovaries. As such, the ...transcription factors WT1 and GATA4 are pivotal for proper gonadal development. Here we address the contributions of GATA4 and WT1 to the sex differentiation phase in testes and ovaries. We applied an ex vivo technique for cultivating gonads in hanging droplets of media that were supplemented with vivo-morpholinos to knockdown WT1 and GATA4 either alone or in combination at the same developmental stage. We show that WT1 is equally important for both, the initial establishment and the maintenance of the sex-specific gene expression signature in testes and ovaries. We further identified Foxl2 as a novel putative downstream target gene of WT1. Moreover, knockdown of WT1 reduced mRNA levels of several molecular components of the hedgehog signaling pathway in XY gonads, whereas Gata4 vivo-morpholino treatment increased transcripts of Dhh and Ptch1 in embryonic testes. The data suggest that for its proper function, WT1 relies on the correct expression of the GATA4 protein. Furthermore, GATA4 down-regulates several ovarian promoting genes in testes, such as Ctnnb1, Fst, and Bmp2, suggesting that this repression is required for maintaining the male phenotype. In conclusion, this study provides novel insights into the role of WT1 and GATA4 during the sex differentiation phase and represents an approach that can be applied to assess other proteins with as yet unknown functions during gonadal development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The severity of neonatal abstinence syndrome (NAS) may be assessed with the Finnegan score (FS). Since the FS is laborious and subjective, alternative ways of assessment may improve quality of care.
...In this pilot study, we examined associations between the FS and routine monitoring data obtained from the electronic health record system.
The study included 205 neonates with NAS after intrauterine (n=23) or postnatal opioid exposure (n=182). Routine monitoring data were analyzed at 60±10 minutes (t-1) and 120±10 minutes (t-2) before each FS assessment. Within each time period, the mean for each variable was calculated. Readings were also normalized to individual baseline data for each patient and parameter. Mixed effects models were used to assess the effect of different variables.
Plots of vital parameters against the FS showed heavily scattered data. When controlling for several variables, the best-performing mixed effects model displayed significant effects of individual baseline-controlled mean heart rate (estimate 0.04, 95% CI 0.02-0.07) and arterial blood pressure (estimate 0.05, 95% CI 0.01-0.08) at t-1 with a goodness of fit (R2m) of 0.11.
Routine electronic data can be extracted and analyzed for their correlation with FS data. Mixed effects models show small but significant effects after normalizing vital parameters to individual baselines.
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