School of Paediatrics & Reproductive Health

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1024C>T (R342X) is a recurrent RHF6 mutation also found in the original Börjeson-Forssman-Lehmann syndrome family
(Nature Publishing Group, 2004) Lower, K.; Solders, G.; Bondeson, M.; Nelson, J.; Brun, A.; Crawford, J.; Malm, G.; Borjeson, M.; Turner, G.; Partington, M.; Gecz, J.
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1210 Methodological approaches to conceptualizing and modeling the effect of dynamic family structure on child behavior
(Nature Publishing Group, 2010) McDonald, S.; Moodie, E.; Lynch, J.; Satellite Symposia
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14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements
(Nature Publishing Group, 2012) Allou, L.; Lambert, L.; Amsallem, D.; Bieth, E.; Edery, P.; Destree, A.; Rivier, F.; Amor, D.; Thompson, E.; Nicholl, J.; Harbord, M.; Nemos, C.; Saunier, A.; Moustaine, A.; Vigouroux, A.; Jonveaux, P.; Philippe, C.
The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (−4 to−6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.
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17-alpha-hydroxyprogesterone caproate for the prevention of adverse neonatal outcome in multiple pregnancies: A randomized controlled trial
(Lippincott Williams & Wilkins, 2011) Lim, A.; Schuit, E.; Bloemenkamp, K.; Bernardus, R.; Duvekot, J.; Erwich, J.; van Eyck, J.; Groenwold, R.; Hasaart, T.; Hummel, P.; Kars, M.; Kwee, A.; van Oirschot, C.; van Pampus, M.; Papatsonis, D.; Porath, M.; Spaanderman, M.; Willekes, C.; Wilpshaar, J.; Mol, B.; et al.
OBJECTIVE: To estimate whether administration of 17[alpha]-hydroxyprogesterone caproate can prevent neonatal morbidity in multiple pregnancies by reducing the preterm birth rate. METHODS: We conducted a multicenter, double-blind, placebo-controlled randomized trial in 55 obstetric clinics in the Netherlands. Women with a multiple pregnancy were randomized to weekly injections of either 250 mg 17[alpha]-hydroxyprogesterone caproate or placebo, starting between 16 and 20 weeks of gestation and continuing until 36 weeks of gestation. The main outcome measure was adverse neonatal outcome. Secondary outcome measures were gestational age at delivery and delivery before 28, 32, and 37 weeks of gestation. RESULTS: We randomized 671 women. A composite measure of adverse neonatal outcome was present in 110 children (16%) born to mothers in the 17[alpha]-hydroxyprogesterone caproate group, and in 80 children (12%) of mothers in the placebo group (relative risk [RR] 1.34; 95% confidence interval [CI] 0.95–1.89). The mean gestational age at delivery was 35.4 weeks for the 17[alpha]-hydroxyprogesterone caproate group and 35.7 weeks for the placebo group (P=.32). Treatment with 17[alpha]-hydroxyprogesterone caproate did not reduce the delivery rate before 28 weeks (6% in the 17[alpha]-hydroxyprogesterone caproate group compared with 5% in the placebo group, RR 1.04; 95% CI 0.56–1.94), 32 weeks (14% compared with 10%, RR 1.37; 95% CI 0.91–2.05), or 37 weeks of gestation (55% compared with 50%, RR 1.11; 95% CI 0.97–1.28). CONCLUSION: 17[alpha]-hydroxyprogesterone caproate does not prevent neonatal morbidity or preterm birth in multiple pregnancies. CLINICAL TRIAL REGISTRATION: ISRCTN Register, www.isrctn.org, ISRCTN40512715. LEVEL OF EVIDENCE: I
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17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis
(Wiley-Blackwell, 2016) Combs, C.; Schuit, E.; Caritis, S.; Lim, A.; Garite, T.; Maurel, K.; Rouse, D.; Thom, E.; Tita, A.; Mol, B.
Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective.To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc).We searched literature databases, trial registries and references in published articles.Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies.Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34 weeks of gestation.Three RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32 weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes.Prophylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration.17-Hydroxyprogesterone caproate had no significant impact on the outcome or duration of triplet pregnancy.
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1D09C3, an mAb specific for MHC-II
(Pharmapress Ltd, 2008) Zola, H.; Beare, A.
GPC Biotech AG is developing 1D09C3, an anti-MHC class II (HLA-DR) fully human IgG4 antibody isolated by MorphoSys AG (from its HuCAL library of human antibodies), for the potential treatment of hematological malignancies. In December 2006, positive safety data from two phase I clinical trials were reported. Final phase I data were expected in mid-2007; however, no additional data have been released at the time of publication.
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2015 RANZCOG Arthur Wilson Memorial Oration 'From little things, big things grow: the importance of periconception medicine'
(Wiley, 2015) Norman, R.
The time of our conception is when we are most vulnerable to survival and growing as a healthy human being. Genetic and environmental effects on gametes and the developing embryo can be literally life-and-death events with regard to the successful outcome of pregnancy. In the past decade, we have also understood that environmental factors under which the gametes grow and the embryo develops have lifelong implications with regard to developmental origins of health and disease. We now know that parenting begins before conception in that a compromised egg or sperm from either parent can alter the trajectory of development even if the embryo and intrauterine environment is optimal. There are now a large number of factors known to impact on the gametes to adversely affect them, including obesity, nutrition, cigarette smoking and environmental pollutants. The increasing use of in vitro fertilisation across the world exposes developing embryos to less than optimal environmental conditions through altered culture media, gases and potential pollutants from plastics, air and water. Many of these environmental exposures have not undergone experimental investigation and yet widely implemented in thousands of laboratories across the world. There have been many attempts to set up periconception planning either through the health service, the print and electronic media or through government action. We as a profession, as well as our Colleges, could do much better job in this area of preventative medicine by developing better guidelines and education for professional colleagues, the health service and the community.
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236 effect of cyclic adenosine monophosphate modulator regulators in association with bmp15 on bovine embryo development in vitro
(CSIRO, 2015) Machado, M.F.; Nogueira, M.F.; Gilchrist, R.B.; Sutton-McDowall, M.L.; Mottershead, D.G.; White, M.A.; Thompson, J.G.; : Australia)
BMP15 is a promising peptide to improve oocyte competence; also, addition of cyclic adenosine monophosphate modulator (cAMP) regulators prevents spontaneous maturation in vitro and promotes embryo development. We aimed to assess embryo development after prematuration [pre-in vitro maturation (IVM)] with IBMX and Forskolin (FSK) and maturation in the presence or absence of a purified pro mature region of BMP15. Immature cumulus-oocyte complexes (COC) were cultured in vitroMat (IVF Vet Solutions, Adelaide, Australia) plus 4mgmL(-1) fatty acid free-BSA and rhFSH (0.1IUmL(-1)), then divided into the following treatment groups: 1) spontaneous IVM: 24h of IVM; 2) spontaneous IVM+BMP15: 24h of IVM in the presence of BMP15 (100ngmL(-1)); 3) Pre 2 h: pretreatment with IBMX (500µM; Sigma-Aldrich) and FSK (100µM; Sigma-Aldrich) for 2h following 24h maturation; and 4) Pre 2 h+BMP15: pretreatment with IBMX and FSK for 2h following 24h maturation in the presence of BMP15 (100ngmL(-1)). After maturation, oocytes were inseminated and zygotes were cultured for 5 days in VitroCleave (IVF Vet Solutions, Adelaide, Australia) and transferred into VitroBlast (IVF Vet Solutions, Adelaide, Australia) until blastocyst assessment (Days 7 and 8). Zona-intact embryos were retrieved to assess differential staining of trophectoderm and inner cell mass. Data were transformed into a logarithm and analysed by 1-way ANOVA and post hoc least significant difference using SigmaStat software (SPSS Inc., San Jose, CA, USA; P<0.05). There was no difference among groups on cleavage rates or blastocyst rates at Day 7; however, both Pre 2h treatments increase hatched blastocyst rates at Day 8 of embryo development (Table 1). Supplementation with BMP15 increased total blastocyst rates at Day 8, regardless of pretreatment with IBMX+FSK (Table 1). Our data demonstrate that embryos from oocytes matured in the presence of BMP15 or pretreated with IBMX+FSK increase trophectoderm and total cell numbers; however, no differences were observed for inner cell mass. We conclude that Pre 2h treatment or BMP15 increase embryo development; however, no effect of cAMP regulators in association with BMP15 on embryo development was observed.
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25-hydroxyvitamin D concentrations in children with Crohn's disease supplemented with either 2000 or 400 IU daily for 6 months: a randomized controlled study
(Mosby, 2014) Wingate, K.E.; Jacobson, K.; Issenman, R.; Carroll, M.; Barker, C.; Israel, D.; Brill, H.; Weiler, H.; Barr, S.I.; Li, W.; Lyon, M.R.; Green, T.J.
OBJECTIVES: To assess vitamin D status of pediatric patients with Crohn's disease (CD) and to compare their serum 25-hydroxyvitamin D (s-25OHD) with established cutoffs and assess whether 6 months of supplementation with 2000 IU/d, vs 400 IU/d, would reduce the group prevalence of vitamin D below these cutoffs. STUDY DESIGN: Subjects 8-18 years (n = 83) with quiescent CD were randomized to either 400 or 2000 IU vitamin D3/d for 6 months. RESULTS: Baseline mean ± SD s-25OHD was 24 ± 8 ng/mL; 13 subjects (16%) had an s-25OHD <16 ng/mL, 27 (33%) < 20 ng/mL, and 65 (79%) < 30 ng/mL. There was no significant difference between groups in achieving the cutoffs of 16 ng/mL or 20 ng/mL at 6 months; however, only 35% of the 400 IU group achieved the greater cutoff of 30 ng/mL compared with 74% in the 2000 IU group (P < .001). Baseline adjusted mean s-25OHD concentrations at 6 months were 9.6 ng/mL (95% CI 6.0-13.2, P < .001) greater in the 2000 IU than the 400 IU group. Disease activity was not affected by supplement dose. Few subjects exceeded safety marker cutoffs, and this did not differ by dose. CONCLUSIONS: At baseline, a high proportion of patients had a mean s-25OHD >20 ng/mL. 2000 IU vitamin D3/d is more effective in raising s-25OHD concentrations to > 30 ng/mL in children with CD than 400 IU/d, but both treatments were equally effective at achieving 16 or 20 ng/mL.
Open Access
4-aminobutyrate aminotrasferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease
(Public Library of Science, 2011) Jirholt, J.; Asling, B.; Hammond, P.; Davidson, G.; Knutsson, M.; Walentinsson, A.; Jensen, J.; Lehmann, A.; Agreus, L.; Lagerstrom-Fermer, M.; Dubé, M.-P.
Gastro-esophageal reflux disease (GERD) is partly caused by genetic factors. The underlying susceptibility genes are currently unknown, with the exception of COL3A1. We used three independent GERD patient cohorts to identify GERD susceptibility genes. Thirty-six families, demonstrating dominant transmission of GERD were subjected to whole genome microsatellite genotyping and linkage analysis. Five linked regions were identified. Two families shared a linked region (LOD 3.9 and 2.0) on chromosome 16. We used two additional independent GERD patient cohorts, one consisting of 219 trios (affected child with parents) and the other an adult GERD case control cohort consisting of 256 cases and 485 controls, to validate individual genes in the linked region through association analysis. Sixty six single nucleotide polymorphism (SNP) markers distributed over the nine genes present in the linked region were genotyped in the independent GERD trio cohort. Transmission disequilibrium test analysis followed by multiple testing adjustments revealed a significant genetic association for one SNP located in an intron of the gene 4-aminobutyrate aminotransferase (ABAT) (Padj = 0.027). This association did not replicate in the adult case-control cohort, possibly due to the differences in ethnicity between the cohorts. Finally, using the selective ABAT inhibitor vigabatrin (c-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3611.4 % (p = 0.007) and the reflux events from 3.160.4 to 0.860.4 (p = 0.007). Our results demonstrate the direct involvement of ABAT in pathways affecting lower esophageal sphincter (LES) control and identifies ABAT as a genetic risk factor for GERD.
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4-Hydroxyglutamate is a novel predictor of preeclampsia
(Elsevier, 2019) Sovio, U.; McBride, N.; Wood, A.M.; Cook, E.; Gaccioli, F.; Charnock-Jones, D.S.; Lawlor, D.A.; Smith, G.C.S.
BACKGROUND:Pre-term pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A multi-centre randomized-controlled trial has shown that first-trimester screening followed by treatment of high-risk women with aspirin reduces the risk of pre-term pre-eclampsia. However, the biomarkers currently employed in risk prediction are only weakly associated with the outcome. METHODS:We conducted a case-cohort study within the Pregnancy Outcome Prediction study to analyse untargeted maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age (wkGA) in women with pre-eclampsia delivering at term (n = 165) and pre-term (n = 29), plus a random sample of the cohort (n = 325). We used longitudinal linear mixed models to identify candidate metabolites at 20/28 wkGA that differed by term pre-eclampsia status. Candidates were validated using measurements at 36 wkGA in the same women. We then tested the association between the 12-, 20- and 28-wkGA measurements and pre-term pre-eclampsia. We externally validated the association using 24- to 28-wkGA samples from the Born in Bradford study (25 cases and 953 controls). RESULTS:We identified 100 metabolites that differed most at 20/28 wkGA in term pre-eclampsia. Thirty-three of these were validated (P < 0.0005) at 36 wkGA. 4-Hydroxyglutamate and C-glycosyltryptophan were independently predictive at 36 wkGA of term pre-eclampsia. 4-Hydroxyglutamate was also predictive (area under the receiver operating characteristic curve, 95% confidence interval) of pre-term pre-eclampsia at 12 (0.673, 0.558-0.787), 20 (0.731, 0.657-0.806) and 28 wkGA (0.733, 0.627-0.839). The predictive ability of 4-hydroxyglutamate at 12 wkGA was stronger than two existing protein biomarkers, namely PAPP-A (0.567, 0.439-0.695) and placenta growth factor (0.589, 0.463-0.714). Finally, 4-hydroxyglutamate at 24-28 wkGA was positively associated with pre-eclampsia (term or pre-term) among women from the Born in Bradford study. CONCLUSIONS:4-hydroxyglutamate is a novel biochemical predictor of pre-eclampsia that provides better first-trimester prediction of pre-term disease than currently employed protein biomarkers.
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[46-OR]: early and late onset preeclampsia versus small for gestational age risks in subsequent pregnancies
(Elsevier, 2015) Bernardes, T.; Mol, B.; Ravelli, A.; van den Berg, P.; Stolk, R.; Groen, H.
OBJECTIVES: Current literature suggests that early and late onset preeclampsia should be treated as distinct entities and that early onset preeclampsia shares pathophysiology aspects with intrauterine growth restriction. Our objective was to investigate whether 5th percentile small for gestational age (SGA) in a 1st pregnancy increases 2nd pregnancy risk of early and late onset preeclampsia, and vice versa. METHODS: We studied a cohort of 1st and 2nd singleton pregnancies of 262.934 women from the Dutch Perinatal Registry who gave birth between 2000 and 2007. We analyzed 2nd pregnancy risk of SGA, early and late onset preeclampsia using logistic regression considering in each case the absence of the outcome in the first pregnancy. Gestational age, maternal age, iatrogenic preterm birth, chronic hypertension, max diastolic pressure, diabetes, ethnicity and socioeconomic status were adjusted for. RESULTS: In women without 1st pregnancy preeclampsia, prevalences of early and late onset preeclampsia in the 2nd pregnancy were 0.05% and 0.6%, respectively. SGA in the 1st pregnancy increased these prevalences to 0.1% and 1.1%. After adjustment for confounders, 2nd pregnancy late onset preeclampsia risk was increased (aOR 1.3; 95% CI 1.1-1.6) due to SGA in the 1st pregnancy but early onset preeclampsia did not increase (aOR 1.3; 95% 0.7-2.3). In women that did not present SGA in the 1st pregnancy, SGA prevalence in term 2nd pregnancies was 3.3%. Prevalence was higher in women who presented 1st pregnancy late and early preeclampsia: 5.4% (aOR 1.6; 95% CI 1.4-1.9) and 10.2% (aOR 3.2; 95% CI 2.5-4.0), respectively. CONCLUSIONS: In the absence of preeclampsia in the 1st pregnancy, SGA increased late but not early onset 2nd pregnancy preeclampsia risks. Second pregnancy SGA risk was increased by preeclampsia in the 1st pregnancy, especially in early onset cases. DISCLOSURES: T.P. Bernardes: None. B.W. Mol: None. A.C. Ravelli: None. P.P. van den Berg: None. R.P. Stolk: None. H. Groen: None.
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4CMenB sustained vaccine effectiveness against invasive meningococcal B disease and gonorrhoea at three years post program implementation
(Elsevier, 2023) Wang, B.; Giles, L.; Andraweera, P.; McMillan, M.; Almond, S.; Beazley, R.; Mitchell, J.; AHoure, M.; Denehy, E.; Flood, L.; Marshall, H.
Abstract not available
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A 'no-fault' cerebral palsy pension scheme would benefit all Australians
(Blackwell Publishing Asia, 2011) MacLennan, A.
The Australian Federal Productivity Commission is proposing two new schemes to better support those with major disability. The main National Disability Insurance Scheme (NDIS) will provide long-term care and support for the disabled. A smaller scheme, the National Injury Insurance Scheme (NIIS), will provide ‘no-fault ‘support for those following an accident or ‘medical injury’. It is proposed that cerebral palsy (CP) is part of the NIIS. While this brings quicker and more equitable benefits to CP families, the scheme labels CP as a ‘medical accident’ and infers preventability. Obstetricians will fund much of the system. Despite being labelled a ‘no-fault’ system, maternity staff can still be litigated for extensive ‘head of damages’, eg loss of earning capacity. An additional option is for federal/state legislation to introduce a true ‘no-fault’ lifetime pension specifically for all children on CP registers. This pension would be graded by degree of disability and dependent on waiving civil litigation. Savings in medico-legal costs and potentially a 7% reduction in caesarean delivery would cover the estimated annual cost of $50 000 per annum indexed life pension for severe CP cases and the total annual cost of AUD $93 million for Australia. This pension and the NDIS would help cover the needs of children with CP without recourse to prolonged litigation and without detriment to the maternity services of Australia, caused by defensive obstetrics and maternity hospital closure because of CP litigation.
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A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology
(Karger, 2009) Talseth-Palmer, B.; Bowden, N.; Meldrum, C.; Nicholl, J.; Thompson, E.; Friend, K.; Liebelt, J.; Bratkovic, D.; Haan, E.; Yu, S.; Scott, R.
Children with intellectual disability, dysmorphic features, malformations and/or growth abnormalities frequently display normal karyotypes. Recent studies have shown that genome-wide single nucleotide polymorphism (SNP) arrays can be effective in detecting abnormalities involving copy number variation (CNV), deletions, duplications and loss of heterozygosity (LOH) that routine cytogenetic tests fail to identify. Five patients with various degrees of intellectual disability and/or dysmorphic features and other malformations were whole-genome genotyped using the Human-1 Genotyping BeadChip--Exon-Centrix 100K SNP arrays (Illumina). All patients had undergone routine cytogenetic testing; four patients had normal karyotypes, while one patient had an apparently balanced complex translocation involving chromosomes 1q25, 1q32, 2q23, 7q22 and 16q24. We detected deletions on chromosome 1q44 and 13q31.1 in one patient, and LOH of the entire chromosome 2 in another patient, both with cytogenetically normal karyotypes. The patient with the complex translocation had a deletion on chromosome 7q22.2-22.3, which is in conjunction with one of the translocation breakpoints. Our findings provide further evidence of there being a critical region for the development of microcephaly and corpus callosum abnormalities in children with distal 1q deletions. We have also shown that apparently balanced complex translocations might not be balanced at the DNA level, and we report the fourth case of paternal uniparental disomy of chromosome 2. The results of this study suggest that it may be desirable to investigate idiopathic mental retardation using genome-wide SNP arrays, in conjunction with other cytogenetic and molecular techniques.
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A 3-year follow-up of the intellectual and academic functioning of children receiving central nervous system prophylactic chemotherapy for leukemia
(LIPPINCOTT WILLIAMS & WILKINS, 1996) Brown, R.; Sawyer, M.; Antoniou, G.; Toogood, I.; Rice, M.; Thompson, N.; Madan-Swain, A.
This prospective study compared the intellectual and academic functioning of two groups of children treated for cancer over the 3 years after their diagnosis. One group consisted of children who received central nervous system (CNS) prophylactic chemotherapy, and the other group consisted of children with cancer who did not receive CNS chemotherapy. The results suggest that the children who received CNS chemotherapy experienced more adverse effects from their treatment in the area of academic functioning than the children who did not receive CNS chemotherapy. Although there were no differences in the academic functioning of the two groups of children immediately after their diagnosis, 3 years postdiagnosis, the CNS-treated children scored more poorly on academic tests of reading, spelling, and arithmetic than the non-CNS-treated children. The results suggest that CNS chemotherapy prophylaxis may impede academic achievement.
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A 41-year-old woman with premature menopause
(Medicine Today Pty Ltd, 2006) MacLennan, A.
Should this woman be encouraged to continue hormone therapy (HT) until the normal age of menopause? [Author's abstract]
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A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF
(Elsevier, 2020) Simón, C.; Gómez, C.; Cabanillas, S.; Vladimirov, I.; Castillón, G.; Giles, J.; Boynukalin, K.; Findikli, N.; Bahçeci, M.; Ortega, I.; Vidal, C.; Funabiki, M.; Izquierdo, A.; López, L.; Portela, S.; Frantz, N.; Kulmann, M.; Taguchi, S.; Labarta, E.; Colucci, F.; et al.
RESEARCH QUESTION:Does clinical performance of personalized embryo transfer (PET) guided by endometrial receptivity analysis (ERA) differ from frozen embryo transfer (FET) or fresh embryo transfer in infertile patients undergoing IVF? DESIGN:Multicentre, open-label randomized controlled trial; 458 patients aged 37 years or younger undergoing IVF with blastocyst transfer at first appointment were randomized to PET guided by ERA, FET or fresh embryo transfer in 16 reproductive clinics. RESULTS:Clinical outcomes by intention-to-treat analysis were comparable, but cumulative pregnancy rate was significantly higher in the PET (93.6%) compared with FET (79.7%) (P = 0.0005) and fresh embryo transfer groups (80.7%) (P = 0.0013). Analysis per protocol demonstrates that live birth rates at first embryo transfer were 56.2% in PET versus 42.4% in FET (P = 0.09), and 45.7% in fresh embryo transfer groups (P = 0.17). Cumulative live birth rates after 12 months were 71.2% in PET versus 55.4% in FET (P = 0.04), and 48.9% in fresh embryo transfer (P = 0.003). Pregnancy rates at the first embryo transfer in PET, FET and fresh embryo transfer arms were 72.5% versus 54.3% (P = 0.01) and 58.5% (P = 0.05), respectively. Implantation rates at first embryo transfer were 57.3% versus 43.2% (P = 0.03), and 38.6% (P = 0.004), respectively. Obstetrical outcomes, type of delivery and neonatal outcomes were similar in all groups. CONCLUSIONS:Despite 50% of patients dropping out compared with 30% initially planned, per protocol analysis demonstrates statistically significant improvement in pregnancy, implantation and cumulative live birth rates in PET compared with FET and fresh embryo transfer arms, indicating the potential utility of PET guided by the ERA test at the first appointment.
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A Biosensing System Based on Extracellular Potential recording of Ligand-Gated Ion Channel Function Overexpressed in Insect cells
(Amer Chemical Soc, 2003) Haruyama, T.; Bongsebandhu-Phubhakdi, S.; Nakamura, I.; Mottershead, D.; Keinanen, K.; Kobatake, E.; Aizawa, M.
We have used outer cell potential measurement to record agonist-dependent cellular responses in cells engineered to express ligand-gated ion channels and grown on a microelectrode surface. Application of glutamate, a natural agonist, induced a complex and robust potentiometric response in cells expressing homomeric GluR-D glutamate receptor, but not in nonexpressing control cells. The response consisted of an initial decrease in outer potential followed by a transient increase and was not obtained for other amino acids devoid of agonist activity at glutamate receptors. Furthermore, the pharmacological agonist of the GluR-D receptor, kainate, also produced the potentiometric response whereas 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive antagonist, was not active in itself but attenuated the responses to glutamate. The time course of the measured changes was slow, which may be partially due to the ligand being applied by free diffusion but may also reflect a contribution by secondary changes in the behavior of the cells. This novel approach should be applicable to other ligand-gated ion channels and holds promise as a cell-based biosensor for high-throughput drug screening and other applications.
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A bivalent Neisserie meningitidis recombinant lipidated factor H binding protein vaccine in young adults: results of a randomised, controlled, dose-escalation phase 1 trial
(Elsevier Sci Ltd, 2012) Richmond, P.; Nissen, M.; Marshall, H.; Lambert, S.; Roberton, D.; Gruber, W.; Jones, T.; Arora, A.
Neisseria meningitidis is a leading cause of meningitis and septicaemia, but a broadly-protective vaccine against endemic serogroup B disease is not licensed and available. The conserved, outer-membrane lipoprotein factor H binding protein (fHBP, also known as LP2086) is expressed as one of two subfamily variants in virtually all meningococci. This study investigated the safety, tolerability, and immunogenicity of a recombinant-expressed bivalent fHBP (r-fHBP) vaccine in healthy adults. Participants (N=103) aged 18-25 years were recruited into three ascending dose level cohorts of 20, 60, and 200μg of a bivalent r-fHBP vaccine formulation and randomised to receive vaccine or placebo at 0, 1, and 6 months. The vaccine was well tolerated. Geometric mean titres (GMTs) for r-fHBP subfamily-specific IgG antibodies increased 19-168-fold from pre-vaccination to post-dose 2 in a dose level-dependent manner. In addition, robust serum bactericidal assay using human complement (hSBA) responses for strains expressing both homologous and heterologous fHBP variants were observed. After three vaccinations, 16-52% of the placebo group and 47-90%, 75-100%, and 88-100%, of the 20, 60, and 200μg dose levels, respectively, had seroprotective (≥ 1:4) hSBA titres against six serogroup B strains. The bivalent r-fHBP vaccine was well tolerated and induced robust bactericidal activity against six diverse serogroup B strains in young adults at the 60 and 200μg dose levels.

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