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Biomedical subjects

L Regan

Publications and source records attributed to L Regan.

At least 55 records · Page 3Linked to original sources
PubMed2001

Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage.

Activated protein C (APC) resistance, both in its congenital form, due to the factor V Leiden mutation, and in its acquired form, are important risk factors for systemic venous thrombosis. In view of the suspected thrombotic aetiology of some cases of recurrent miscarriage, the prevalence of APC resistance was determined among 1111 consecutive Caucasian women with a history of either recurrent early miscarriage (three or more consecutive pregnancy losses at <12 weeks gestation; n = 904) or a history of at least one late miscarriage (>12 weeks gestation; n = 207). A control group of 150 parous Caucasian women with no previous history of adverse pregnancy outcome was also studied. Acquired APC resistance was significantly more common among both women with recurrent early miscarriage (8.8%: 80/904; P = 0.02) and those with late miscarriage (8.7%: 18/207; P = 0.04) compared with controls (3.3%: 5/150). In contrast, the frequency of the factor V Leiden allele was similar among (i) women with recurrent early miscarriage (3.3%:60/1808; 58 heterozygotes and one homozygote), (ii) those with late miscarriage (3.9%:16/414; 14 heterozygotes and one homozygote) and (iii) the control group (4.0%:12/300; 12 heterozygotes). Acquired but not congenital APC resistance (due to the factor V Leiden mutation) is associated with both early and late miscarriage.

Abortion, Habitual↗
PubMed2001

Intrauterine haematomas in a recurrent miscarriage population.

BACKGROUND: This study examines the effect of intrauterine haematomas (IUH) discovered during early pregnancy ultrasound scanning in patients with recurrent miscarriage. Previous studies of IUHs have reported conflicting findings, and none studied women with recurrent miscarriage. METHODS: A total of 341 women with a viable pregnancy was included. Women with an IUH (n = 41) were compared with those without (n = 300). RESULTS: An IUH was identified by ultrasound in 12% (41/341) women. There were no differences in the number of live births between the two groups (25/41, 61% in the IUH group compared with 169/300, 56% without an IUH) or the number of miscarriages (6/41, 15% with an IUH compared with 72/300, 24% without an IUH). Anti-phospholipid antibodies were more common in the IUH group (21/31, 68% compared with 103/244, 42% P < 0.01). More women with haematomas experienced vaginal bleeding (16/31, 52% compared with 47/244, 19%, P < 0.01). These associations did not affect pregnancy outcome. Also, no increase in the rate of pregnancy complications was observed in the IUH group. CONCLUSIONS: The presence of an IUH in this potentially high risk patient group does not have a deleterious effect on pregnancy outcome.

Abortion, Habitual↗
PubMed2001

Is maternal underweight really a risk factor for adverse pregnancy outcome? A population-based study in London.

OBJECTIVE: To determine the maternal and fetal risk of adverse outcome during pregnancy in relation to low maternal body mass index in an unselected population. DESIGN: Retrospective analysis. METHODS: Information for the years between 1988 and 1997 was extracted from a validated maternity database, including all but one of the maternity units in the North West Thames Region; 215,105 completed singleton pregnancies were studied. Comparison of pregnancy outcome was made on the basis of maternal body mass index at booking. There were 176,923 with a normal weight body mass index ( = 20 < 25). There were 38,182 with an underweight body mass index (< 20). Comparisons included antenatal complications (e.g. gestational diabetes, pre-eclampsia); intervention in labour, maternal morbidities (e.g. infection, postpartum haemorrhage, pulmonary thromboembolism); and neonatal outcome (admitted to special care baby unit at 24 hour of age, gestation at delivery, birthweight, stillbirth). Data are presented as percentages of outcomes in the normal and underweight groups with adjusted odds ratios and confidence intervals according to body mass index group. RESULTS: In the underweight group only antenatal anaemia, preterm delivery and birthweight below the 5th centile were more frequent than in women of normal body mass index. The prevalence of certain complications, including development of gestational diabetes mellitus, pre-eclampsia, obstetric intervention and postpartum haemorrhage, were significantly lower in those with low body mass index. CONCLUSION: Low maternal body mass index is associated with increased prevalence of some pregnancy complications, notably preterm delivery and low birthweight, but overall the outcome is favourable and several adverse outcomes are less common in this group of women.

Body Mass Index↗
PubMed2001

G20210A prothrombin gene mutation: prevalence in a recurrent miscarriage population.

Many recurrent pregnancy losses appear to have a thrombotic etiology. We have investigated the prevalence of the G20210A prothrombin gene mutation in 122 women with a history of three or more early (< or = 12 weeks gestation; n = 91), late (> 12 weeks gestation: n = 2), or mixed (n = 29) consecutive pregnancy losses. A control group of 66 healthy parous women with no history of thrombosis or miscarriage was also studied. Four heterozygotes that suffered only early pregnancy losses were detected in the patient group giving a prevalence of 3.3%. Three of the control group women were heterozygous for the mutation. giving a prevalence of 4.5% (p = 0.32: odds ratio 0.71: 95% confidence interval [CI] 0.15-3.27). When only Caucasians were analyzed, a prevalence of 3.9% (4/103) was observed in the patient group and 4.2% (2/48) in the control group (p = 0.28; odds ratio 0.89; 95% CI 0.16-5.05). The prevalence of the G20210A prothrombin gene mutation is not increased in women with recurrent miscarriage, although it was only found in women who had suffered early pregnancy losses. However, it remains possible that this mutation is relevant in a selected subgroup of women with recurrent miscarriage, additional thrombophilic defects, and in whom fetal loss is associated with placental infarction and thrombosis.

Abortion, Habitual↗
PubMed2000

Dramatic structural and thermodynamic consequences of repacking a protein's hydrophobic core.

BACKGROUND: Rop is an RNA binding, dimeric, four-helix bundle protein with a well-defined, regular hydrophobic core ideally suited for redesign studies. A family of Rop variants in which the hydrophobic core was systematically redesigned has previously been created and characterized. RESULTS: We present a structural and thermodynamic analysis of Ala2Ile2-6, a variant of Rop with an extensively redesigned hydrophobic core. The structure of Ala2Ile2-6 reveals a completely new fold formed by a conformational "flip" of the two protomers around the dimeric interface. The free-energy profile of Ala2Ile2-6 is also very different from that of wild-type Rop. Ala2Ile2-6 has a higher melting temperature than Rop, but undergoes a slightly smaller free-energy change on unfolding. CONCLUSIONS: The structure of Ala2Ile2-6, along with molecular modeling results, demonstrate the importance of tight packing of core residues and the adoption of favorable core side chain rotamer values in determining helix-helix interactions in the four-helix bundle fold. Structural disorder at the N and C termini of Ala2Ile2-6 provides a basis for the large differences in the enthalpy and entropy of Ala2Ile2-6 folding compared with wildtype Rop.

Amino Acid Sequence↗
PubMed2000

Modulating protein folding rates in vivo and in vitro by side-chain interactions between the parallel beta strands of green fluorescent protein.

We have identified pairs of residues across the two parallel beta strands of green fluorescent protein that facilitate native strand register of the surface-exposed beta barrel. After constructing a suitable host environment around two guest residues, minimizing interactions of the guest residues with surrounding side-chains yet maintaining the wild-type protein structure and the chromophore environment, we introduced a library of cross-strand pairings by cassette mutagenesis. Colonies of Escherichia coli transformed with the library differ in intracellular fluorescence. Most of the fluorescent pairs have predominantly charged and polar guest site residues. The magnitude and the rate of fluorescence acquisition in vivo from transformed E. coli cells varies among the mutants despite comparable levels of protein expression. Spectroscopic measurements of purified mutants show that the native protein structure is maintained. Kinetic studies using purified protein with fully matured chromophores demonstrate that the mutants span a 10-fold range in folding rates with undetectable differences in unfolding rates. Thus, green fluorescent protein provides an ideal system for monitoring determinants of in vivo protein folding. Cross-strand pairings affect both protein stability and folding kinetics by favoring the formation of native strand register preferentially to non-native strand alignments.

Animals↗
PubMed2000

Proteomics of Mycoplasma genitalium: identification and characterization of unannotated and atypical proteins in a small model genome.

We present the results of a comprehensive analysis of the proteome of Mycoplasma genitalium (MG), the smallest autonomously replicating organism that has been completely sequenced. Our aim was to identify and characterize all soluble proteins in MG that are structurally and functionally uncharacterized. We were particularly interested in identifying proteins that differed significantly from typical globular proteins, for example, proteins which are unstructured in the absence of a 'partner' molecule or those that exhibit unusual thermodynamic properties. This work is complementary to other structural genomics projects whose primary aim is to determine the three-dimensional structures of proteins with unknown folds. We have identified all the full-length open reading frames (ORFs) in MG that have no homologs of known structure and are of unknown function. Twenty-five of the total 483 ORFs fall into this category and we have expressed, purified and characterized 11 of them. We have used circular dichroism (CD) to rapidly investigate their biophysical properties. Our studies reveal that these proteins have a wide range of structures varying from highly helical to partially structured to unfolded or random coil. They also display a variety of thermodynamic properties ranging from cooperative unfolding to no detectable unfolding upon thermal denaturation. Several of these proteins are highly conserved from mycoplasma to man. Further information about target selection and CD results is available at http://bioinfo.mbb.yale.edu/genome

Amino Acid Sequence↗
PubMed2000

A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro.

There are a number of diseases in which normally soluble proteins associate into regular, insoluble amyloid fibrils. The development of in vitro model systems in which detailed structural, kinetic, and thermodynamic characterization are feasible is of critical importance to our understanding of the amyloid fibril phenomenon. The formation of amyloid fibrils by proteins that are not associated with disease has been recently described, suggesting that this may be a common property of many proteins and not only of the few proteins associated with amyloidoses. The B1 Ig-binding domain of protein G (beta1) is an extremely well-characterized model system. We have found that under certain experimental conditions, some variants of beta1 form fibrils with high reproducibility. By controlling the stability of the protein-either by mutations or by changing experimental conditions-we are able to modulate the ability of the protein to form fibrils. For all of the variants, we find that the key requirement for fibril formation is to choose conditions in which the population of intermediate conformations present during the unfolding transition is maximized.

Amyloid↗
PubMed2000

Absence of scaling for the intermediate scattering function of a hard-sphere suspension: static and dynamic x-ray scattering from concentrated polystyrene latex spheres.

X-ray photon correlation spectroscopy and small-angle scattering measurements are presented of the dynamics and structure of concentrated suspensions of charge-stabilized polystyrene latex spheres dispersed in glycerol, for volume fractions from 3% to 52%. The static structures of the suspensions show essentially hard-sphere behavior, and the short-time dynamics shows good agreement with predictions for the wave-vector-dependent collective diffusion coefficient. However, the intermediate scattering function is found to violate a scaling behavior found previously for a sterically stabilized hard-sphere suspension.

Journal Article↗
PubMed2000

Magnetic resonance-guided percutaneous laser ablation of uterine fibroids.

Laser ablation of uterine fibroids using a percutaneous approach under local anesthetic in an open magnetic resonance (MR) scanner was performed in 12 symptomatic women awaiting hysterectomy. Accurate laser fiber placement was assisted by the use of an MR needle tracking system, as well as laser heat dissipation monitored during treatment by a real-time imaging processor. This day case procedure was well tolerated by all women, with eight women subsequently declining their planned surgery. Follow-up measurements of treated fibroid volume by MRI demonstrated a mean decrease of 37.5% at 3 months. This novel minimally invasive approach offers an alternative to surgery for women with fibroids, but longer follow-up is required to ascertain maximal fibroid shrinkage and to compare outcome with traditional surgery.

Adult↗
PubMed2000

Pregnancy outcome is not affected by antiphospholipid antibody status in women referred for in vitro fertilization.

OBJECTIVE: To determine the prevalence of antiphospholipid (aPL) and anti-beta 2 glycoprotein I (anti-beta2-GPI) antibodies in women referred for IVF and to prospectively evaluate the effect of these antibodies on IVF outcome. DESIGN: Prospective observational study. SETTING: A university hospital and IVF unit. PATIENT(S): Three hundred eighty consecutive women referred for IVF. INTERVENTION(S): Blood samples taken before commencement of IVF cycles were tested for the presence of aPL (lupus anticoagulant [LA], anticardiolipin [aCL], and antiphosphatidyl serine antibodies [aPS]) and anti-beta2-GPI antibodies. MAIN OUTCOME MEASURE(S): Antibody prevalence, pregnancy rates, and live birth rates. RESULT(S): Of the total 380 women, 89 tested persistently positive for aPL (23.4%). None of 176 women tested for IgG aPS antibodies had a positive titer. Only 3.3% (11 of 329) tested positive for anti-beta2-GPI antibodies. Pregnancy rate, live birth rate, gestational age at delivery, and birth weight were not affected by aPL status. CONCLUSION(S): Although women referred for IVF have a high prevalence of aPL, these antibodies do not affect the outcome of treatment. Screening women undergoing IVF for aPL is not justified.

Adult↗
PubMed2000

Obstetric risks of pregnancy in women less than 18 years old.

OBJECTIVE: To quantify the age-related risks of adverse outcome during pregnancy in women less than 18 years old. METHODS: We analyzed data from 341,708 completed singleton pregnancies in the North West Thames region between 1988 and 1997. Pregnancy outcomes were compared by age at delivery in women less than 18 years old (n = 5246) and 18-34 years old (n = 336,462); women 35 years old or older (n = 48,658) were excluded. Data are presented as percentages of women less than 18 and 18-34-year-old women, with adjusted odds ratios (OR) and 99% confidence intervals (CI). RESULTS: Pregnancy in women less than 18 years old was associated with increased risk of preterm labor before 32 weeks' gestation (OR 1.41, CI 1.02, 1.90), maternal anemia (OR 1.82, CI 1.63, 2.03), chest infection (OR 2.70, CI 1.21, 6.70), and urinary tract infection (OR 1.60, CI 1.11, 2.31), but less obstetric intervention. Operative vaginal delivery (OR 0. 46, CI 0.41, 0.56), elective cesarean (OR 0.47, CI 0.35, 0.65), or emergency cesarean (OR 0.45, CI 0.38, 0.53) were all less likely in women aged less than 18 years. Women less than 18 years old were no more likely to have stillbirths (OR 0.75, CI 0.42, 1.34) or small-for-gestational-age infants (OR 0.95, CI 0.82, 1.09) than women aged 18-34 years. CONCLUSION: Pregnant women less than 18 years old were more likely to deliver preterm than older women. In most other respects they have less maternal and perinatal morbidity and were more likely to have normal vaginal deliveries.

Adolescent↗
PubMed2000

Epidemiology and the medical causes of miscarriage.

Human reproduction is extraordinarily wasteful. The reasons for this have taxed all of the contributors to this book. As we move into the 21st century it is sobering to reflect on the fact that we have failed to harness the power of the evolving revolution in molecular medical biology to answer the fundamental question: why is the fate of a fertilized egg so hazardous and so unsuccessful? The following account summarizes our limited knowledge of the epidemiology of miscarriage and then moves on to consider some of the medical causes of miscarriage. The contribution of genetic abnormalities to the problem of pregnancy wastage is discussed elsewhere in this volume.

Abortion, Spontaneous↗
PubMed2000

Thrombophilia and adverse pregnancy outcome.

The hemostatic system plays an important role in three crucial stages of pregnancy: ovulation, implantation, and placentation. A thrombophilic defect is an abnormality in the coagulation pathways that predisposes an individual to thrombosis. Pregnancy is a hypercoaguable state and interest has focused on the potential role that thrombophilic defects may play in the etiology not only of recurrent miscarriage but also of late pregnancy complications. Maternal intervillous blood flow does not develop to any significant extent before 8 weeks of gestation and thrombophilic defects are therefore unlikely to contribute to pregnancy loss before this time. Retrospective studies have reported a similar prevalence of genetic thrombophilic defects among women with recurrent first-trimester miscarriage and controls but an increased prevalence among those with second-trimester miscarriage and later pregnancy complications. There is a paucity of data documenting the prospective outcome of untreated pregnancies among women with thrombophilic defects and of the placental histology in these pregnancies. Until these issues have been addressed, routine thromboprophylaxis during pregnancy cannot be recommended for women with thrombophilic abnormalities.

Abortion, Habitual↗
PubMed2000

The use of whole rat embryo culture as a technique for investigating potential serum toxicity in recurrent miscarriage patients.

Previously, the rat embryo model has been used as an experimental technique in investigations of the aetiology of idiopathic recurrent miscarriage. The aim of the present study was to validate it as a tool in the investigation of the aetiology of this condition. Subjects (n = 36) with a history of recurrent miscarriage were recruited from two dedicated recurrent miscarriage clinics and compared with control women with at least one previous pregnancy resulting in a live birth (n = 23). Serum from each woman was used as culture medium in the rat embryo model. Cultured embryos were scored for growth and differentiation. No statistical difference was found in any parameter between the two groups. Furthermore, patients from the recurrent miscarriage group whose serum demonstrated a trend towards lower scores, subsequently conceived and underwent uncomplicated pregnancies.

Abortion, Habitual↗
PubMed2000

Recurrent miscarriage--an aspirin a day?

Recurrent miscarriage and later pregnancy complications are in some cases associated with placental thrombosis and infarction. The aim of this study was to assess the value of low dose aspirin (75 mg daily) in improving the subsequent livebirth rate amongst women with either unexplained recurrent early miscarriage (<13 weeks gestation; n = 805) or unexplained late pregnancy loss (n = 250). Amongst women with recurrent early miscarriages, there was no significant difference in the livebirth rate between those who took aspirin (251/367; 68.4%) compared with those who did not take aspirin [278/438; 63.5%; odds ratio (OR) 1.24; 95% confidence interval (CI) 0.93-1.67]. This relationship was independent of the number of previous early miscarriages. In contrast, women with a previous late miscarriage who took aspirin had a significantly higher livebirth rate (122/189; 64.6%) compared with those who did not take aspirin (30/61; 49.2%: OR 1.88; 95% CI 1.04-3.37). The empirical use of low dose aspirin amongst women with unexplained recurrent early miscarriage is not justified. We are currently investigating the role of incremental doses of aspirin in the treatment of women both with early miscarriages associated with thrombophilic abnormalities and in those with late pregnancy losses.

Abortion, Habitual↗