Search PubMed⌕ Search

Biomedical subjects

L Regan

Publications and source records attributed to L Regan.

At least 109 records · Page 6Linked to original sources
PubMed1997

Future pregnancy outcome in unexplained recurrent first trimester miscarriage.

The future pregnancy outcome of 201 consecutive women, median age 34 years (range 22-43), with a history of unexplained recurrent first trimester miscarriage (median 3; range 3-13), was studied. All women and their partners had normal peripheral blood karyotypes; none had antiphospholipid antibodies and none hypersecreted luteinizing hormone (LH). No pharmacological treatment was prescribed and early pregnancy supportive care was encouraged. Women aged < or = 30 years had a subsequent miscarriage rate of 25% (14/57) which rose to 52% (13/25) in women aged > or = 40 years (P = 0.02). After three consecutive miscarriages, the risk of miscarriage of the next pregnancy was 29% (34/119) but increased to 53% (9/17) after six or more previous losses (P = 0.04). A past history of a livebirth did not influence the outcome of the next pregnancy. Supportive care in early pregnancy conferred a significant beneficial effect on pregnancy outcome. Of 160 women who attended the early pregnancy clinic, 42 (26%) miscarried in the next pregnancy compared with 21 out of 41 (51%) who did not attend the clinic (P = 0.002). After thorough investigation, women with unexplained recurrent first trimester miscarriage have an excellent pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated miscarriage clinic.

Abortion, Habitual↗
PubMed1997

Undetected gynaecological disorders in women with renal disease.

Women with chronic renal disease (CRD) who are on dialysis or have a functioning renal transplant are typically stoical in their attitude towards other health problems. We undertook a prospective study of 100 women with CRD to assess the prevalence of gynaecological disorders in this group of patients. Assessment included the measurement of follicle stimulating hormone, luteinizing hormone, prolactin and oestradiol concentrations, cervical cytology and a pelvic ultrasound scan. We found that gynaecological problems are highly prevalent and frequently unrecognized. Of these women, 58% had a menstrual disorder, with uncontrolled menorrhagia being a significant problem when it aggravated the chronic anaemia of renal disease, and 35% were menopausal, including seven women under the age of 40 years. Menopausal symptoms were undertreated. We identified a 14-fold increase in premature ovarian failure secondary to CRD and the use of cyclophosphamide therapy. In all, 22% of the women were subfertile and 10% had an abnormal smear, with cervical dyskariosis being significantly increased because of long-term immunosuppression. Contraceptive advice had often been absent or inappropriate. We conclude that formal gynaecological review should be routinely available for women with CRD.

Adolescent↗
PubMed1997

Antiphospholipid antibodies, infertility and recurrent miscarriage.

Antiphospholipid antibodies are found in 15% of women with recurrent miscarriage. These women have only a 10% live birth rate in subsequent pregnancies in which no pharmacological treatment is given. Pregnancy loss is often attributable to uteroplacental insufficiency subsequent to placental thrombosis. Treatment with low dose aspirin improves the live birth rate amongst women with antiphospholipid antibodies to 40% but this is further and significantly increased to 70% when they are treated with aspirin together with low-dose heparin.

Abortion, Habitual↗
PubMed1997

Obstetric complications of antiphospholipid antibodies.

Pregnancies occurring in women with antiphospholipid antibodies are at significantly increased risk of miscarriage, prematurity, intrauterine growth retardation and preeclampsia. Insights into the pathological basis of these conditions suggest that antiphospholipid antibodies impair embryonic implantation and in later gestations cause thrombosis of the uteroplacental vasculature. This offers a rational basis for thromboprophylaxis during pregnancy.

Abortion, Spontaneous↗
PubMed1996

Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial.

OBJECTIVE: To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone. DESIGN: Randomised controlled trial. SETTING: Specialist recurrent miscarriage clinic. SUBJECTS: 106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone. INTERVENTIONS: Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy. MAIN OUTCOME MEASURES: Conception and live birth rates over six cycles. RESULTS: Conception rates in the pituitary suppression and luteal phase support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26/50 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS). CONCLUSIONS: Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent.

Abortion, Habitual↗
PubMed1996

What makes a protein a protein? Hydrophobic core designs that specify stability and structural properties.

Here we describe how the systematic redesign of a protein's hydrophobic core alters its structure and stability. We have repacked the hydrophobic core of the four-helix-bundle protein, Rop, with altered packing patterns and various side chain shapes and sizes. Several designs reproduce the structure and native-like properties of the wild-type, while increasing the thermal stability. Other designs, either with similar sizes but different shapes, or with decreased sizes of the packing residues, destabilize the protein. Finally, overpacking the core with the larger side chains causes a loss of native-like structure. These results allow us to further define the roles of tight residue packing and the burial of hydrophobic surface area in the construction of native-like proteins.

Bacterial Proteins↗
PubMed1996

Surface point mutations that significantly alter the structure and stability of a protein's denatured state.

Significantly different m values (1.9-2.7 kcal mol-1 M-1) were observed for point mutations at a single, solvent-exposed site (T53) in a variant of the B1 domain of streptococcal Protein G using guanidine hydrochloride (GuHCl) as a denaturant. This report focuses on elucidating the energetic and structural implications of these m-value differences in two Protein G mutants, containing Ala and Thr at position 53. These two proteins are representative of the high (m+) and low (m-) m-value mutants studied. Differential scanning calorimetry revealed no evidence of equilibrium intermediates. A comparison of GuHCl denaturation monitored by fluorescence and circular dichroism showed that secondary and tertiary structure denatured concomitantly. The rates of folding (286 S-1 for the m+ mutant and 952 S-1 for the m- mutant) and the rates of unfolding (11 S-1 for m+ mutant and 3 S-1 for the m- mutant) were significantly different, as determined by stopped-flow fluorescence. The relative solvation free energies of the transition states were identical for the two proteins (alpha ++ = 0.3). Small-angle X-ray scattering showed that the radius of gyration of the denatured state (Rgd) of the m+ mutant did not change with increasing denaturant concentrations (Rgd approximately 23 A); whereas, the Rgd of the m- mutant increased from approximately 17 A to 23 A with increasing denaturant concentration. The results indicate that the mutations exert significant effects in both the native and GuHCl-induced denatured state of these two proteins.

Bacterial Proteins↗
PubMed1996

Amino-acid substitutions in a surface turn modulate protein stability.

A surface turn position in a four-helix bundle protein, Rop, was selected to investigate the role of turns in protein structure and stability. Although all twenty amino acids can be substituted at this position to generate a correctly folded protein, they produce an unusually large range of thermodynamic stabilities. Moreover, the majority of substitutions give rise to proteins with enhanced thermal stability compared to that of the wild type. By introducing the same twenty mutations at this position, but in a simplified context, we were able to deconvolute intrinsic preferences from local environmental effects. The intrinsic preferences can be explained on the basis of preferred backbone dihedral angles, but local environmental context can significantly modify these effects.

Amino Acids↗
PubMed1996

Second-trimester pregnancy loss is associated with activated C resistance.

We have investigated whether activated protein C resistance (APCR) is associated with second-trimester miscarriage. The prevalence of APCR was significantly higher amongst women with a history of second-trimester miscarriage (10/50; 20%) compared with either women with a history of first-trimester miscarriages only (4/70; 5.7%) or a control group of parous women with no previous history of pregnancy losses (3/70; 4.3%) (P < 0.02). These results suggest that APCR may be an important mechanism of second-trimester pregnancy loss, possibly related to the increase in intravascular coagulation that occurs during pregnancy.

Abortion, Habitual↗
PubMed1996

Association of bacterial vaginosis with a history of second trimester miscarriage.

The aim of this study was to determine whether bacterial vaginosis (BV) is associated with a history of recurrent pregnancy loss. A total of 500 consecutive patients attending the Recurrent Miscarriage Clinic were screened for the presence of BV. In women who had had at least one late miscarriage BV was found twice as commonly (27/130; 21%) as in women who had had only early losses (31/370; 8%) (P < 0.001). The difference was even larger (26 versus 8%) if women who had had term pregnancies were excluded. Moreover, BV was found three times more commonly in Afro-Caribbean women [17 (29%) of 58] than in Caucasian women [36 (9%) of 379] and, in both groups of women, BV was diagnosed at least twice as frequently in those with a history of at least one late miscarriage than in those who had experienced first trimester pregnancy losses only (P < 0. 001). The condition occurred twice as often among smokers than non-smokers and, in both groups, it was at least twice as common in women with a history of at least one late miscarriage as in those who had had early pregnancy losses only (P < 0.001). However, the relationship between BV and smoking was independent of ethnic origin. Women who douched with chloroxylenol were mostly Afro-Caribbean and had BV more than twice as often as women who did not douche.

Abortion, Habitual↗
PubMed1995

Guidelines for protein design: the energetics of beta sheet side chain interactions.

To determine the interaction energy between cross-strand pairs of side chains on an antiparallel beta sheet, pairwise amino acid substitutions were made on the solvent-exposed face of the B1 domain of streptococcal protein G. The measured interaction energies were substantial (1.8 kilocalories per mole) and comparable to the magnitude of the beta sheet propensities. The experimental results paralleled the statistical frequency with which the residue pairs are found in beta sheets of known structure.

Bacterial Proteins↗
PubMed1995

Flux analysis of microbial metabolic pathways using a visual programming environment.

This paper describes the use of a visual programming environment (LabVIEW) for the flux analysis of metabolic pathways. Representations of metabolic pathways are constructed in software from individual reaction elements (icons) which are linked together to indicate potential flux routes. Off-line bioprocess data are then used to supply the inputs and outputs to the metabolic pathway and the pathway fluxes are calculated. The metabolic system can be modelled at different levels of complexity and new pathways can be inserted into existing models. To illustrate this, flux analyses are performed on three Escherichia coli mutants with metabolic pathway deletions and insertions. The first analysis looks at organic acid production and the second at the effect of the presence in E. coli of an engineered pathway for toluene degradation.

Acetates↗
PubMed1995

Redesigning the topology of a four-helix-bundle protein: monomeric Rop.

The topology of alpha-helices and beta-sheets in folded proteins is largely specified by the connectivities of the loops and turns which join them. We have used the protein Rop to test the feasibility of using short glycine-rich linkers to reconnect the alpha-helices within a four-helix-bundle protein. In wild-type Rop the four-helix-bundle structure is formed by the association of two identical helix-turn-helix monomers. Our redesigns encode Rop as a single chain to create a monomeric, rather than a dimeric, form of the protein. Characterization of a series of such variants demonstrates that new connections of this type can be used to generate stable, native-like proteins. The length of the connections is of key importance; if the loops are too short, correct association of the helices is prevented, and misfolded, higher order oligomers occur. Designs with sufficiently long loop connections, however, generate exclusively the desired monomeric form of the protein. Moreover, the successful monomeric designs bind Rop's RNA substrate with affinities that are equal to that of the wild-type protein. This result provides strong confirmation that the positioning of the helices in the monomeric variants is closely similar to that in wild-type Rop.

Bacterial Proteins↗
PubMed1995

Characterization of metal binding by a designed protein: single ligand substitutions at a tetrahedral Cys2His2 site.

The tetrahedral Cys2His2 Zn(II)-binding site in the de novo designed protein Z alpha 4 [Regan, L., & Clarke, N. D. (1990) Biochemistry 29, 10878] has been studied by independently mutating each of the metal-binding ligands to alanine. The contribution of each ligand to the geometry and affinity of metal binding has been characterized using Co(II), Zn(II), and Cd(II). The results indicate that all four ligands contribute to high-affinity metal binding in Z alpha 4. Two of the four metal-site mutants retain the tetrahedral Zn(II)-binding geometry of Z alpha 4, with one water molecule presumed to bind in the vacant ligand position. These mutants provide the first examples of a demonstrated de novo tetrahedral three-coordinate site designed into a protein and as such are a first step toward the design of catalytic rather than structural Zn(II) sites. One of the metal-site mutants binds Zn(II) with either tetrahedral four-coordinate or five-coordinate geometry, while the last ligand-to-alanine substitution abolishes tetrahedral binding. The importance of ligand type for metal-binding in Z alpha 4 was investigated by characterizing two ligand-swap mutants in which a cysteine residue was replaced with a histidine. In both cases, tetrahedral metal binding was lost. Collectively, these results affirm the strategy used to design Z alpha 4 by showing that all designed liganding residues are participating in metal binding, and by suggesting that the tetrahedral geometry of the binding site is perturbed when the designed side chain ligands are replaced with alternate ligands.

Binding Sites↗
PubMed1995

Dissecting RNA-protein interactions: RNA-RNA recognition by Rop.

The ColE1 plasmid of E. coli encodes a small RNA-binding protein, Rop, which is involved in the regulation of plasmid copy number. Rop, a 4-helix bundle protein, facilitates sense-antisense RNA pairing by binding to the transiently formed hairpin pairs of RNA I and the complementary RNA II. We have identified the residues of Rop that are involved in RNA recognition. The residues form a narrow stripe down one face of the bundle and are symmetrically arranged, with recognition centered about two phenylalanine residues. Our results suggest that these phenylalanine residues interact with the loop region of the hairpin pair, with additional interactions between eight polar residues and the phosphate backbone. By modifying the identity of residue 14, we have created a variant of Rop that displays altered RNA binding specificity. The results of our studies allow us to present a detailed picture of RNA-protein recognition in a novel model system.

Amino Acid Sequence↗