APCR, factor V gene known and novel SNPs and adverse pregnancy outcomes in an Irish cohort of pregnant women

<p>Abstract</p> <p>Background</p> <p>Activated Protein C Resistance (APCR), a poor anticoagulant response of APC in haemostasis, is the commonest heritable thrombophilia. Adverse outcomes during pregnancy have been linked to APCR. This study determined the frequency of APCR, factor V gene known and novel SNPs and adverse outcomes in a group of pregnant women.</p> <p>Methods</p> <p>Blood samples collected from 907 pregnant women were tested using the Coatest^®Classic and Modified functional haematological tests to establish the frequency of APCR. PCR-Restriction Enzyme Analysis (PCR-REA), PCR-DNA probe hybridisation analysis and DNA sequencing were used for molecular screening of known mutations in the factor V gene in subjects determined to have APCR based on the Coatest^®Classic and/or Modified functional haematological tests. Glycosylase Mediated Polymorphism Detection (GMPD), a SNP screening technique and DNA sequencing, were used to identify SNPs in the factor V gene of 5 APCR subjects.</p> <p>Results</p> <p>Sixteen percent of the study group had an APCR phenotype. Factor V Leiden (FVL), FV Cambridge, and haplotype (H) R2 alleles were identified in this group. Thirty-three SNPs; 9 silent SNPs and 24 missense SNPs, of which 20 SNPs were novel, were identified in the 5 APCR subjects. Adverse pregnancy outcomes were found at a frequency of 35% in the group with APCR based on Classic Coatest^®test only and at 45% in the group with APCR based on the Modified Coatest^®test. Forty-eight percent of subjects with FVL had adverse outcomes while in the group of subjects with no FVL, adverse outcomes occurred at a frequency of 37%.</p> <p>Conclusions</p> <p>Known mutations and novel SNPs in the factor V gene were identified in the study cohort determined to have APCR in pregnancy. Further studies are required to investigate the contribution of these novel SNPs to the APCR phenotype. Adverse outcomes including early pregnancy loss (EPL), preeclampsia (PET) and intrauterine growth restriction (IGUR) were not significantly more frequent in subjects with APCR compared to normal pregnant women however Pregnancy induced hypertension (PIH) was found to be associated with FVL in our study group.</p

Investigating the role of early low-dose aspirin in diabetes: A phase III multicentre double-blinded placebo-controlled randomised trial of aspirin therapy initiated in the first trimester of diabetes pregnancy

Background: Preeclampsia, preterm birth and low birth weight represent key contributing factors to perinatal morbidity and mortality. Pregnancies complicated by type 1 and type 2 diabetes are at increased risk of these complications, which are purported to be largely attributed to placental dysfunction. Studies investigating a potential role for aspirin therapy in optimizing perinatal outcome have consistently failed to demonstrate a benefit among women with pre-existing diabetes, and yet widespread aspirin administration has become common practice in many centres. This study seeks to examine the effect of aspirin therapy, administered from the first trimester until 36 weeks gestation, on perinatal outcome in women with established pre-pregnancy diabetes. Our hypothesis is that aspirin therapy will reduce complications mediated by placental dysfunction, and improve perinatal outcomes. Methods: This phase III double-blinded, placebo-controlled randomized clinical trial will be conducted in seven tertiary-level perinatology centres in Ireland. Consenting participants who meet all eligibility criteria will be allocated randomly to either aspirin 150 mg once daily or matching placebo, commenced between 11 + 0 and 13 + 6 weeks. Allocation will take place electronically using software by Clininfo with randomization tables provided by the trial biostatistician. The primary outcome will be a composite clinical measure of placental dysfunction (preeclampsia, preterm birth before 34 weeks, birthweight below the 10th centile or perinatal mortality). This trial has been set up such that it is parallel in design and is a superiority study. No participants have been recruited yet. The trial has been registered with Eudra Clinical Trials - EudraCT Number 2018-000770-29. Funding for this trial was granted by the Health research Board (HRB) 1/9/2017(DIFA-2017-026). Discussion: Aspirin therapy has been investigated for the prevention of preeclampsia owing to its reduction on thromboxane production. Previous studies have failed to demonstrate a beneficial effect of aspirin on perinatal outcome amongst women with type I or type II diabetes. It is plausible that the failure to observe benefit to date, among the limited aspirin studies that have included participants with diabetes, may be a consequence of aspirin initiation too late in pregnancy to exert any effect on placentation. We believe that if aspirin is to be used for the prevention of placental dysfunction, it must be initiated before the second active phase of trophoblast invasion, which takes place from 14 weeks’ gestation onwards. No randomized trials investigating the role of aspirin in prevention of preeclampsia in pregnancies complicated by diabetes have previously initiated treatment in the first trimester, the gestational period at which it is most likely to exert an effect on placentation

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Healing trauma in a traumatising environment with young adult men

In this article, the authors outline the interventions offered by the Offender Personality Disorder (OPD) Pathways Complex Needs Service (PCNS) in a Young Offenders Institute and Category C men’s prison for addressing trauma with young adult men within the prison environment and highlight the challenges of trauma-informed practice and interventions within this context. The importance of collaborative work with the young men will be emphasised within the development of clinical formulations and responsive treatment plans. Direct and non-direct trauma therapies offered by the PCNS will be outlined (e.g., Eye Movement Desensitisation and Reprocessing (EMDR) Therapy, sensory approaches). The article will emphasise the importance of adopting a multidisciplinary and system-wide approach to healing trauma, and the crucial role of the PCNS prison officers. The various clinical spaces available for staff to process traumatogenic material will be highlighted as key to maintaining staff wellbeing and resilience. A reflection from a prison officer working in the service will be provided. This article aims to highlight the importance of adopting a holistic and system-wide approach to healing trauma for young men in custody

Apcr, factor v gene known and novel snps and adverse pregnancy outcomes in an irish cohort of pregnant women

Background: Activated Protein C Resistance (APCR), a poor anticoagulant response of APC in haemostasis, is the commonest heritable thrombophilia. Adverse outcomes during pregnancy have been linked to APCR. This study determined the frequency of APCR, factor V gene known and novel SNPs and adverse outcomes in a group of pregnant women. Methods: Blood samples collected from 907 pregnant women were tested using the Coatest (R) Classic and Modified functional haematological tests to establish the frequency of APCR. PCR-Restriction Enzyme Analysis (PCR-REA), PCR-DNA probe hybridisation analysis and DNA sequencing were used for molecular screening of known mutations in the factor V gene in subjects determined to have APCR based on the Coatest (R) Classic and/or Modified functional haematological tests. Glycosylase Mediated Polymorphism Detection (GMPD), a SNP screening technique and DNA sequencing, were used to identify SNPs in the factor V gene of 5 APCR subjects. Results: Sixteen percent of the study group had an APCR phenotype. Factor V Leiden (FVL), FV Cambridge, and haplotype (H) R2 alleles were identified in this group. Thirty-three SNPs; 9 silent SNPs and 24 missense SNPs, of which 20 SNPs were novel, were identified in the 5 APCR subjects. Adverse pregnancy outcomes were found at a frequency of 35% in the group with APCR based on Classic Coatest (R) test only and at 45% in the group with APCR based on the Modified Coatest (R) test. Forty-eight percent of subjects with FVL had adverse outcomes while in the group of subjects with no FVL, adverse outcomes occurred at a frequency of 37%. Conclusions: Known mutations and novel SNPs in the factor V gene were identified in the study cohort determined to have APCR in pregnancy. Further studies are required to investigate the contribution of these novel SNPs to the APCR phenotype. Adverse outcomes including early pregnancy loss (EPL), preeclampsia (PET) and intrauterine growth restriction (IGUR) were not significantly more frequent in subjects with APCR compared to normal pregnant women however Pregnancy induced hypertension (PIH) was found to be associated with FVL in our study group

Acquired Activated Protein C Resistance, Thrombophilia and Adverse Pregnancy Outcomes: A Study Performed in an Irish Cohort of Pregnant Women

The combination of thrombophilia and pregnancy increases the risk of thrombosis and the potential for adverse outcomes during pregnancy. The most significant common inherited risk factor for thrombophilia is activated protein C resistance (APCR), a poor anticoagulant response of APC in haemostasis, which is mainly caused by an inherited single-nucleotide polymorphism (SNP), factor V G1691A (FV Leiden) (FVL), referred as inherited APCR. Changes in the levels of coagulation factors: FV, FVIII, and FIX, and anticoagulant factors: protein S (PS) and protein C (PC) can alter APC function causing acquired APCR. Prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T are prothrombotic SNPs which in association with APCR can also increase the risk of thrombosis amongst Caucasians. In this study, a correlation between an acquired APCR phenotype and increased levels of factors V, VIII, and IX was demonstrated. Thrombophilic mutations amongst our acquired APCR pregnant women cohort are relatively common but do not appear to exert a severe undue adverse effect on pregnancy

Apcr, factor v gene known and novel snps and adverse pregnancy outcomes in an irish cohort of pregnant women

Background: Activated Protein C Resistance (APCR), a poor anticoagulant response of APC in haemostasis, is the commonest heritable thrombophilia. Adverse outcomes during pregnancy have been linked to APCR. This study determined the frequency of APCR, factor V gene known and novel SNPs and adverse outcomes in a group of pregnant women. Methods: Blood samples collected from 907 pregnant women were tested using the Coatest (R) Classic and Modified functional haematological tests to establish the frequency of APCR. PCR-Restriction Enzyme Analysis (PCR-REA), PCR-DNA probe hybridisation analysis and DNA sequencing were used for molecular screening of known mutations in the factor V gene in subjects determined to have APCR based on the Coatest (R) Classic and/or Modified functional haematological tests. Glycosylase Mediated Polymorphism Detection (GMPD), a SNP screening technique and DNA sequencing, were used to identify SNPs in the factor V gene of 5 APCR subjects. Results: Sixteen percent of the study group had an APCR phenotype. Factor V Leiden (FVL), FV Cambridge, and haplotype (H) R2 alleles were identified in this group. Thirty-three SNPs; 9 silent SNPs and 24 missense SNPs, of which 20 SNPs were novel, were identified in the 5 APCR subjects. Adverse pregnancy outcomes were found at a frequency of 35% in the group with APCR based on Classic Coatest (R) test only and at 45% in the group with APCR based on the Modified Coatest (R) test. Forty-eight percent of subjects with FVL had adverse outcomes while in the group of subjects with no FVL, adverse outcomes occurred at a frequency of 37%. Conclusions: Known mutations and novel SNPs in the factor V gene were identified in the study cohort determined to have APCR in pregnancy. Further studies are required to investigate the contribution of these novel SNPs to the APCR phenotype. Adverse outcomes including early pregnancy loss (EPL), preeclampsia (PET) and intrauterine growth restriction (IGUR) were not significantly more frequent in subjects with APCR compared to normal pregnant women however Pregnancy induced hypertension (PIH) was found to be associated with FVL in our study group

ATLANTIC-DIP:raised maternal body mass index (BMI) adversely affects maternal and fetal outcomes in glucose-tolerant women according to International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria

Context: Raised maternal body mass index (BMI) in association with hyperglycemia is associated with adverse pregnancy outcome. The contribution of raised BMI as an independent risk factor for adverse pregnancy outcome is of growing concern and increasing prevalence. Objective: The aim of this study was to investigate the effects of raised maternal BMI on pregnancy outcome in glucose-tolerant women using the International Association of Diabetes and Pregnancy Study Groups criteria. Participants and Setting: We studied a cohort of glucose-tolerant, pregnant women (n = 3656) who were attending antenatal obstetric clinics and were recruited to a universal screening program for gestational diabetes under the ATLANTIC-DIP partnership. Design: We conducted a prospective observational study of pregnancy outcome. Maternal outcomes include glucose, delivery mode, pregnancy-induced hypertension, preeclampsia, antepartum hemorrhage, and postpartum hemorrhage. Fetal outcomes included birth weight, congenital malformation, fetal death, neonatal jaundice, hypoglycemia, and respiratory distress. Results: Increasing maternal BMI was associated with adverse pregnancy outcomes: higher cesarean section rates, preeclampsia, pregnancy-induced hypertension, increased birth weight, and congenital malformation. The association of glucose with adverse pregnancy outcome was weak and did not interact with raised BMI. A BMI threshold of 28 kg/m(2) was associated with a significant rise in adverse pregnancy outcome. Conclusions: Raised maternal BMI, within the overweight range, is associated with adverse pregnancy outcomes. These adverse effects of BMI occur independently of maternal glucose. It is apparent that pregnancy unmasks an underlying unhealthy metabolic milieu in obese and overweight women. (J Clin Endocrinol Metab 97: E608-E612, 2012