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Nicholas M Fisk

Publications and source records attributed to Nicholas M Fisk.

At least 19 recordsLinked to original sources
PubMed2006

Widespread distribution and muscle differentiation of human fetal mesenchymal stem cells after intrauterine transplantation in dystrophic mdx mouse.

Duchenne muscular dystrophy (DMD) is a common X-linked disease resulting from the absence of dystrophin in muscle. Affected boys suffer from incurable progressive muscle weakness, leading to premature death. Stem cell transplantation may be curative, but is hampered by the need for systemic delivery and immune rejection. To address these barriers to stem cell therapy in DMD, we investigated a fetal-to-fetal transplantation strategy. We investigated intramuscular, intravascular, and intraperitoneal delivery of human fetal mesenchymal stem cells (hfMSCs) into embryonic day (E) 14-16 MF1 mice to determine the most appropriate route for systemic delivery. Intramuscular injections resulted in local engraftment, whereas both intraperitoneal and intravascular delivery led to systemic spread. However, intravascular delivery led to unexpected demise of transplanted mice. Transplantation of hfMSCs into E14-16 mdx mice resulted in widespread long-term engraftment (19 weeks) in multiple organs, with a predilection for muscle compared with nonmuscle tissues (0.71% vs. 0.15%, p < .01), and evidence of myogenic differentiation of hfMSCs in skeletal and myocardial muscle. This is the first report of intrauterine transplantation of ontologically relevant hfMSCs into fully immunocompetent dystrophic fetal mice, with systemic spread across endothelial barriers leading to widespread long-term engraftment in multiple organ compartments. Although the low-level of chimerism achieved is not curative for DMD, this approach may be useful in other severe mesenchymal or enzyme deficiency syndromes, where low-level protein expression may ameliorate disease pathology.

Animals↗
PubMed2006

Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.

The biological properties of stem cells are key to the success of cell therapy, for which MSC are promising candidates. Although most therapeutic applications to date have used adult bone marrow MSC, increasing evidence suggests that MSC from neonatal and mid-gestational fetal tissues are more plastic and grow faster. Fetal stem cells have been isolated earlier in development, from first-trimester blood and hemopoietic organs, raising the question of whether they are biologically closer to embryonic stem cells and thus have advantages over adult bone marrow MSC. In this study, we show that human first-trimester fetal blood, liver, and bone marrow MSC but not adult MSC express the pluripotency stem cell markers Oct-4, Nanog, Rex-1, SSEA-3, SSEA-4, Tra-1-60, and Tra-1-81. In addition, fetal MSC, irrespective of source, had longer telomeres (p < .001), had greater telomerase activity (p < .01), and expressed more human telomerase reverse transcriptase (p < .01). Fetal MSC were also more readily expandable and senesced later in culture than their adult counterparts (p < .01). Compared with adult MSC, first-trimester fetal tissues constitute a source of MSC with characteristics that appear advantageous for cell therapy.

Adult↗
PubMed2006

Galectin-1 induces skeletal muscle differentiation in human fetal mesenchymal stem cells and increases muscle regeneration.

Cell therapy for degenerative muscle diseases such as the muscular dystrophies requires a source of cells with the capacity to participate in the formation of new muscle fibers. We investigated the myogenic potential of human fetal mesenchymal stem cells (hfMSCs) using a variety of stimuli. The use of 5-azacytidine or steroids did not produce skeletal muscle differentiation, whereas myoblast-conditioned medium resulted in only 1%-2% of hfMSCs undergoing muscle differentiation. However, in the presence of galectin-1, 66.1% +/- 5.7% of hfMSCs, but not adult bone marrow-derived mesenchymal stem cells, assumed a muscle phenotype, forming long, multinucleated fibers expressing both desmin and sarcomeric myosin via activation of muscle regulatory factors. Continuous exposure to galectin-1 resulted in more efficient muscle differentiation than pulsed exposure (62.3% vs. 39.1%; p < .001). When transplanted into regenerating murine muscle, galectin-1-exposed hfMSCs formed fourfold more human muscle fibers than nonstimulated hfMSCs (p = .008), with similar results obtained in a scid/mdx dystrophic mouse model. These data suggest that hfMSCs readily undergo muscle differentiation in response to galectin-1 through a stepwise progression similar to that which occurs during embryonic myogenesis. The high degree of myogenic conversion achieved by this method has relevance for the development of therapies for muscular dystrophies.

Adult↗
PubMed2006

Pragmatic comparison of beta2-agonist side effects within the Worldwide Atosiban versus Beta Agonists study.

OBJECTIVE: While beta2-agonists for the acute treatment of preterm labour unequivocally reduce the odds of delivery within 48 h and 7 days, they have been associated with substantial maternal and fetal side effects. We aimed to compare side effect profiles of beta2-agonist tocolytics. STUDY DESIGN: Pragmatic comparison of ritodrine, salbutamol and terbutaline from re-analysis of data obtained within three comparator arms of three simultaneous comparable randomised controlled trials of beta2-agonists against atosiban in 742 women in preterm labour. The prevalence of categoric side effects between treatment groups was analysed using a chi2 test. The differences in continuous variables between treatment groups were analysed in analyses of covariance. RESULTS: The prevalence of categoric side effects was similar with the three drugs, with the exception of the subjective symptom of palpitations (ritodrine 24.0%, terbutaline 9.3% and salbutamol 12.3%, P=0.003). There were also some differences in maternal diastolic blood pressure (P<0.001) and serum glucose levels (P<0.001), although these were small (<3 mmHg and < or =2.8 mmol/L, respectively) and clinically unimportant. CONCLUSION: Side effects were common with all three drugs. Thus, choosing one beta2-agonist over the other to minimise side effects has little rationale, especially now that safer tocolytics are available.

Adrenergic beta-Agonists↗
PubMed2006

Determinants of flow along arterio-arterial anastomoses in monochorionic placentae by dynamic computer modelling of chorionic plate vasculature.

OBJECTIVES: To investigate anatomical and physiological determinants of inter-fetal transfusion along arterio-arterial (AA) anastomoses in monochorionic placentae. METHODS: A computer model of chorionic arterial vasculature was constructed in QuickBASIC using data collected from experimentation and the published literature. After validating the model, the influence of various physiological and anatomical variables on anastomotic flow rates was examined. RESULTS: AA anastomotic flow rates were significantly related to changes in fetal mean arterial pressure (p < 0.0001) and heart rate (p < 0.0005). AA flow rates were also related to the imbalance in number of arterio-venous (AV) anastomoses, to placental territory share, and to the branch number of the AA anastomosis (AAAs) from the chorionic arterial tree. CONCLUSIONS: Net blood flow and direction along AA anastomoses are influenced by fetal cardiac output, by the presence of compensatory AV anastomoses, and by the branch number of the chorionic arteries connected by the anastomosis. This study provides insight into the determinants of chronic transfusional imbalance as well as acute inter-fetal transfusion.

Arterio-Arterial Fistula↗
PubMed2006

Inhibitory effect of erythropoietin on contractility of human chorionic plate vessels.

OBJECTIVE: Placenta is a major source of erythropoietin production in the fetus; hypoxia is associated with elevated erythropoietin levels in the fetal circulation. We investigated fetoplacental vascular reactivity after exposure to erythropoietin in vitro. STUDY DESIGN: Third-order chorionic plate arteries from human term placentae were incubated in culture medium with or without erythropoietin (3 U/mL) for 24 hours. Vessels were mounted in a myograph for isometric tension recording, and their responses to vasopressors and vasorelaxants were studied. RESULTS: Contractile responses to endothelin-1 and the thromboxane analogue U46619 were decreased in erythropoietin-exposed vessels compared with controls. Relaxant responses to the nitric oxide donor sodium nitroprusside and the phosphodiesterase inhibitor papaverine were not influenced by erythropoietin. CONCLUSION: Exposure to elevated levels of erythropoietin has an inhibitory effect on contractile responses in human placental chorionic plate arteries. We speculate that this may improve fetoplacental perfusion in hypoxic fetuses with elevated erythropoietin production.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Fetal stem cells: betwixt and between.

Fetal stem cells can be isolated not only from fetal blood and hemopoietic organs in early pregnancy, but from a variety of somatic organs as well as amniotic fluid and placenta throughout gestation. Fetal blood is a rich source of hemopoietic stem cells, which proliferate more rapidly than those in cord blood or adult bone marrow. First-trimester fetal blood, liver, and bone marrow also contain a population of mesenchymal stem cells, which appear to be more primitive with greater multipotentiality than their adult counterparts. Fetal stem cells may thus represent an intermediate cell type in the current debate focusing on dichotomized adult versus embryonic stem cells, and thus prove advantageous as a source for downstream cell therapy applications. They have also been implicated in fetomaternal trafficking in pregnancy, and in long-term microchimerism in postreproductive women.

Female↗
PubMed2005

High risk of unexpected late fetal death in monochorionic twins despite intensive ultrasound surveillance: a cohort study.

BACKGROUND: The rationale for fetal surveillance in monochorionic twin pregnancies is timely intervention to prevent the increased fetal/perinatal morbidity and mortality attributed to twin-twin transfusion syndrome and intrauterine growth restriction. We investigated the residual risk of fetal death after viability in otherwise uncomplicated monochorionic diamniotic twin pregnancies. METHODS AND FINDINGS: We searched an electronic database of 480 completed monochorionic pregnancies that underwent fortnightly ultrasound surveillance in our tertiary referral fetal medicine service between 1992 and 2004. After excluding pregnancies with twin-twin transfusion syndrome, growth restriction, structural abnormalities, or twin reversed arterial perfusion sequence, and monoamniotic and high-order multiple pregnancies, we identified 151 uncomplicated monochorionic diamniotic twin pregnancies with normal growth, normal liquor volume, and normal Doppler studies on fortnightly ultrasound scans. Ten unexpected intrauterine deaths occurred in seven (4.6%) of 151 previously uncomplicated monochorionic diamniotic pregnancies, within 2 wk of a normal scan, at a median gestational age of 34(+1) wk (weeks(+days); range 28(+0) to 36(+3)). Two of the five cases that underwent autopsy had features suggestive of acute late onset twin-twin transfusion syndrome, but no antenatal indicators of transfusional imbalance or growth restriction, either empirically or in a 1:3 gestation-matched case-control comparison. The prospective risk of unexpected antepartum stillbirth after 32 wk was 1/23 monochorionic diamniotic pregnancies (95% confidence interval 1/11 to 1/63). CONCLUSION: Despite intensive fetal surveillance, structurally normal monochorionic diamniotic twin pregnancies without TTTS or IUGR are complicated by a high rate of unexpected intrauterine death. This prospective risk of fetal death in otherwise uncomplicated monochorionic diamniotic pregnancies after 32 wk of gestation might be obviated by a policy of elective preterm delivery, which now warrants evaluation.

Adolescent↗
PubMed2005

Can routine commercial cord blood banking be scientifically and ethically justified?

BACKGROUND TO THE DEBATE: Umbilical cord blood--the blood that remains in the placenta after birth--can be collected and stored frozen for years. A well-accepted use of cord blood is as an alternative to bone marrow as a source of hematopoietic stem cells for allogeneic transplantation to siblings or to unrelated recipients; women can donate cord blood for unrelated recipients to public banks. However, private banks are now open that offer expectant parents the option to pay a fee for the chance to store cord blood for possible future use by that same child (autologous transplantation).

Blood Banks↗
PubMed2005

Insights into the pathophysiology of twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) is attributed to trans-anastomotic transfusion between twins. Anastomoses are ubiquitous in monochorionic (MC) placentae, yet TTTS develops in only 15%. Although ex vivo and in vivo studies fail to identify a unique anastomotic signature, TTTS placentae are typically associated with an imbalance in unidirectional arteriovenous anastomoses with absent bidirectional anastomoses. Doppler detection of an artery-artery anastomosis reduces the chance of TTTS, whereas, in those that develop the disease, it improves stage-independent survival. Selective laser is often curative, but an increasingly recognized risk of persistent or reverse TTTS may be attributable to atypical arteriovenous anastomoses not identifiable from the chorionic plate. Simple dysvolaemia fails to explain several phenotypic features, including haematological concordancy, recipient hypertension, and reversibly absent end diastolic flow in the donor. The renin-angiotensin system is upregulated in the donor and downregulated in the recipient's kidneys, while paradoxically raised renin levels in the recipient may contribute to raised afterload along with endothelin. Although research is limited in humans by therapy and the lack of a suitable experimental model, further studies of placental and vascular pathophysiology may not only refine current treatment modalities but may also, in addition, suggest further avenues for downstream management such as genetic predisposition testing or pharmacological intervention.

Chorion↗
PubMed2005

A randomized trial of amnioreduction versus septostomy in the treatment of twin-twin transfusion syndrome.

OBJECTIVE: Left untreated, severe twin-to-twin transfusion syndrome (TTTS) presenting in the early second trimester of pregnancy is often associated with significant maternal morbidity and almost universal perinatal loss. Removal of excessive amounts of amniotic fluid through serial amniocenteses (amnioreduction) has been the mainstay of therapy. We sought to compare amnioreduction to intentional perforation of the intervening twin membrane (septostomy). STUDY DESIGN: Pregnant women with TTTS before 24 weeks' gestation were randomly assigned to serial amnioreduction or septostomy. A single puncture technique under ultrasound guidance was used for the septostomy. The primary outcome measure was survival to neonatal discharge, and was assessed based on the number of pregnancies or the number of fetuses as appropriate. RESULTS: The study was terminated at the planned interim analysis stage after 73 women were enrolled. This was because the rate of survival of at least 1 infant was similar in the amnioreduction group compared to the septostomy group (78% vs 80% of pregnancies, respectively; RR=0.94, 95%CI 0.55-1.61; P=.82). Patient undergoing septostomy were more likely to require a single procedure for treatment (64% vs 46%; P=.04). CONCLUSION: Although overall perinatal survival is not enhanced, septostomy offers the advantage of often requiring a single procedure compared to serial amnioreduction in the treatment of severe twin-to-twin transfusion syndrome.

Amniotic Fluid↗
PubMed2005

Non-invasive intrapartum fetal ECG: preliminary report.

OBJECTIVES: To obtain fetal heart rate, detailed fetal electrocardiography (fECG) signals and uterine contractions during labour using a single device. DESIGN: Prospective observational study. SETTING: Delivery suite at a tertiary referral hospital, London, UK. POPULATION: Fifteen patients at median gestation of 39 weeks (range 24-41) were recruited at median cervical dilatation of 4.0 cm (range 0-10) of whom 8/15 (53%) had intact amniotic membranes. METHODS: Using 12 abdominally sited electrodes, we recorded the composite abdominal signal in pregnancies intrapartum. The recorded data were analysed off-line using a blind signal separation technique. MAIN OUTCOME MEASURES: Success of signal separation and fECG time intervals. RESULTS: Successful fECG signal acquisition was achieved in 12/15 (80%) patients and an averaged fECG waveform acquired. In these patients, P and QRS waves were seen in all cases, and T waves in 11/12 (92%). True beat-to-beat heart rate (HR) was displayed and measures of its variability obtained. The mother's ECG and uterine electrical activity, shown to match tocographically recorded uterine contractions, were also separated and displayed. Failure to acquire fECG in three cases was attributed to excessive abdominal muscular activity and electrical interference. CONCLUSIONS: This study demonstrates a non-invasive technique that displays detailed intrapartum fECG waveforms, HR variability, maternal ECG and uterine contractions simultaneously, all in a single device and which avoids the potential risks of invasive monitoring with a fetal scalp electrode.

Cardiotocography↗
PubMed2005

Paradoxic activation of the renin-angiotensin system in twin-twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient.

Despite advances in treatment, twin-to-twin transfusion syndrome (TTTS) still carries a high risk for perinatal mortality and morbidity. Simple blood transfer from the donor to the recipient twin cannot explain all of the features of this disease, in particular the recipient's hypertensive cardiomyopathy. We report a case in which TTTS resulted in preterm delivery with early neonatal death of both twins, allowing assessment of the renin angiotensin system (RAS) status of each fetus, both by cord blood renin and aldosterone assay and by renal immunohistochemistry. The donor had severe oliguria/oligohydramnios, whereas the recipient, in addition to severe polyuria/polyhydramnios, had cardiomyopathy, atrioventricular regurgitation, and ascites. Although immunohistochemistry demonstrated that renal secretion of renin was up-regulated in the donor and down-regulated in the recipient, cord blood levels of renin and aldosterone were similar, with high renin levels in both twins. This observation supports the hypothesis that despite renal RAS down-regulation, the recipient is exposed to RAS effectors elaborated in the donor and transferred via placental shunts. This may contribute to cardiomyopathy and hypertension in the recipient, which cannot be accounted for by hypervolemia alone. We thus hypothesized that in TTTS, the recipient's hypertensive cardiomyopathy could be due to a mechanism similar to the classical model of hypertension referred to as "2 kidneys-1 clip." Thus the hypovolemic donor twin, comparable to the clipped kidney, produces vasoactive hormones that compromise the recipient, comparable to the normal kidney, causing hypertension and cardiomyopathy.

Adult↗
PubMed2005

Human fetal mesenchymal stem cells as vehicles for gene delivery.

First-trimester fetal blood contains a readily expandable population of stem cells, human fetal mesenchymal stem cells (hfMSCs), which might be exploited for autologous intrauterine gene therapy. We investigated the self-renewal and differentiation of hfMSCs after transduction with onco-retroviral and lentiviral vectors. After transduction with either a MoMuLV retrovirus or an HIV-1-based lentiviral vector carrying the ss-galactosidase and green fluorescent reporter gene, respectively, transgene expression, self-renewal, and differentiation capabilities were assessed 2 and 14 weeks later. Transduction with the lentiviral vector resulted in higher efficiencies than with the MoMuLV-based vector (mean, 97.7 +/- 1.4% versus 80.2 +/- 5.4%; p = .02). Transgene expression was maintained with lentiviral-transduced cells (94.6 +/- 2.6%) but decreased over 14 weeks in culture with onco-retroviral-transduced cells (48.3 +/- 3.9%). The self-renewal capability of these cells and their ability to undergo osteogenic, adipogenic, and myogenic differentiation was unimpaired after transduction with either vector. Finally, clonal expansion of lentivirally modified cells was expanded over 20 population doublings with maintenance of multiline age differentiation capacity. These results suggest that hfMSCs may be suitable targets for ex vivo genetic manipulation with onco-retroviral or lentiviral vectors without affecting their stem cell properties.

Cell Differentiation↗
PubMed2004

Accurate and robust quantification of circulating fetal and total DNA in maternal plasma from 5 to 41 weeks of gestation.

BACKGROUND: Detection of fetal DNA in maternal plasma is achievable at 5 weeks of gestation, but few large-scale studies have reported circulating fetal and maternal DNA across all trimesters. METHODS: Blood samples were collected from 201 women between 5 and 41 weeks of pregnancy. Quantitative PCR was used to assess total and fetal DNA concentrations, and allelic discrimination analysis was investigated as a route to detecting specifically fetal DNA. RESULTS: Male fetuses were detectable from 5 weeks amenorrhea with increasing fetal DNA concentrations across gestation. The sensitivity of fetal male gender determination in pregnancies with live birth confirmation was 99%, with 100% specificity. Total DNA concentrations did not correlate with gestational age, but appeared slightly higher in the first and third trimesters than in mid-pregnancy. Analysis of short tandem repeats demonstrated that significant improvements in the detection limit are required for specific detection of fetal DNA. CONCLUSIONS: The high sensitivity of PCR-based detection, together with quantification provided by real-time DNA analysis, has clear potential for clinical application in noninvasive prenatal diagnosis. However, accurate quantification using best-fit data analysis, standardization of methods, and performance control indicators are necessary for robust routine noninvasive diagnostics.

Age Factors↗