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Biomedical subjects

H Lacey

Publications and source records attributed to H Lacey.

11 recordsLinked to original sources
PubMed2006

The extent and variability of effects of culture conditions on the secretion of human chorionic gonadotrophin and interleukin-6 by human, term placental explants in culture.

Culture of explants derived from third trimester human placenta is used in a range of contexts as an experimental model that retains tissue architecture. This study aimed to explore the variability between, and within, individuals of secretion by explants of human chorionic gonadotrophin (hCG) and interleukin-6 (IL-6). Standard culture medium contained hydrocortisone, insulin, retinoic acid and serum. Under these conditions explants displayed significant differences in the time-course and extent of hCG secretion. Peak hCG secretion varied between 1.19 and 242 mIU/mg protein/h (coefficient of variation (CV) = 111%) and could occur between days 4 and 7 of culture. hCG secretion was more variable if explant protein was < 400 microg. Unadjusted day 7 hCG secretion showed marked variation: intra-placental CV = 15%, inter-placental CV = 86%. When day 7 hCG secretion was standardised by day 6 secretion, intra-placental CV was 6.9%, inter-placental CV was 4.0%. When this standardisation was applied, hCG secretion during day 7 of culture was not affected by removal of hydrocortisone, insulin or serum from the medium or by the addition of tumour necrosis factor-alpha (TNF-alpha). The secretion of IL-6 during day 7 of culture (standardised by taking natural logarithms) was increased markedly by the addition of TNF-alpha but unaltered by removing hydrocortisone, insulin or serum. Thus, we have shown that although variable, secretion by placental explants can be used to investigate how placental tissue adapts to different culture conditions. However, explants of the same protein content may have markedly different secretory properties.

Chorionic Gonadotropin↗
PubMed2002

Regulation of placental transfer: the Na(+)/H(+) exchanger--a review.

This review article considers the purposes and mechanisms of regulation of placental transfer in general terms and then illustrates some key points with reference to the Na(+)/H(+) exchanger (NHE), a transport protein found in the syncytiotrophoblast. NHE probably has a role in the homeostasis of syncytiotrophoblast intracellular pH and may also be involved in syncytiotrophoblast cell volume regulation as well as H(+) loss from and Na(+) transfer to the fetus. The activity and expression of NHE in the microvillous plasma membrane of the syncytiotrophoblast is reduced in placentas from preterm, growth restricted babies as compared to their gestationally matched normally grown counterparts. There are differential effects of gestation in normal pregnancy on NHE mRNA, NHE protein and NHE activity. There is also evidence of acute modulation of NHE activity. Regulation of NHE in syncytiotrophoblast is therefore complex with control at transcription, post transcription and post translational loci.

Adult↗
PubMed2000

Growth factor-extracellular matrix synergy in the control of trophoblast invasion.

At the periphery of the human placenta, trophoblast attaches to the uterine wall. The tissue interface contains many anchoring sites, with cytotrophoblast columns that form bridges between the overlying extraembryonic (villous) mesenchyme and the maternal decidual stroma beneath. From the periphery of these columns, large numbers of trophoblast cells detach, migrate through the decidua and eventually colonize and transform maternal arteries. In this way the placenta increases and gives priority to the maternal blood supply to the conceptus. We have shown that when early villous tissue is explanted on a collagen gel in serum-free medium, anchoring-site morphogenesis occurs. Thus, in the presence of placental mesenchyme but in the absence of maternal cells, contact with a permissive extracellular matrix (ECM) is necessary and sufficient for cytotrophoblast column development. Proliferation of trophoblast occurs, followed by differentiation into a columnar cell phenotype in which cells remain attached to one another and to the ECM. At this stage, interaction between fibronectin and integrin alpha5beta1 at the cell surface stabilizes the column and the cells remain as a contiguous multilayered sheet. However, the addition of serum-free conditioned medium from first-trimester placental fibroblasts stimulates cytotrophoblast to detach from the distal column and migrate in streams across the ECM. The removal of insulin-like growth factor I (IGF-I) from the fibroblast medium decreases streaming activity, whereas the addition of exogenous IGF-I (10 ng/ml) to serum-free medium produces a streaming phenotype. In contrast, transforming growth factor beta1 (10 ng/ml) maintains the cells in a tight sheet. These results suggest the possibility of a paracrine interaction between villous mesenchyme and cytotrophoblast in anchoring sites to stimulate the infiltration of the maternal ECM by trophoblast. Such a mechanism would be self-limiting because the signal diminishes with distance from the placenta.

Animals↗
PubMed2000

Tissue interactions in the control of trophoblast invasion.

On the basis of observations made in an explant model of anchoring villus development, it is proposed that two discrete types of signal are required to trigger the entry of cytotrophoblast into the migratory extravillous lineage. The first is mediated by contact of the tip of the first trimester mesenchymal villus with decidual extracellular matrix, in response to which stem villous cytotrophoblast undergoes a proliferative burst and differentiates into cells of the cytotrophoblast column, anchoring peripheral villi to the uterus. Column stability is dependent on the interaction between extracellular fibronectin and integrin alpha 5 beta 1 expressed at the cell surface, both of which are upregulated in this pathway. Subsequently, cells detach in large numbers from the periphery of the column and become migratory infiltrative cells. This step is dependent on paracrine signalling from the mesenchymal cells that lie directly beneath the villous basement membrane. As the signal decreases with increasing distance from the placental anchoring villus, this mechanism might account for the fact that trophoblast invasion progresses no deeper than the inner myometrium.

Cell Adhesion Molecules↗
PubMed2000

GP referral to an eating disorder service: why the wide variation?

BACKGROUND: Early detection and management of patients with eating disorders is thought to improve prognosis, yet little is known about the factors associated with referral of these patients to treatment centres. AIM: To calculate general practitioner (GP) referral rates to a specialist eating disorder service and determine the association between referral rate and general practice and practitioner factors. METHOD: Referral rate was calculated from a database of routine referrals to St George's Hospital Eating Disorder Service from January 1990 to May 1996 and correlated with practice and practitioner details obtained from medical directories and health authority data. RESULTS: There was a wide variation in referral rates. A higher referral rate was found to be associated with practice size, proximity to the clinic, female GPs, GPs having the MRCGP qualification, being United Kingdom qualified, and offering full contraceptive services. Fundholding was associated with lower rates of referral. CONCLUSION: Patients with eating disorders may be at a disadvantage in certain practices. Educational interventions could be targeted towards low referrals.

Adolescent↗
PubMed1997

Phase I trial and pharmacokinetics of the tubulin inhibitor 1069C85--a synthetic agent binding at the colchicine site designed to overcome multidrug resistance.

The orally administered tubulin-binding agent 1069C85 was developed with the hope of overcoming the multidrug resistance associated with existing anti-tubulin agents, such as the vinca alkaloids. A phase I study was performed using a single oral dose every 3 weeks, administered as a suspension reconstituted in 0.1% Tween 80 and 0.9% saline. The starting dose was 2.8 mg m-2, and dose doubling was permitted until the area under curve (AUC) was > or = 40% of that at the mouse LD10; thereafter, a modified Fibonacci scheme was used. The formulation proved to be unsatisfactory, resulting in inconsistent absorption. The terminal elimination half-life was prolonged (range 18-73.5 h). Sporadic central neurotoxicity was observed, which was grade 3 in one patient treated at 200 mg m-2. A revised formulation with micronized drug was more easily suspended and appeared to increase the bioavailability by a factor of 2-4. Severe central neurotoxicity, up to grade 4, was then observed at doses of 50-100 mg m-2. Unfortunately, toxicity was not predictable and one patient, with a previous history of partial intestinal obstruction, treated at 50 mg m-2, cleared the drug very slowly, possibly because of prolonged, delayed absorption. This patient died from pancytopenia and severe gastrointestinal damage. It was concluded that such unpredictable behaviour would be incompatible with safe evaluation in phase II studies; the trial was closed and further clinical development abandoned.

Administration, Oral↗
PubMed1990

Avascular necrosis of the hip in a man with HIV infection.

The development of an osteonecrotic (avascular necrosis) hip joint in a patient with symptomatic CDC Stage 1V C2 disease is reported. The diagnosis was aided by radiological assessment and confirmed by radioisotope bone scan. This case serves as yet another musculoskeletal manifestation in association with HIV infection.

Adult↗