The Rayne Institute

London, United Kingdom

The Rayne Institute

London, United Kingdom
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PubMed | The Rayne Institute, Guys and St Thomass NHS Foundation Trust and University of Oxford
Type: Journal Article | Journal: Journal of cardiovascular electrophysiology | Year: 2015

Cardiac resynchronization therapy (CRT) using quadripolar left ventricular (LV) leads provides more pacing vectors compared to bipolar leads. This may avoid phrenic nerve stimulation (PNS) and allow optimal lead placement to maximize biventricular pacing. However, a long-term improvement in patient outcome has yet to be demonstrated.A total of 721 consecutive patients with conventional CRTD criteria implanted with quadripolar (n = 357) or bipolar (n = 364) LV leads were enrolled into a registry at 3 UK centers. Lead performance and mortality was analyzed over a 5-year period.Patients receiving a quadripolar lead were of similar age and sex to those receiving a bipolar lead, although a lower proportion had ischemic heart disease (62.6% vs. 54.1%, P = 0.02). Both groups had similar rates of procedural success, although lead threshold, impedance, and procedural radiation dose were significantly lower in those receiving a quadripolar lead. PNS was more common in those with quadripolar leads (16.0% vs. 11.6%, P = 0.08), but was eliminated by switching pacing vector in all cases compared with 60% in the bipolar group (P < 0.001). Furthermore, LV lead displacement (1.7% vs. 4.6%, P = 0.03) and repositioning (2.0% vs. 5.2%, P = 0.03) occurred significantly less often in those with a quadripolar lead. All-cause mortality was also significantly lower in the quadripolar compared to bipolar lead group in univariate and multivariate analysis (13.2% vs. 22.5%, P < 0.001).In a large, multicenter experience, the use of quadripolar LV leads for CRT was associated with elimination of PNS and lower overall mortality. This has important implications for LV pacing lead choice.

Abildtrup M.,King's College London | Shattock M.,The Rayne Institute
Journal of Huntington's disease | Year: 2013

Huntington's disease is a fatal, hereditary, neurodegenerative disorder best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances. Although a disease of the central nervous system, mortality surveys indicate that heart disease is a leading cause of death. The nature of such cardiac abnormalities remains unknown. Clinical findings indicate a high prevalence of autonomic nervous system dysfunction - dysautonomia - which may be a result of pathology of the central autonomic network. Dysautonomia can have profound effects on cardiac health, and pronounced autonomic dysfunction can be associated with neurogenic arrhythmias and sudden cardiac death. Significant advances in the knowledge of neural mechanisms in cardiac disease have recently been made which further aid our understanding of cardiac mortality in Huntington's disease. Even so, despite the evidence of aberrant autonomic activity the potential cardiac consequences of autonomic dysfunction have been somewhat ignored. In fact, underlying cardiac abnormalities such as arrhythmias have been part of the exclusion criteria in clinical autonomic Huntington's disease research. A comprehensive analysis of cardiac function in Huntington's disease patients is warranted. Further experimental and clinical studies are needed to clarify how the autonomic nervous system is controlled and regulated in higher, central areas of the brain - and how these regions may be altered in neurological pathology, such as Huntington's disease. Ultimately, research will hopefully result in an improvement of management with the aim of preventing early death in Huntington's disease from cardiac causes.

Janssen N.,University of Tübingen | Fortis S.P.,Saint Savas Cancer Hospital | Speigl L.,University of Tübingen | Haritos C.,Saint Savas Cancer Hospital | And 12 more authors.
Breast Cancer Research and Treatment | Year: 2016

Purpose: Breast cancer is a leading cause of cancer deaths in women, but despite steady improvements in therapies, treatment is still suboptimal. Immunotherapy holds promise as a more effective therapy for breast cancer; supporting this, our prior study showed that patients possessing HER2-reactive CD8+ T cells in blood experience survival superior to patients without these cells. Here, we define a composite set of biomarkers that identify patients with T cell responses to tumour antigens. Methods: We assessed T cell responses following in vitro stimulation with the HER2, MUC1 and SUR tumour-associated antigens (TAA) by flow cytometry and intracellular cytokine staining in 50 breast cancer patients. We also measured HLA type, serum cytokines, tumour-infiltrating leukocytes and blood leukocyte populations. Results: We found few correlations between TAA-reactive T cells and HLA type, serum cytokines and tumour-infiltrating leukocytes, whereas blood leukocyte phenotypes broadly correlated with TAA responses. This showed monocytes, natural killer cells, dendritic cells and T cells to be inversely associated with both CD4+ and CD8+ T cells reactive to tumour antigens. Moreover, combining multiple parameters improved the accuracy in predicting patients with TAA-responsive T cells. Conclusion: This study therefore defines composite immune profiles that identify patients responding to TAAs which may allow better personalisation of cancer therapies. © 2016 Springer Science+Business Media New York

Mourtada-Maarabouni M.,Keele University | Watson D.,Keele University | Munir M.,Keele University | Munir M.,University of Birmingham | And 3 more authors.
Current Cancer Drug Targets | Year: 2013

Targets for cancer therapy are conventionally selected by identification of molecules acting downstream of established tumour suppressors and oncoproteins, such as p53, c-Myc and Ras. However, the forward genetics approach provides an alternative, conceptually distinct, strategy for identifying target molecules de novo. This approach, which uses unbiased selection protocols relying directly on the effects of the genes themselves on cell fate, has the potential to identify novel cancer targets which have not been highlighted by conventional approaches. PLAC8, a small cysteine-rich protein with little homology to other proteins, has been identified by both these strategies. Here we confirm that PLAC8 overexpression protects some cancer cell lines from apoptosis, but we also demonstrate for the first time that, in other cell lines, the effect of PLAC8 overexpression is reversed, and, in this context, PLAC8 induces apoptosis. In both cases siRNA-mediated down-regulation of PLAC8 confirms that the activity of endogenously expressed PLAC8 is consistent with that shown by exogenous PLAC8. The striking reversal of the effects of PLAC8 in different cell types is not readily explained by the level of PLAC8 expressed within the cells, by the differential expression of PLAC8 splice variants observed, or by the p53 status of the host cells. This intriguing contrast in the effects of PLAC8 on cell fate in different cellular contexts presents attractive possibilities for the development of novel therapies for cancers, such as pancreatic cancers, where PLAC8 has been shown to be overexpressed. © 2013 Bentham Science Publishers.

Brydon L.,University College London | Strike P.C.,University College London | Bhattacharyya M.R.,University College London | Whitehead D.L.,University College London | And 3 more authors.
Journal of Psychosomatic Research | Year: 2010

Objective: Evidence suggests that emotional stress can trigger acute coronary syndromes in patients with advanced coronary artery disease (CAD), although the mechanisms involved remain unclear. Hostility is associated with heightened reactivity to stress in healthy individuals, and with an elevated risk of adverse cardiac events in CAD patients. This study set out to test whether hostile individuals with advanced CAD were also more stress responsive. Methods: Thirty-four men (aged 55.9±9.3 years) who had recently survived an acute coronary syndrome took part in laboratory testing. Trait hostility was assessed by the Cook Medley Hostility Scale, and cardiovascular activity, salivary cortisol, and plasma concentrations of interleukin-6 were assessed at baseline, during performance of two mental tasks, and during a 2-h recovery. Results: Participants with higher hostility scores had heightened systolic and diastolic blood pressure (BP) reactivity to tasks (both P<.05), as well as a more sustained increase in systolic BP at 2 h post-task (P=.024), independent of age, BMI, smoking status, medication, and baseline BP. Hostility was also associated with elevated plasma interleukin-6 (IL-6) levels at 75 min (P=.023) and 2 h (P=.016) poststress and was negatively correlated with salivary cortisol at 75 min (P=.034). Conclusion: Hostile individuals with advanced cardiovascular disease may be particularly susceptible to stress-induced increases in sympathetic activity and inflammation. These mechanisms may contribute to an elevated risk of emotionally triggered cardiac events in such patients. © 2010 Elsevier Inc. All rights reserved.

Ishida M.,The Rayne Institute
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance | Year: 2011

The dual-bolus protocol enables accurate quantification of myocardial blood flow (MBF) by first-pass perfusion cardiovascular magnetic resonance (CMR). However, despite the advantages and increasing demand for the dual-bolus method for accurate quantification of MBF, thus far, it has not been widely used in the field of quantitative perfusion CMR. The main reasons for this are that the setup for the dual-bolus method is complex and requires a state-of-the-art injector and there is also a lack of post processing software. As a solution to one of these problems, we have devised a universal dual-bolus injection scheme for use in a clinical setting. The purpose of this study is to show the setup and feasibility of the universal dual-bolus injection scheme. The universal dual-bolus injection scheme was tested using multiple combinations of different contrast agents, contrast agent dose, power injectors, perfusion sequences, and CMR scanners. This included 3 different contrast agents (Gd-DO3A-butrol, Gd-DTPA and Gd-DOTA), 4 different doses (0.025 mmol/kg, 0.05 mmol/kg, 0.075 mmol/kg and 0.1 mmol/kg), 2 different types of injectors (with and without "pause" function), 5 different sequences (turbo field echo (TFE), balanced TFE, k-space and time (k-t) accelerated TFE, k-t accelerated balanced TFE, turbo fast low-angle shot) and 3 different CMR scanners from 2 different manufacturers. The relation between the time width of dilute contrast agent bolus curve and cardiac output was obtained to determine the optimal predefined pause duration between dilute and neat contrast agent injection. 161 dual-bolus perfusion scans were performed. Three non-injector-related technical errors were observed (1.9%). No injector-related errors were observed. The dual-bolus scheme worked well in all the combinations of parameters if the optimal predefined pause was used. Linear regression analysis showed that the optimal duration for the predefined pause is 25s to separate the dilute and neat contrast agent bolus curves if 0.1 mmol/kg dose of Gd-DO3A-butrol is used. The universal dual-bolus injection scheme does not require sophisticated double-head power injector function and is a feasible technique to obtain reasonable arterial input function curves for absolute MBF quantification.

Chen R.,University of Leeds | Folarin N.,The Rayne Institute | Ho V.H.B.,University of Cambridge | McNally D.,University of Cambridge | And 3 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Desthiobiotin-tagged lentiviral vectors have been metabolically produced by DBL producer cells in a 7,8-diaminopelargonic acid (7-DAPA) dependent manner for envelope independent, single-step affinity purification. 7-DAPA, which has little or no affinity for avidin/streptavidin, was synthesised and verified by NMR spectroscopy and mass spectrometry. By expressing the biotin acceptor, biotin ligase and desthiobiotin synthase bioD, DBL cells converted exogenous 7-DAPA into membrane-bound desthiobiotin. Desthiobiotin on the DBL cell surface was visualised by confocal microscopy and the desthiobiotin density was quantified by HABA-avidin assay. Desthiobiotin was then spontaneously incorporated onto the surface of lentiviral vectors produced by the DBL cells. It has been demonstrated by flow cytometry that the desthiobiotinylated lentiviruses were captured from the crude 7-DAPA-containing viral supernatant by Streptavidin Magnespheres ® and eluted by biotin solution efficiently whilst retaining infectivity. The practical, high yielding virus purification using Pierce monomeric avidin coated columns indicates a highly efficient biotin-dependent recovery of infectious lentiviruses at 68%. The recovered lentiviral vectors had a high purity and the majority were eluted within 45min. This 7-DAPA mediated desthiobiotinylation technology can be applied in scalable production of viral vectors for clinical gene therapy. © 2010 Elsevier B.V.

PubMed | The Rayne Institute
Type: Journal Article | Journal: Journal of neuroendocrinology | Year: 2011

Our recent observations in man suggested that the secretion of the thymic peptide, thymulin, is influenced by hormones of the pituitary-adrenal axis. In the present study, we have used the rat as a model in order to examine 1) the effects of corticotrophin (ACTH) and glucocorticoids on the release of thymulin in vivo and in vitro, and 2) the influence of an acute rise in plasma thymulin on the secretion of corticosterone and luteinizing hormone. Immunoreactive thymulin was readily detectable in plasma from male Sprague-Dawley rats(200 g). Chronic bilateral adrenalec-tomy, which effectively removed endogenous corticosterone, produced highly significant (P<0.01) increases in the plasma concentrations of both ACTH and thymulin. Treatment of the adrenalectomized rats with dexamethasone, in a dose sufficient to suppress the hypersecretion of ACTH, maintained the plasma thymulin at a low level which did not differ significantly (P > 0.2) from that in sham-operated controls. In vitro, two non-specific depolarizing agents, K(+) (56 mM) and veratridine (10 M), caused significant (P<0.01) Ca(2+) -dependent increases in thymulin release from segments of rat thymic tissue. Their effects were mimicked by ACTH(1-39) . The secretory responses to ACTH (0.025 to 1 ng/ml) were concentration-dependent but a very high concentration (2 ng/ml) of the peptide was without effect. Dexamethasone (0.1 M) reduced (P<0.05) the spontaneous release of thymulin in vitro but potentiated markedly (P<0.01) the secretory responses to ACTH (0.5 to 1.0 ng/ml). Administration of thymulin (0.1 and 10 g/kg ip) produced, within 10 min, striking increases in the plasma thymulin concentration which were still evident at 30 min. The peptide concentration then declined rapidly and, within 24 h, was lower than that in the corresponding vehicle-treated controls. The serum concentrations of corticosterone and luteinizing hormone were unaffected by the thymulin treatment. The saline vehicle (2.0 ml/kg ip) also produced a small increase in plasma thymulin concentration which was maximal at 10 min; a further small rise was evident 6 h after the injection but thereafter the thymulin values were indistinguishable from those in uninjected controls. A similar biphasic profile of serum corticosterone was apparent after the saline injection but the serum luteinizing hormone was unaffected. The results suggest that ACTH is a physiological enhancer of thymulin release and that, in certain circumstances, its effects may be potentiated by glucocorticoids.

Hussain S.T.,Papworth Hospital NHS trust | Morton G.,Portsmouth Hospitals NHS Trust | de Silva K.,The Rayne Institute | Jogiya R.,Biomedical Imaging Center | And 4 more authors.
Clinical Research in Cardiology | Year: 2016

Aims: This study assesses the relationship between classical anatomical jeopardy scores, functional jeopardy scores (combined anatomical and haemodynamic data), and the extent of ischaemia identified on cardiovascular magnetic resonance (CMR) perfusion imaging. Methods and results: In 42 patients with stable angina and suspected coronary artery disease (CAD), CMR perfusion imaging was performed. Fractional Flow Reserve (FFR) was measured in vessels with ≥50 % stenosis. The APPROACH and BCIS jeopardy scores were calculated based on QCA results with both a 70 % (APP70 and BCIS70) and a 50 % stenosis (APP50, and BCIS50) used as the threshold for significance, as well as after integration of FFR and compared with the extent of ischaemia identified on CMR. The correlation between the extent of ischaemia measured by CMR and the anatomical jeopardy scores was moderate (APPROACH: r = 0.58; BCIS: r = 0.48, p = 0.001). Integrating physiological information improved this significantly to r = 0.82, p = 0.0001 for APPROACH and r = 0.82, p = 0.0001 for BCIS scores (z-statistic = −2.04, p = 0.04; z-statistic = −2.63, p = 0.009). In relation to CMR, the APPROACH and BCIS scores overestimated the volume of ischaemic myocardium by 29.2 and 25.2 %, respectively, which was reduced to 12.8 and 12 % after integrating functional data. Conclusions: Anatomical and functional jeopardy scores overestimate ischaemic burden when compared to CMR. Integrating physiological information from FFR to generate a functional score improves ischaemic burden estimation. © 2016 Springer-Verlag Berlin Heidelberg

Inactivation of the DNA mismatch repair pathway manifests as microsatellite instability, an accumulation of mutations that drives carcinogenesis. Here, we determined whether microsatellite instability in acute myeloid leukemia and myelodysplastic syndrome correlated with chromosomal instability and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity through disruption of DNA repair function. Acute myeloid leukemia cell lines (n=12) and primary cell samples (n=18), and bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients (n=63) were profiled for microsatellite instability using fluorescent fragment polymerase chain reaction. PARP inhibitor sensitivity was performed using cell survival, annexin V staining and cell cycle analysis. Homologous recombination was studied using immunocytochemical analysis. SNP karyotyping was used to study chromosomal instability. RNA silencing, Western blotting and gene expression analysis was used to study the functional consequences of mutations. Acute myeloid leukemia cell lines (4 of 12, 33%) and primary samples (2 of 18, 11%) exhibited microsatellite instability with mono-allelic mutations in CtIP and MRE11. These changes were associated with reduced expression of mismatch repair pathway components, MSH2, MSH6 and MLH1. Both microsatellite instability positive primary acute myeloid leukemia samples and cell lines demonstrated a downregulation of homologous recombination DNA repair conferring marked sensitivity to PARP inhibitors. Similarly, bone marrow mononuclear cells from 11 of 56 (20%) patients with de novo high-risk myelodysplastic syndrome exhibited microsatellite instability. Significantly, all 11 patients with microsatellite instability had cytogenetic abnormalities with 4 of them (36%) possessing a mono-allelic microsatellite mutation in CtIP. Furthermore, 50% reduction in CtIP expression by RNA silencing also down-regulated homologous recombination DNA repair responses conferring PARP inhibitor sensitivity, whilst CtIP differentially regulated the expression of homologous recombination modulating RecQ helicases, WRN and BLM. In conclusion, microsatellite instability dependent mutations in DNA repair genes, CtIP and MRE11 are detected in myeloid malignancies conferring hypersensitivity to PARP inhibitors. Microsatellite instability is significantly correlated with chromosomal instability in myeloid malignancies.

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