Publications by authors named "Helen Spencer"

53 Publications

What are the essential ingredients of a CBT case conceptualization for voices and delusions in schizophrenia spectrum disorders? A study of expert consensus.

Schizophr Res 2020 10 14;224:74-81. Epub 2020 Oct 14.

Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, United Kingdom.

Evidence supports the use of cognitive behavioural therapy (CBT) for the treatment of patients with schizophrenia spectrum disorders. A case conceptualization (CC) (or case formulation) is seen as the keystone of CBT in terms of making sense of a patient's difficulties, to guide and inform such treatment. Despite the importance placed on CC there is no known consensus amongst experts as to the essential ingredients involved in this fundamental process. This study used the Delphi method to establish expert consensus for the essential components of a CC when working to treat auditory hallucinations (voices), and persecutory delusions. An international panel of 78 CBT for psychosis (CBTp) experts from 12 different countries participated in the main stage of this study. This 3-stage process involved producing and rating statements that addressed key areas of CC in terms of: presenting issues, predisposing, precipitating, perpetuating and protective factors. One presenting issue and 6 perpetuating factors were endorsed as essential by >80% of the expert panel. The exact same items were endorsed for both voices, and persecutory delusions. The findings are unique in that a large panel of international experts reached consensus that case conceptualizations (CCs) should be parsimonious and focused on the perpetuating (maintaining) factors to facilitate change. Overall, the proposed recommendations should lead to core guidance for the process of developing CCs, and improvements in training for clinicians that conceptualize voices, and persecutory delusions in CBT for schizophrenia spectrum disorders.
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http://dx.doi.org/10.1016/j.schres.2020.09.026DOI Listing
October 2020

Inhaled hypertonic saline after pediatric lung transplant-Caution required?

Pediatr Transplant 2020 12 7;24(8):e13843. Epub 2020 Oct 7.

Department of Cardiothoracic Transplantation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Management of pulmonary infection following lung transplant is multifaceted and includes respiratory physiotherapy. Inhaled hypertonic saline (HTS) has been introduced as an adjunct to physiotherapy in pediatric transplant patients. There are no published studies investigating the use of HTS in this population. This study aimed to evaluate the effect of inhaled HTS, in the acute post-operative period, in pediatric lung transplant patients. A retrospective case-note review was completed at a single UK pediatric transplant center. An intervention group who received HTS was compared to a historical control group. Participants were frequency matched for age, gender, and diagnosis (14 per group); median age in years was 13.7(IQR 12.7-15.3) in the controls and 14.8(IQR 12.4-16.1) in the intervention group. Primary outcome was the requirement of invasive and non-invasive ventilation. Secondary outcomes included oxygen use and length of stay. Median days of invasive ventilation were shorter in the control group (1, 95% CI 1-1) compared to the intervention group (2, 95% CI 1-2.5) (P < .05). Days of non-invasive ventilation and oxygen were higher in the HTS group, but this was not statistically significant. The controls displayed shorter median length of stay (23 days, 95% CI 20-24) compared to the intervention group (31 days, 95% CI 24.5-39) (P < .05). The results of this small study provide uncertainty regarding the safety of inhaled hypertonic saline after lung transplant. There was a trend of poorer acute outcomes in patients who received HTS. However, the findings should be interpreted with caution and further investigation using larger samples is required.
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http://dx.doi.org/10.1111/petr.13843DOI Listing
December 2020

Cell-Free DNA in Pediatric Solid Organ Transplantation Using a New Detection Method of Separating Donor-Derived from Recipient Cell-Free DNA.

Clin Chem 2020 Oct;66(10):1300-1309

Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: The use of cell-free DNA (cfDNA) as a noninvasive biomarker to detect allograft damage is expanding rapidly. However, quantifying the low fraction of donor-derived cfDNA (ddcfDNA) is challenging and requires a highly sensitive technique. ddcfDNA detection through unique donor single nucleotide polymorphisms (SNPs) is a recent new approach, however there are limited data in pediatric solid organ transplant (SOT) recipients.

Methods: We developed an assay using a combination of 61 SNPs to quantify the ddcfDNA accurately using a custom R script to model for both the patient and donor genotypes requiring only a single sample from the allograft recipient. Performance of the assay was validated using genomic DNA (gDNA), cfDNA and donor samples where available.

Results: The R "genotype-free" method gave results comparable to when using the known donor genotype. applicable to both related and unrelated pairs and can reliably measure ddcfDNA (limit of blank, below 0.12%; limit of detection, above 0.25%; limit of quantification 0.5% resulting in 84% accuracy). 159 pediatric SOT recipients (kidney, heart, and lung) were tested without the need for donor genotyping. Serial sampling was obtained from 82 patients.

Conclusion: We have developed and validated a new assay to measure the fraction of ddcfDNA in the plasma of pediatric SOT recipients. Our method can be applicable in any donor-recipient pair without the need for donor genotyping and can provide results in 48 h at a low cost. Additional prospective studies are required to demonstrate its clinical validity in a large cohort of pediatric SOT recipients.
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http://dx.doi.org/10.1093/clinchem/hvaa173DOI Listing
October 2020

Pediatric lung transplantation: Results of volume reduction in smaller children.

Pediatr Transplant 2020 08 1;24(5):e13752. Epub 2020 Jun 1.

Department of Cardiothoracic Surgery, Great Ormond Street Hospital, London, UK.

Pediatric LTX is challenged by the scarcity of suitable donor organs. To alleviate the problem of size matching, volume reduction of the donor is a possible option. Previous reports address mostly older teenagers, and data about younger patients are lacking. The purpose of this study was to investigate whether trimming had influence on the morbidity and mortality in slightly younger recipients, operated in a single center. Between 2015 and 2018, 20 patients were transplanted at the GOSH London. The mean age was 11.5 (±4.6) years. Nine patients underwent volume reduction prior to transplantation (T group). The other patients received classical bilateral LTX (NT group). Ischemia times were longer in the T group, but this difference was not statistically significant. We observed no 30-day mortality. Hospital survival in the T group was 78% vs 90% in the NT group. After almost 3 years, mortality in the T group was 22% vs 28% in the NT group. None of these differences was statistically significant. The mean duration of MV, intensive care stay, and hospital stay were 11.5, 19.9, and 44.8 days, respectively. Results were equal in terms of morbidity, defined as respiratory and neurological complications or the need for ECMO. Results show that volume reduction prior to LTX is a feasible option, even in smaller children. While awaiting long-term results, accepting larger donor organs could be a strategy to further reduce waiting list time and subsequently lower the mortality on the waiting list.
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http://dx.doi.org/10.1111/petr.13752DOI Listing
August 2020

Outcome according to subspecies following lung transplantation in cystic fibrosis pediatric patients infected with Mycobacterium abscessus.

Transpl Infect Dis 2020 Jun 18;22(3):e13274. Epub 2020 Mar 18.

Department of Cardiothoracic Transplantation, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Mycobacterium abscessus infection has been associated with variable outcomes following lung transplantation. M abscessus comprises three subspecies (M abscessus subsp abscessus, M abscessus subsp massiliense, and M abscessus subsp bolletii). We investigated whether lung transplantation outcome in cystic fibrosis (CF) patients in a single center was related to the M abscessus subspecies and genetic cluster.

Methods: CF patients with chronic M abscessus infection transplanted at Great Ormond Street Hospital between 2004 and 2017 were retrospectively examined. All M abscessus isolates were identified to subspecies level by polymerase chain reaction and sequencing. Genetic cluster was determined by variable number tandem repeat profiling and whole-genome sequencing (WGS), and sequence type inferred from WGS.

Results: Thirteen patients with chronic M abscessus infection underwent heart/lung or lung transplantation. Subspecies identification showed n = 1 with M abscessus bolletii, n = 5 with M abscessus massiliense, and n = 7 with M abscessus abscessus infection. Eight (62%) patients (one with M abscessus massiliense and seven with M abscessus abscessus) died post-lung transplant. The patient with M abscessus bolletii and three patients with M abscessus massiliense did well post-transplant. One patient with M abscessus massiliense is receiving ongoing treatment.

Conclusions: Dramatically worse outcomes are observed in patients infected with M abscessus subspecies abscessus, the majority of whom were infected with ST-1 and ST-26 strains. Patients infected with other M abcsessus strains can have acceptable outcomes.
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http://dx.doi.org/10.1111/tid.13274DOI Listing
June 2020

The LINC00961 transcript and its encoded micropeptide, small regulatory polypeptide of amino acid response, regulate endothelial cell function.

Cardiovasc Res 2020 Oct;116(12):1981-1994

University/BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

Aims: Long non-coding RNAs (lncRNAs) play functional roles in physiology and disease, yet understanding of their contribution to endothelial cell (EC) function is incomplete. We identified lncRNAs regulated during EC differentiation and investigated the role of LINC00961 and its encoded micropeptide, small regulatory polypeptide of amino acid response (SPAAR), in EC function.

Methods And Results: Deep sequencing of human embryonic stem cell differentiation to ECs was combined with Encyclopedia of DNA Elements (ENCODE) RNA-seq data from vascular cells, identifying 278 endothelial enriched genes, including 6 lncRNAs. Expression of LINC00961, first annotated as an lncRNA but reassigned as a protein-coding gene for the SPAAR micropeptide, was increased during the differentiation and was EC enriched. LINC00961 transcript depletion significantly reduced EC adhesion, tube formation, migration, proliferation, and barrier integrity in primary ECs. Overexpression of the SPAAR open reading frame increased tubule formation; however, overexpression of the full-length transcript did not, despite production of SPAAR. Furthermore, overexpression of an ATG mutant of the full-length transcript reduced network formation, suggesting a bona fide non-coding RNA function of the transcript with opposing effects to SPAAR. As the LINC00961 locus is conserved in mouse, we generated an LINC00961 locus knockout (KO) mouse that underwent hind limb ischaemia (HLI) to investigate the angiogenic role of this locus in vivo. In agreement with in vitro data, KO animals had a reduced capillary density in the ischaemic adductor muscle after 7 days. Finally, to characterize LINC00961 and SPAAR independent functions in ECs, we performed pull-downs of both molecules and identified protein-binding partners. LINC00961 RNA binds the G-actin sequestering protein thymosin beta-4x (Tβ4) and Tβ4 depletion phenocopied the overexpression of the ATG mutant. SPAAR binding partners included the actin-binding protein, SYNE1.

Conclusion: The LINC00961 locus regulates EC function in vitro and in vivo. The gene produces two molecules with opposing effects on angiogenesis: SPAAR and LINC00961.
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http://dx.doi.org/10.1093/cvr/cvaa008DOI Listing
October 2020

Language in schizophrenia and aphasia: the relationship with non-verbal cognition and thought disorder.

Cogn Neuropsychiatry 2019 11 25;24(6):389-405. Epub 2019 Sep 25.

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

To determine the relationship between language abnormalities and broader cognitive impairment and thought disorder by examining language and cognition in schizophrenia and aphasia (a primary language disorder). Cognitive and linguistic profiles were measured with a battery of standardised tests, and compared in a clinical population of  = 50 ( = 30 with schizophrenia and  = 20 with aphasia) and  = 61 non-clinical comparisons ( = 45 healthy controls and  = 16 non-affected first-degree relatives of patients with schizophrenia). Both clinical groups showed linguistic deficits. Verbal impairment was more severe in participants with aphasia, whereas non-verbal performance was more affected in participants with schizophrenia. In schizophrenia, but not in aphasia, verbal and non-verbal performance were associated. Formal thought disorder was associated with impairment in executive function and in grammatical, but not naming, tasks. While patients with schizophrenia and aphasia showed language impairments, the nature and cognitive basis of these impairments may be different; language performance disassociates from broader cognitive functioning in aphasia but may be an intrinsic expression of a broader cognitive impairment in schizophrenia. Thought disorder may represent a core malfunction of grammatical processing. Results suggests that communicative ability may be a valid target in cognitive remediation strategies in schizophrenia.
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http://dx.doi.org/10.1080/13546805.2019.1668758DOI Listing
November 2019

Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus.

Nat Med 2019 05 8;25(5):730-733. Epub 2019 May 8.

Great Ormond Street Hospital, London, UK.

A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.
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http://dx.doi.org/10.1038/s41591-019-0437-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557439PMC
May 2019

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1113-1124

From the Bristol Heart Institute, Bristol Medical School, Translational Health Sciences, University of Bristol, United Kingdom (H.L.S., E.J., W.C., E.A., I.R.-A., A.C.T., V.V.A., G.S.-N., Z.D., M.F., C.R., J.R., G.A., P.M.).

Objective- To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization. Approach and Results- Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells. This involves the transcriptional modulator CITED2 (Atypical chemokine receptor 3 CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail) and downstream activation of CXCL12 (chemokine [C-X-C motif] ligand-12) signaling through the CXCR7 (C-X-C chemokine receptor type 7) receptor and ERK1/2 (extracellular signal-regulated kinases 1/2). TPBG silencing by siRNA transfection downregulated CXCL12, CXCR7, and pERK (phospho Thr202/Tyr204 ERK1/2) and reduced the APC migratory and proangiogenic capacities. TPBG forced expression induced opposite effects, which were associated with the formation of CXCR7/CXCR4 (C-X-C chemokine receptor type 4) heterodimers and could be contrasted by CXCL12 and CXCR7 neutralization. In vivo Matrigel plug assays using APCs with or without TPBG silencing evidenced TPBG is essential for angiogenesis. Finally, in immunosuppressed mice with limb ischemia, intramuscular injection of TPBG-overexpressing APCs surpassed naïve APCs in enhancing perfusion recovery and reducing the rate of toe necrosis. Conclusions- TPBG orchestrates the migratory and angiogenic activities of pericytes through the activation of the CXCL12/CXCR7/pERK axis. This novel mechanism could be a relevant target for therapeutic improvement of reparative angiogenesis.
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http://dx.doi.org/10.1161/ATVBAHA.119.312665DOI Listing
June 2019

Successful lung donation at the age of 6 weeks: Challenges and lessons learned.

Pediatr Transplant 2019 06 23;23(4):e13419. Epub 2019 Apr 23.

Royal Papworth Hospital, Cambridge, UK.

A clinical case of successful procurement and transplantation of bilateral lungs from 6-week-old infant with sepsis secondary to bacterial meningitis is reported. Forty-one-day-old male infant (height 60 cm, weight 4 kg) died of cerebral edema secondary to Escherichia coli meningitis and bacteremia. Preretrieval assessment included the following: arterial gases; pO 50.4 kPa (378 mm Hg), pCO 4.9 kPa (37 mm Hg), on FiO 100%, PEEP 5 cm H O. Fiberoptic bronchoscopy showed no secretions nor mucosal inflammation; CXR revealed clear lung fields and pleural spaces. Inspection revealed dense adhesions in pericardial cavity and purulent left hemithorax effusion (urgent Gram-stain came back as negative) but there was no consolidation in the lung. Good compliance of the lungs on inflation/deflation test was observed. The lungs were retrieved using the technique described. The recipient was a 4-month-old infant with alveolar capillary dysplasia and malaligned pulmonary veins. Implantation of the lungs was performed via bilateral thoracosternotomy on cardiopulmonary bypass, cooling to 30°C. Elective support with nitric oxide was used postoperatively. Two years after the transplantation, the recipient doing well with normal lung function. Lung procurement from a 6-week donor with infectious complications and prolonged ventilation is a challenging undertaking but can be successful and should be attempted whenever possible given the paucity of organs available for pediatric recipients.
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http://dx.doi.org/10.1111/petr.13419DOI Listing
June 2019

Children With Cystic Fibrosis Are Infected With Multiple Subpopulations of Mycobacterium abscessus With Different Antimicrobial Resistance Profiles.

Clin Infect Dis 2019 10;69(10):1678-1686

Department of Microbiology, Virology and Infection Control.

Background: Children with cystic fibrosis (CF) can develop life-threatening infections of Mycobacterium abscessus. These present a significant clinical challenge, particularly when the strains involved are resistant to antibiotics. Recent evidence of within-patient subclones of M. abscessus in adults with CF suggests the possibility that within-patient diversity may be relevant for the treatment of pediatric CF patients.

Methods: We performed whole-genome sequencing (WGS) on 32 isolates of M. abscessus that were taken from multiple body sites of 2 patients with CF who were undergoing treatment at Great Ormond Street Hospital, United Kingdom, in 2015.

Results: We found evidence of extensive diversity within patients over time. A clustering analysis of single nucleotide variants revealed that each patient harbored multiple subpopulations, which were differentially abundant between sputum, lung samples, chest wounds, and pleural fluid. The sputum isolates did not reflect the overall within-patient diversity and did not allow for the detection of subclones with mutations previously associated with macrolide resistance (rrl 2058/2059). Some variants were present at intermediate frequencies before the lung transplants. The time of the transplants coincided with extensive variation, suggesting that this event is particularly disruptive for the microbial community, but the transplants did not clear the M. abscessus infections and both patients died as a result of these infections.

Conclusions: Isolates of M. abscessus from sputum do not always reflect the entire diversity present within the patient, which can include subclones with differing antimicrobial resistance profiles. An awareness of this phenotypic variability, with the sampling of multiple body sites in conjunction with WGS, may be necessary to ensure the best treatment for this vulnerable patient group.
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http://dx.doi.org/10.1093/cid/ciz069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821159PMC
October 2019

Contrasting Effects of Pressure Compensation on TEOAE and DPOAE in Children With Negative Middle Ear Pressure.

Trends Hear 2018 Jan-Dec;22:2331216518812251

5 Institute of Medical Statistics and Informatics, University of Belgrade School of Medicine, Serbia.

In children with normal cochlear acuity, middle ear fluid often abolishes otoacoustic emissions (OAEs), and negative middle ear pressure (NMEP) reduces them. No convincing evidence of beneficial pressure compensation on distortion product OAE (DPOAE) has yet been presented. Two studies aimed to document effects of NMEP on transient OAE (TEOAE) and DPOAE. In Study 1, TEOAE and DPOAE pass/fail responses were analyzed before and after pressure compensation in 50 consecutive qualifying referrals having NMEP from -100 to -299 daPa. Study 2 concentrated on DPOAE, recording both amplitude (distortion product amplitude) and signal-to-noise ratio (SNR) before and after pressure compensation. Of the 20 participants, 5 had both ears qualifying. An effect of compensation on meeting a pass criterion was present in TEOAE for both left and right ear data in Study 1 but not demonstrable in DPOAE. In Study 2, the distortion product amplitude compensation effect was marginal overall, and depended on recording frequency band. SNR values improved moderately after pressure compensation in the two (overlapping) sets of single-ear data. In the five cases with both ears qualifying, a stronger compensation effect size, over 3 dB, was seen. The absolute dependence of SNR on frequency was also strongly replicated, but in no analysis, the frequency × compensation interaction was significant. Independent of particular frequency range, the data support a limited SNR improvement in 2 to 3 dB for compensation in DPOAE, with slightly larger effects in ears giving SNRs between 0 dB and +6 dB, where pass/fail cutoffs would generally be located.
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http://dx.doi.org/10.1177/2331216518812251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277756PMC
April 2019

Contrasting Effects of Pressure Compensation on TEOAE and DPOAE in Children With Negative Middle Ear Pressure.

Trends Hear 2018 Jan-Dec;22:2331216518812251

5 Institute of Medical Statistics and Informatics, University of Belgrade School of Medicine, Serbia.

In children with normal cochlear acuity, middle ear fluid often abolishes otoacoustic emissions (OAEs), and negative middle ear pressure (NMEP) reduces them. No convincing evidence of beneficial pressure compensation on distortion product OAE (DPOAE) has yet been presented. Two studies aimed to document effects of NMEP on transient OAE (TEOAE) and DPOAE. In Study 1, TEOAE and DPOAE pass/fail responses were analyzed before and after pressure compensation in 50 consecutive qualifying referrals having NMEP from -100 to -299 daPa. Study 2 concentrated on DPOAE, recording both amplitude (distortion product amplitude) and signal-to-noise ratio (SNR) before and after pressure compensation. Of the 20 participants, 5 had both ears qualifying. An effect of compensation on meeting a pass criterion was present in TEOAE for both left and right ear data in Study 1 but not demonstrable in DPOAE. In Study 2, the distortion product amplitude compensation effect was marginal overall, and depended on recording frequency band. SNR values improved moderately after pressure compensation in the two (overlapping) sets of single-ear data. In the five cases with both ears qualifying, a stronger compensation effect size, over 3 dB, was seen. The absolute dependence of SNR on frequency was also strongly replicated, but in no analysis, the frequency × compensation interaction was significant. Independent of particular frequency range, the data support a limited SNR improvement in 2 to 3 dB for compensation in DPOAE, with slightly larger effects in ears giving SNRs between 0 dB and +6 dB, where pass/fail cutoffs would generally be located.
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http://dx.doi.org/10.1177/2331216518812251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277756PMC
April 2019

The language profile of formal thought disorder.

NPJ Schizophr 2018 Sep 19;4(1):18. Epub 2018 Sep 19.

Department of Translation and Language Sciences, Universitat Pompeu Fabra, Barcelona, Spain.

Formal thought disorder (FTD) is clinically manifested as disorganized speech, but there have been only few investigations of its linguistic properties. We examined how disturbance of thought may relate to the referential function of language as expressed in the use of noun phrases (NPs) and the complexity of sentence structures. We used a comic strip description task to elicit language samples from 30 participants with schizophrenia (SZ), 15 with moderate or severe FTD (SZ + FTD), and 15 minimal or no FTD (SZ-FTD), as well as 15 first-degree relatives of people with SZ (FDRs) and 15 neurotypical controls (NC). We predicted that anomalies in the normal referential use of NPs, sub-divided into definite and indefinite NPs, would identify FTD; and also that FTD would also be linked to reduced linguistic complexity as specifically measured by the number of embedded clauses and of grammatical dependents. Participants with SZ + FTD produced more referential anomalies than NC and produced the fewest definite NPs, while FDRs produced the most and thus also differed from NC. When referential anomalies were classed according to the NP type in which they occurred, the SZ + FTD group produced more anomalies in definite NPs than NC. Syntactic errors did not distinguish groups, but the SZ + FTD group exhibited significantly less syntactic complexity than non-SZ groups. Exploratory regression analyses suggested that production of definite NPs distinguished the two SZ groups. These results demonstrate that FTD can be identified in specific grammatical patterns which provide new targets for detection, intervention, and neurobiological studies.
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http://dx.doi.org/10.1038/s41537-018-0061-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145886PMC
September 2018

Technical challenges of lung transplantation in children after arterial switch operation.

Interact Cardiovasc Thorac Surg 2019 03;28(3):493-495

Department of Cardiothoracic Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Pulmonary arterial hypertension after arterial switch operation for transposition of the great arteries is rare. Lung transplantation can be the last option in cases of failed medical therapy. We report 2 paediatric patients who underwent lung transplantation for this indication. Altered hilar anatomy, mediastinal adhesions and haemostatic control represent the main technical challenges. Volume-reduction surgery is sometimes necessary to address altered cardiopulmonary relationships while expanding the donor pool.
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http://dx.doi.org/10.1093/icvts/ivy253DOI Listing
March 2019

Cognitive Behavioral Therapy for antipsychotic-free schizophrenia spectrum disorders: Does therapy dose influence outcome?

Schizophr Res 2018 12 13;202:385-386. Epub 2018 Jul 13.

Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; School of Psychology, Newcastle University, Newcastle upon Tyne, United Kingdom.

This study investigated the effect of "dose" and the components of Cognitive Behavioral Therapy (CBT) on treatment effects. It is a secondary analysis of the ACTION (Assessment of Cognitive Therapy Instead of Neuroleptics) trial which investigated CBT for people with schizophrenia spectrum disorders that chose not to take antipsychotic medication. Using instrumental variable methods, we found a "dose-response" such that each CBT session attended, reduced the primary outcome measure (the PANSS total score) by approximately 0.6 points (95% CI -1.20 to -0.06, p = 0.031). This suggests that length of therapy is important for those that receive CBT in the absence of antipsychotic medication. Secondly, using principal stratification we examined the process variables that modified treatment effects. Findings revealed that those who received a longitudinal formulation in the first 4 sessions of CBT had poorer treatment effects than those who did not, however this finding was not statistically significant (95% CI -37.244, 6.677, p = 0.173). However, it is important to note that these findings were evident in an exploratory analysis with a small sample. Future larger scale studies are needed to help understand components of effective treatment.
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http://dx.doi.org/10.1016/j.schres.2018.07.016DOI Listing
December 2018

Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product.

Mol Ther 2018 07 28;26(7):1669-1684. Epub 2018 Mar 28.

University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. Electronic address:

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31/CD144), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy.
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http://dx.doi.org/10.1016/j.ymthe.2018.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035339PMC
July 2018

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction.

J Am Heart Assoc 2018 01 22;7(2). Epub 2018 Jan 22.

Bristol Heart Institute, School of Clinical Sciences, University of Bristol, United Kingdom

Background: Transplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model.

Methods And Results: We performed a blind, randomized, placebo-controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone.

Conclusions: Immunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.
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http://dx.doi.org/10.1161/JAHA.117.006727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850145PMC
January 2018

Psychometric characteristics of the chronic Otitis media questionnaire 12 (COMQ - 12): stability of factor structure and replicability shown by the Serbian version.

Health Qual Life Outcomes 2017 Oct 23;15(1):207. Epub 2017 Oct 23.

School of Medicine, University of Belgrade, Institute for Medical Statistics and Informatics, Belgrade, Serbia.

Background: Recently, demand for and supply of short-form patient-reported outcome measures (PROMs) have risen throughout the world healthcare. Our contribution to meeting that demand has been translating and culturally adapting the Chronic Otitis Media Questionnaire-12 (COMQ-12) for adults into Serbian and enhancing its psychometric base on the relatively large Serbian COM caseload. Chronic otitis media can seriously affect quality of life progressively and in long-term, and it remains the major source of hearing problems in the developing world.

Methods: The translated questionnaire was given twice to 60 adult patients with chronic otitis media of three types (inactive, active mucosal and active squamous disease) and to 60 healthy volunteers. Both patients and volunteers also filled the generic Short-Form 36 questionnaire (SF-36). Conventional statistical procedures were used in strategically driven development of scoring. Additionally, item responses were scaled by linear mapping against the provisional total score. Generalizability, detailed factor interpretation and supportability of scores were criteria, for the best compromise factor solution.

Results: Test-retest reliability was very high (0.924 to 0.989, depending on score). The a priori content dimensions of the questionnaire were strongly supported by 3-factor exploratory and confirmatory factor analyses for content validity, separating (i) ear symptoms from (ii) hearing problems, from (iii) daily activity restriction plus healthcare uptake. The 3-factor structure was furthermore highly stable on replication. The very large effect sizes when contrasting patients with healthy volunteers, and active with inactive disease established construct validity for the total score. A strong association with disease activity and a moderate one with generic health-related quality of life (HRQoL), the SF-36, supported construct validity for two of three factors extracted (ear symptoms, and impact on daily activities plus healthcare uptake).

Conclusions: Given the minimal psychometric work to date on COMQ-12, this interim sample with 120 data points adds materially to knowledge of its reliability, several forms of validity and the feasibility of profile sub-scores to supplement total scores. The good psychometric properties shown for COMQ-12 justify both its routine clinical use and acquisition of the necessarily larger sample for generality, score optimisation and the evaluation of responsiveness.
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http://dx.doi.org/10.1186/s12955-017-0782-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651611PMC
October 2017

The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease.

Mol Ther Nucleic Acids 2017 Sep 28;8:494-507. Epub 2017 Jul 28.

Cardiovascular Research Unit, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg. Electronic address:

The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus.
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http://dx.doi.org/10.1016/j.omtn.2017.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565632PMC
September 2017

Befriending: active placebo or effective psychotherapy?

Br J Psychiatry 2017 07;211(1):5-6

Douglas Turkington, MD, FRCPsych, Academic Psychiatry, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle General Hospital, Newcastle upon Tyne, Northumberland, Tyne and Wear NHS Mental Health Foundation Trust, and Institute of Neuroscience, Newcastle University; Helen Spencer, BA, Latoyah Lebert, BSc, Academic Psychiatry, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle General Hospital, Newcastle upon Tyne, Northumberland, Tyne and Wear NHS Mental Health Foundation Trust, and School of Psychology, Newcastle University; Robert Dudley, PhD, DCIinPsy, Early Intervention in Psychosis Service, Tranwell Unit, Queen Elizabeth Hospital, Gateshead, Northumberland, Tyne and Wear NHS Mental Health Foundation Trust, and School of Psychology, Newcastle University, UK.

Befriending allows for control of the non-specific factors of the therapist-patient interaction in psychosocial research. Manualised befriending is at the very least an active placebo and potentially an effective intervention. Befriending now merits increased research attention to determine indications for use and to elucidate mechanisms of action.
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http://dx.doi.org/10.1192/bjp.bp.116.197467DOI Listing
July 2017

Identifying Four Subgroups of Trauma in Psychosis: Vulnerability, Psychopathology, and Treatment.

Front Psychiatry 2017 13;8:21. Epub 2017 Feb 13.

Northumberland, Tyne and Wear NHS Mental Health Foundation Trust , Newcastle upon Tyne , UK.

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http://dx.doi.org/10.3389/fpsyt.2017.00021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303718PMC
February 2017

The Chronic Otitis Media Benefit Inventory (COMBI): Development and Validation of a Dynamic Quality of Life Questionnaire for Chronic Ear Disease.

Otol Neurotol 2017 06;38(5):701-707

*Norfolk & Norwich University Hospital, Norwich, Norfolk †Multi-Centre Otitis Media Study Group, Department of Psychology, University of Cambridge, Cambridge ‡Ipswich Hospital, Ipswich, Suffolk, United Kingdom.

Objective: This study introduces a change-oriented short-form health-related quality of life questionnaire suited to symptoms of adult chronic middle ear disease and its consequences, and describes its properties.

Study Design: Two-centre prospective correlational study primarily for instrument development.

Setting: Two otology secondary care centers in England.

Patients: Fifty-two consecutive adult patients with active chronic otitis media undergoing surgery.

Methods: The 12 items for the chronic otitis media benefit inventory (COMBI) were appraised chiefly for internal consistency of resulting score and for factor structure (exploratory factor analysis).

Results: The internal consistency of the COMBI was high within our cohort of patients, with a Cronbach's alpha value of 0.907. The three-factor solution from factor analysis explaining 73.6% of the variance was readily interpretable in terms of the intended item content: changes in hearing, ear symptoms, and daily activities plus healthcare uptake.

Conclusions: The COMBI has suitable properties for the dynamic assessment of active chronic otitis media. Initial psychometric appraisal confirms its suitability for early adoption to acquire more comprehensive large-sample information with it and on it, for future refinement and application.
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http://dx.doi.org/10.1097/MAO.0000000000001366DOI Listing
June 2017

Precision-scored parental report questions and HL-scaled tympanometry as informative measures of hearing in otitis media 1: Large-sample evidence on determinants and complementarity to pure-tone audiometry.

Int J Pediatr Otorhinolaryngol 2016 Apr 6;83:113-31. Epub 2016 Feb 6.

Independent, UK.

Introduction: In otitis media with effusion (OME), hearing loss is a core sign/symptom and basis of concern, with absolute pure-tone threshold sensitivity (in dB HL) by air-conduction providing the default measure of hearing. However several fundamental problems limiting the value of HL measures in otitis media are insufficiently appreciated. To appraise the joint value and implications of multiple hearing measures towards more comprehensive hearing assessment in OM, we examine in two related articles the interrelations and common or diverging determinants of three measures, two of them objective: binaural HL, and ACET (the published quasi-continuous scaling of binaural tympanometry to HL). The third measure is partly subjective: parentally reported hearing difficulties (RHD-4); this is the precision-scored total of the 4 items selected for the OM8-30 general purpose questionnaire for parents in OM.

Methods: The Eurotitis-2 study (Total N=2886) internationally standardises OM8-30 and its OMQ-14 short form. The clinical and parent-response variables acquired cover many issues in diagnosis, symptomatology and impact of OM. Data acquisition was built upon routine clinic practice, enabling us also to document some properties of that practice, such as patterns of missing HL data. To address possible confounding or loss of representativeness from this, we investigated the implications of substituting tympanometry-based ACET for missing HL to give an HL/ACET hybrid. ACET is the mapping of categorical tympanometry to continuous HL. We simulated degrees of artificial missingness of HL up to 35% on the 1430 complete-data cases, using random deletion, with 1000-version bootstrapping. Correlations of this HL/ACET hybrid with pure (100%) HL then documented the degree of correlation retained under dilution of HL by an admixture of ACET; we also documented distribution shapes. For RHD-4, we then probed the determining influences on severity of score as an auditory disability measure, both background ones (from centre, age, sex, socio-economic status, length of history, diagnosis and season) and the two underlying objective hearing measures (HL, ACET). We ran these multiple regressions (GLMs), for representativeness and generality, both on 1430 complete-data cases (i.e. all 3 hearing variables present) and also on supplemented samples according to data required only for particular analyses (N increased by +56% to +68%). A further method of sample supplementation (by up to +96%) used the HL/ACET hybrid.

Results: Sex made negligible difference in any analysis. The particular collaborating centre, age, season and diagnosis collectively influenced presence/absence of HL data very strongly. (Area under ROC 0.944). Socio-economic status did not influence HL presence; surprisingly, nor did RHD, ACET or length of history, after control for centre, age, diagnosis and season. Of the inter-correlations between hearing measures, only the one between ACET and RHD was influenced (slightly reduced) by the inclusion of cases without HL data. In the simulated substitutions, Pearson correlation of hybrid HL/ACET with true HL remained above 0.90 for substitution by ACET of up to 30% rate of artificially 'missing' HL. Centre differences were adequately summarised by simple absolute additive differences in mean local case severity. In the determinant models for RHD on the 1430 complete-data cases, HL and the set of background determinants collectively explained broadly similar proportions of RHD's variability, totalling 36.8% explained. On the larger maximum case samples, slightly less absolute variability was explicable than on complete-case data, but relative magnitudes of contribution from individual determinants, both background and hearing measures, remained similar. The expected mean differences in RHD between diagnoses (RAOM, OME, and combined) were found, but the patterns of background and objective measure influences determining RHD did not differ significantly between the diagnoses.

Conclusions: (1) In the Eurotitis-2 database, descriptive differences in various background demographic and clinical measures between cases on whom HL data were obtained versus not, were only of material magnitude for length of history and reported hearing difficulties. Such descriptive differences are not necessarily bases of confounding, so using our framework of 6 background adjuster variables, (particular collaborating centre, age, season, diagnosis, socioeconomic status and length of history) we isolated the determinants of HL data presence. The first four listed strongly predicted HL data presence/absence so are sufficient to control analyses well for any bias or confounding by HL data presence. (2) Diagnoses as OME and combined (OME+RAOM) had higher probability of HL data being present relative to RAOM, indicating that HL acquisition is chiefly seen as confirming and quantifying hearing loss in (suspect) OME, not as ruling it out (e.g. in suspected RAOM). Given this, also using RHD and or ACET as pre-triage to efficiently target capacity and/or reduce costs and opportunity costs of acquiring HL would be rational, but there was no evidence of such precise use of initial hearing-related information to decide on HL acquisition. (3) The full six background variables explained comparable variance in Reported Hearing Difficulties (RHD) to what was explained by ACET, but not quite as much as by HL. Achieving a high percentage explained (32-37% from good models) required both classes of determinant to be entered as predictors. The pattern of background determining influences for RHD was largely stable, with or without objective measures as additional predictors, and on maximum or complete-data cases. Length of history strongly determines RHD for a given concurrent HL. (4) Accepting ACET as substitute where HL was missing in OM cases gave a sample-size enhancement of 17% in Eurotitis-2, with negligible difference in the pattern of determinants. This hybrid measure can be recommended as reasonable next-best when moderate percentages of HL data are missing. (5) The stable pattern of prediction of RHD suggests that our six background determinants provide a very promising low-cost yet comprehensive framework for determination. It hence offers pluripotent statistical adjustment against confounding, applicable to RAOM, OME and combined diagnoses in any analysis using this database. Claims that it thereby offers a sufficient framework for full European standardisation of all the scores from the OM8-30 questionnaire measures await parallel demonstrations for symptom areas other than RHD. As 25% of the variance in RHD severity can be explained by the six adjusters in our framework, none of the six variables should be omitted from acquisition and analytic use in future OM research.
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http://dx.doi.org/10.1016/j.ijporl.2016.01.037DOI Listing
April 2016

Expansion and characterization of neonatal cardiac pericytes provides a novel cellular option for tissue engineering in congenital heart disease.

J Am Heart Assoc 2015 Jun 16;4(6):e002043. Epub 2015 Jun 16.

Division of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, United Kingdom (E.A., I.R.A., H.L.S., F.R., G.M., S.C.S., J.R., V.V.A., O.O.I., S.S., A.O., P.M.).

Background: Living grafts produced by combining autologous heart-resident stem/progenitor cells and tissue engineering could provide a new therapeutic option for definitive correction of congenital heart disease. The aim of the study was to investigate the antigenic profile, expansion/differentiation capacity, paracrine activity, and pro-angiogenic potential of cardiac pericytes and to assess their engrafting capacity in clinically certified prosthetic grafts.

Methods And Results: CD34(pos) cells, negative for the endothelial markers CD31 and CD146, were identified by immunohistochemistry in cardiac leftovers from infants and children undergoing palliative repair of congenital cardiac defects. Following isolation by immunomagnetic bead-sorting and culture on plastic in EGM-2 medium supplemented with growth factors and serum, CD34(pos)/CD31(neg) cells gave rise to a clonogenic, highly proliferative (>20 million at P5), spindle-shape cell population. The following populations were shown to expresses pericyte/mesenchymal and stemness markers. After exposure to differentiation media, the expanded cardiac pericytes acquired markers of vascular smooth muscle cells, but failed to differentiate into endothelial cells or cardiomyocytes. However, in Matrigel, cardiac pericytes form networks and enhance the network capacity of endothelial cells. Moreover, they produce collagen-1 and release chemo-attractants that stimulate the migration of c-Kit(pos) cardiac stem cells. Cardiac pericytes were then seeded onto clinically approved xenograft scaffolds and cultured in a bioreactor. After 3 weeks, fluorescent microscopy showed that cardiac pericytes had penetrated into and colonized the graft.

Conclusions: These findings open new avenues for cellular functionalization of prosthetic grafts to be applied in reconstructive surgery of congenital heart disease.
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http://dx.doi.org/10.1161/JAHA.115.002043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599542PMC
June 2015

Impact of lung function interpretation approach on pediatric bronchiolitis obliterans syndrome diagnosis after lung transplantation.

J Heart Lung Transplant 2015 Aug 26;34(8):1082-8. Epub 2015 Mar 26.

Department of Cardiothoracic Transplantation, Great Ormond Street Hospital for Children NHS Trust, London, UK.

Background: The diagnostic criteria for bronchiolitis obliterans syndrome (BOS) are predominantly adult-focused. The relationship between application and impact of reference equation choice on pediatric baseline lung function achieved and subsequent BOS diagnosis remains unclear.

Methods: Lung function spirometry data (FEV(1), FVC and FEF(25-75)) from pediatric subjects transplanted at the Great Ormond Street Hospital over a 10-year period were collated. Baseline values achieved after lung transplantation and BOS rates were examined. Raw values were compared with 2 different reference equations (the "Brompton" and modern collated "All-age" equations). The impact of FEF(25-75) baseline definition was investigated.

Results: Fifty subjects were included, 17 males and 33 females, transplanted at a median (range) age of 14.0 years (3.2 to 17.3 years, 83% >10 years old), and followed for 1,028 (388 to 2,613) days post-transplantation. Raw values underestimated baseline lung function attainment for all indices. Magnitude of baseline lung function was affected by reference equation choice. Mean FEV(1) values were: Brompton 97.9% (SD 20.3%) and All-age 86.3% (SD 15.4%) of predicted (p < 0.0001). BOS 0p incidence was significantly higher for All-age predicted than for raw values (64% and 40%, respectively, p = 0.027). Modification of FEF(25-75) baseline (to either FEV(1) or FVC baseline) led to a reduction in BOS 0p detection (p < 0.01).

Conclusions: Modern collated reference equations should be used for lung function monitoring in pediatric subjects after lung transplantation. Standardization of FEF(25-75) baseline definition is urgently required. These data question the utility of the FEF(25-75) criterion as an early marker of BOS 0p in pediatric subjects.
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http://dx.doi.org/10.1016/j.healun.2015.03.010DOI Listing
August 2015

Migration towards SDF-1 selects angiogenin-expressing bone marrow monocytes endowed with cardiac reparative activity in patients with previous myocardial infarction.

Stem Cell Res Ther 2015 Apr 11;6:53. Epub 2015 Apr 11.

Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK.

Introduction: Chemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials. Hence, transplantation of chemokine-responsive bone marrow cells may be ideal for treatment of myocardial ischemia. To verify the therapeutic activity of bone marrow mononuclear cells (BM-MNCs) selected by in vitro migration towards the chemokine stromal cell-derived factor-1 (SDF-1) in a mouse model of myocardial infarction (MI), we used BM-MNCs from patients with previous large MI recruited in the TransACT-1&2 cell therapy trials.

Methods: Unfractioned BM-MNCs, SDF-1-responsive, and SDF-1-nonresponsive BM-MNCs isolated by patients recruited in the TransACT-1&2 cell therapy trials were tested in Matrigel assay to evaluate angiogenic potential. Secretome and antigenic profile were characterized by flow cytometry. Angiogenin expression was measured by RT-PCR. Cells groups were also intramyocardially injected in an in vivo model of MI (8-week-old immune deficient CD1-FOXN1(nu/nu) mice). Echocardiography and hemodynamic measurements were performed before and at 14 days post-MI. Arterioles and capillaries density, infiltration of inflammatory cells, interstitial fibrosis, and cardiomyocyte proliferation and apoptosis were assessed by immunohistochemistry.

Results: In vitro migration enriched for monocytes, while CD34(+) and CD133(+) cells and T lymphocytes remained mainly confined in the non-migrated fraction. Unfractioned total BM-MNCs promoted angiogenesis on Matrigel more efficiently than migrated or non-migrated cells. In mice with induced MI, intramyocardial injection of unfractionated or migrated BM-MNCs was more effective in preserving cardiac contractility and pressure indexes than vehicle or non-migrated BM-MNCs. Moreover, unfractioned BM-MNCs enhanced neovascularization, whereas the migrated fraction was unique in reducing the infarct size and interstitial fibrosis. In vitro studies on isolated cardiomyocytes suggest participation of angiogenin, a secreted ribonuclease that inhibits protein translation under stress conditions, in promotion of cardiomyocyte survival by migrated BM-MNCs.

Conclusions: Transplantation of bone marrow cells helps post-MI healing through distinct actions on vascular cells and cardiomyocytes. In addition, the SDF-1-responsive fraction is enriched with angiogenin-expressing monocytes, which may improve cardiac recovery through activation of cardiomyocyte response to stress. Identification of factors linking migratory and therapeutic outcomes could help refine regenerative approaches.
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http://dx.doi.org/10.1186/s13287-015-0028-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440500PMC
April 2015

Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair.

Circ Res 2015 May 23;116(10):e81-94. Epub 2015 Mar 23.

From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).

Rationale: Optimization of cell therapy for cardiac repair may require the association of different cell populations with complementary activities.

Objective: Compare the reparative potential of saphenous vein-derived pericytes (SVPs) with that of cardiac stem cells (CSCs) in a model of myocardial infarction, and investigate whether combined cell transplantation provides further improvements.

Methods And Results: SVPs and CSCs were isolated from vein leftovers of coronary artery bypass graft surgery and discarded atrial specimens of transplanted hearts, respectively. Single or dual cell therapy (300 000 cells of each type per heart) was tested in infarcted SCID (severe combined immunodeficiency)-Beige mice. SVPs and CSCs alone improved cardiac contractility as assessed by echocardiography at 14 days post myocardial infarction. The effect was maintained, although attenuated at 42 days. At histological level, SVPs and CSCs similarly inhibited infarct size and interstitial fibrosis, SVPs were superior in inducing angiogenesis and CSCs in promoting cardiomyocyte proliferation and recruitment of endogenous stem cells. The combination of cells additively reduced the infarct size and promoted vascular proliferation and arteriogenesis, but did not surpass single therapies with regard to contractility indexes. SVPs and CSCs secrete similar amounts of hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, stem cell factor, and stromal cell-derived factor-1, whereas SVPs release higher quantities of angiopoietins and microRNA-132. Coculture of the 2 cell populations results in competitive as well as enhancing paracrine activities. In particular, the release of stromal cell-derived factor-1 was synergistically augmented along with downregulation of stromal cell-derived factor-1-degrading enzyme dipeptidyl peptidase 4.

Conclusions: Combinatory therapy with SVPs and CSCs may complementarily help the repair of infarcted hearts.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.306146DOI Listing
May 2015

Epigenetic profile of human adventitial progenitor cells correlates with therapeutic outcomes in a mouse model of limb ischemia.

Arterioscler Thromb Vasc Biol 2015 Mar 8;35(3):675-88. Epub 2015 Jan 8.

From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).

Objective: We investigated the association between the functional, epigenetic, and expressional profile of human adventitial progenitor cells (APCs) and therapeutic activity in a model of limb ischemia.

Approach And Results: Antigenic and functional features were analyzed throughout passaging in 15 saphenous vein (SV)-derived APC lines, of which 10 from SV leftovers of coronary artery bypass graft surgery and 5 from varicose SV removal. Moreover, 5 SV-APC lines were transplanted (8×10(5) cells, IM) in mice with limb ischemia. Blood flow and capillary and arteriole density were correlated with functional characteristics and DNA methylation/expressional markers of transplanted cells. We report successful expansion of tested lines, which reached the therapeutic target of 30 to 50 million cells in ≈10 weeks. Typical antigenic profile, viability, and migratory and proangiogenic activities were conserved through passaging, with low levels of replicative senescence. In vivo, SV-APC transplantation improved blood flow recovery and revascularization of ischemic limbs. Whole genome screening showed an association between DNA methylation at the promoter or gene body level and microvascular density and to a lesser extent with blood flow recovery. Expressional studies highlighted the implication of an angiogenic network centered on the vascular endothelial growth factor receptor as a predictor of microvascular outcomes. FLT-1 gene silencing in SV-APCs remarkably reduced their ability to form tubes in vitro and support tube formation by human umbilical vein endothelial cells, thus confirming the importance of this signaling in SV-APC angiogenic function.

Conclusions: DNA methylation landscape illustrates different therapeutic activities of human APCs. Epigenetic screening may help identify determinants of therapeutic vasculogenesis in ischemic disease.
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http://dx.doi.org/10.1161/ATVBAHA.114.304989DOI Listing
March 2015

A journey from basic stem cell discovery to clinical application: the case of adventitial progenitor cells.

Regen Med 2015 ;10(1):39-47

Bristol Heart Institute, Bristol Royal Infirmary, Level 7, Bristol, BS2 8HW, UK.

Ischemia is a leading cause of death in the western world. Regenerative medicine aims to improve healing of ischemic injury by complementing pharmacologic/interventional treatments. Navigating regenerative therapies from 'bench-to-bedside' is a multistep time-consuming process, balancing cell expansion, purity, safety and efficacy while complying with regulatory guidelines. Studies started in academic laboratories unused to long-term planning often fail because of poor strategy design, lack of contingency plans or funding. We provide a strategic insight into our translation of saphenous vein-derived adventitial progenitor cells into a clinical grade product to treat angina. We discuss discovery phases, introduction of standard operating procedures and upgrade to clinical standards. We also examine contractual aspects of transferring to GMP-accredited facilities for clinical production and unexpected hurdles.
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http://dx.doi.org/10.2217/rme.14.64DOI Listing
September 2015