Treatment of myocardial ischaemia-reperfusion injury in patients with ST-segment elevation myocardial infarction: promise, disappointment, and hope.

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Timely reperfusion with primary percutaneous coronary intervention (PPCI) remains the gold standard in patients presenting with ST-segment elevation myocardial infarction (STEMI), limiting infarct size, preserving left ventricular ejection fraction (LVEF), and improving clinical outcomes. Despite this, a significant proportion of STEMI patients develop post-infarct heart failure. We review the current understanding and up-to-date evidence base for therapeutic intervention of ischaemia-reperfusion injury (IRI), a combination of myocardial ischaemia secondary to acute coronary occlusion and reperfusion injury leading to further myocardial injury and cell death. Multiple treatment modalities have been shown to be cardioprotective and reduce IRI in experimental animal models. Recent phase II/III randomised controlled trials (RCT) have assessed multiple cardioprotective strategies ranging from ischaemic conditioning, therapeutic hypothermia and hyperoxaemia to pharmacological therapies. While several therapies have been shown to reduce infarct size in animal models or proof-of-concept studies, many larger scale trial results have proven inconsistent and disappointing. Hard clinical outcomes remain elusive. We discuss potential reasons for the difficulties in translation to clinical practice.

Comparative transcriptome analysis identified important genes and regulatory pathways for flower color variation in Paphiopedilum hirsutissimum.

BACKGROUND: Paphiopedilum hirsutissimum is a member of Orchidaceae family that is famous for its ornamental value around the globe, it is vulnerable due to over-exploitation and was listed in Appendix I of the Convention on International Trade in Endangered Species of Wild Fauna and Flora, which prevents its trade across borders. Variation in flower color that gives rise to different flower patterns is a major trait contributing to its high ornamental value. However, the molecular mechanism underlying color formation in P. hirsutissimum still remains unexplored. In the present study, we exploited natural variation in petal and labellum color of Paphiopedilum plants and used comparative transcriptome analysis as well as pigment measurements to explore the important genes, metabolites and regulatory pathways linked to flower color variation in P. hirsutissimum. RESULT: We observed that reduced anthocyanin and flavonoid contents along with slightly higher carotenoids are responsible for albino flower phenotype. Comparative transcriptome analysis identified 3287 differentially expressed genes (DEGs) among normal and albino labellum, and 3634 DEGs between normal and albino petals. Two genes encoding for flavanone 3-hydroxylase (F3H) and one gene encoding for chalcone synthase (CHS) were strongly downregulated in albino labellum and petals compared to normal flowers. As both F3H and CHS catalyze essentially important steps in anthocyanin biosynthesis pathway, downregulation of these genes is probably leading to albino flower phenotype via down-accumulation of anthocyanins. However, we observed the downregulation of major carotenoid biosynthesis genes including VDE, NCED and ABA2 which was inconsistent with the increased carotenoid accumulation in albino flowers, suggesting that carotenoid accumulation was probably controlled at post-transcriptional or translational level. In addition, we identified several key transcription factors (MYB73, MYB61, bHLH14, bHLH106, MADS-SOC1, AP2/ERF1, ERF26 and ERF87) that may regulate structural genes involved in flower color formation in P. hirsutissimum. Importantly, over-expression of some of these candidate TFs increased anthocyanin accumulation in tobacco leaves which provided important evidence for the role of these TFs in flower color formation probably via regulating key structural genes of the anthocyanin pathway. CONCLUSION: The genes identified here could be potential targets for breeding P. hirsutissimum with different flower color patterns by manipulating the anthocyanin and carotenoid biosynthesis pathways.

Massive pulmonary embolism in patients with extreme bleeding risk: a case series on the successful use of ultrasound-assisted, catheter directed thrombolysis in a district general hospital.

Massive pulmonary embolism (PE), characterised by profound arterial hypotension, is a life-threatening emergency with a 90-day mortality of over 50%. Systemic thrombolysis can significantly reduce the risk of death or cardiovascular collapse in these patients, by around 50%, but these benefits are offset by a fivefold increased risk of intracranial haemorrhage and major bleeding, which may limit its use in patients at high risk of catastrophic haemorrhage. We describe a case series of 3 patients presenting with massive PE, each with extreme risk of bleeding and contra-indication to systemic thrombolysis, treated successfully with ultrasound-assisted, catheter directed thrombolysis (U-ACDT). Our experience of this novel technique using the EkoSonic Endovascular System (Ekos, BTG, London, UK) on carefully selected patients has demonstrated the potential to improve clinical status in shocked patients, with minimal bleed risk. There have been several clinical studies evaluating the Ekos system. Both the ULTIMA and SEATTLE II studies have shown significant reductions in RV/LV ratio by CT scanning when compared to standard anticoagulation in patients with intermediate-risk PE, with minimal bleeding complications. However, there is a pressing need for a randomised trial demonstrating improvement in robust clinical outcomes when comparing U-ACDT to simple anticoagulation. We believe that this case series adds new insight and highlights the potential of catheter directed thrombolysis in this high-risk patient cohort and consideration should be made to its use in cases where systemic thrombolysis is felt to be too high risk.

Exercise-based cardiac rehabilitation for adults with stable angina.

BACKGROUND: A previous Cochrane review has shown that exercise-based cardiac rehabilitation (CR) can benefit myocardial infarction and post-revascularisation patients. However, the impact on stable angina remains unclear and guidance is inconsistent. Whilst recommended in the guidelines of American College of Cardiology/American Heart Association and the European Society of Cardiology, in the UK the National Institute for Health and Care Excellence (NICE) states that there is "no evidence to suggest that CR is clinically or cost-effective for managing stable angina". OBJECTIVES: To assess the effects of exercise-based CR compared to usual care for adults with stable angina. SEARCH METHODS: We updated searches from the previous Cochrane review 'Exercise-based cardiac rehabilitation for patients with coronary heart disease' by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, DARE, CINAHL and Web of Science on 2 October 2017. We searched two trials registers, and performed reference checking and forward-citation searching of all primary studies and review articles, to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a follow-up period of at least six months, which compared structured exercise-based CR with usual care for people with stable angina. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data according to the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors also independently assessed the quality of the evidence using GRADE principles and we presented this information in a 'Summary of findings' table. MAIN RESULTS: Seven studies (581 participants) met our inclusion criteria. Trials had an intervention length of 6 weeks to 12 months and follow-up length of 6 to 12 months. The comparison group in all trials was usual care (without any form of structured exercise training or advice) or a no-exercise comparator. The mean age of participants within the trials ranged from 50 to 66 years, the majority of participants being male (range: 74% to 100%). In terms of risk of bias, the majority of studies were unclear about their generation of the randomisation sequence and concealment processes. One study was at high risk of detection bias as it did not blind its participants or outcome assessors, and two studies had a high risk of attrition bias due to the numbers of participants lost to follow-up. Two trials were at high risk of outcome reporting bias. Given the high risk of bias, small number of trials and participants, and concerns about applicability, we downgraded our assessments of the quality of the evidence using the GRADE tool.Due to the very low-quality of the evidence base, we are uncertain about the effect of exercise-based CR on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.18 to 5.67; 195 participants; 3 studies; very low-quality evidence), acute myocardial infarction (RR 0.33, 95% CI 0.07 to 1.63; 254 participants; 3 studies; very low-quality evidence) and cardiovascular-related hospital admissions (RR 0.14, 95% CI 0.02 to 1.1; 101 participants; 1 study; very low-quality evidence). We found low-quality evidence that exercise-based CR may result in a small improvement in exercise capacity compared to control (standardised mean difference (SMD) 0.45, 95% CI 0.20 to 0.70; 267 participants; 5 studies, low-quality evidence). We were unable to draw conclusions about the impact of exercise-based CR on quality of life (angina frequency and emotional health-related quality-of-life score) and CR-related adverse events (e.g. skeletomuscular injury, cardiac arrhythmia), due to the very low quality of evidence. No data were reported on return to work. AUTHORS' CONCLUSIONS: Due to the small number of trials and their small size, potential risk of bias and concerns about imprecision and lack of applicability, we are uncertain of the effects of exercise-based CR compared to control on mortality, morbidity, cardiovascular hospital admissions, adverse events, return to work and health-related quality of life in people with stable angina. Low-quality evidence indicates that exercise-based CR may result in a small increase in exercise capacity compared to usual care. High-quality, well-reported randomised trials are needed to assess the benefits and harms of exercise-based CR for adults with stable angina. Such trials need to collect patient-relevant outcomes, including clinical events and health-related quality of life. They should also assess cost-effectiveness, and recruit participants that are reflective of the real-world population of people with angina.

The impact of an integrated heart failure service in a medium-sized district general hospital.

OBJECTIVES: Assessing the impact of a new integrated heart failure service (IHFS) in a medium-sized district general hospital (DGH) on heart failure (HF) mortality, readmission rates, and provision of HF care. METHODS: A retrospective, observational study encompassing all patients admitted with a diagnosis of HF over two 12-month periods before (2012/2013), and after (2015/2016) IHFS establishment. RESULTS: Total admissions for HF increased by 40% (385 vs 540), with a greater number admitted to the cardiology ward (231 vs 121). After IHFS implementation, patients were more likely to see a cardiologist (35.1% vs 43.7%, p=0.009), undergo echocardiography (70.1% vs 81.5%, p<0.001), be initiated on all three disease modifying HF medications (angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA)) in the heart failure with reduced ejection fraction (HFrEF) group (42% vs 99%, p<0.001) and receive specialist HF input (81.6% vs 85.4%, p=0.2). Both 30-day post-discharge mortality and HF related readmissions were significantly lower in patients with heart failure with preserved ejection fraction (HFpEF) (8.9% vs 3.1%, p=0.032, 58% reduction, p=0.043 respectively) with no-significant reductions in all other HF groups. In-patient mortality was similar. Length of stay in Cardiology wards increased from 8.4 to 12.7 days (p<0.001). CONCLUSION: Establishment of an IHFS within a DGH with limited resources and only a modest service re-design has resulted in significantly improved provision of specialist in-patient care, use of HFrEF medications, early heart failure nurse follow-up, and is associated with a reduction in early mortality, particularly in the HFpEF cohort, and HF related readmissions.

Exercise-based cardiac rehabilitation for stable angina: systematic review and meta-analysis.

Objective: A systematic review was undertaken to assess the effects of exercise-based cardiac rehabilitation (CR) for patients with stable angina. Methods: Databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase and CINAHL) were searched up to October 2017, without language restriction. Randomised trials comparing CR programmes with no exercise control in adults with stable angina were included. Where possible, study outcomes were pooled using meta-analysis. Grading of Recommendations Assessment, Development and Evaluation was used to assess the quality of evidence. The protocol was published on the Cochrane Database of Systematic Reviews. Results: Seven studies (581 patients), with a median of 12-month follow-up, were included. The effect of exercise-based CR on all-cause mortality (risk ratio (RR) 1.01, 95 % CI: 0.18 to 5.67), acute myocardial infarction (RR 0.33, 95% CI: 0.07 to 1.63) and cardiovascular-related hospital admissions (RR 0.14, 95% CI: 0.02 to 1.1) relative to control were uncertain. We found low-quality evidence that exercise-based CR results in a moderate improvement in exercise capacity (standard mean difference 0.45, 95% CI: 0.20 to 0.70). There was limited and very low-quality evidence for the effect of exercise-based CR on health-related quality of life (HRQoL), adverse events and costs. No data were identified on cost-effectiveness or return to work. Conclusions: Exercise-based CR may improve the short-term exercise capacity of patients with stable angina pectoris. Well-designed randomised controlled trials are needed to definitely determine the impact of CR on outcomes including mortality, morbidity, HRQoL, and costs in the population of patients with stable angina receiving contemporary medical therapy.

[cDNA cloning and protein structure analysis of growth hormone from Clarias lazera].

Total RNA was isolated from pituitary gland of Clarias lazera, and the cDNA encoding growth hormone (GH) protein was amplified and cloned by reverse transcription polymerase chain reaction (RT-PCR). The open reading frame (ORF) of cDNA is of 603 nt which encodes GH precursor consisted of a signal peptide with 22 amino acid residues and a mature peptide with 178 amino acid residues. Sequence alignment indicated that the amino acid sequence homology approached to 95.8% between C. lazera and other 6 species of Siluriforms catfish. Secondary structure assessment showed that the GH protein contained different structural regions of alpha-helix, beta-sheet, beta-turn and random coil, among which alpha-helix has main proportion. Antigenicity analysis indicates that there exist 4 domains in amino acid sequence where B cell dominant epitopes could form. Summarily, the structure characteristics of C. lazera GH should provide a great benefit in its modification into recombinant vaccine or monoclonal antibody for future application.

Clival osteomyelitis and hypoglossal nerve palsy--rare complications of Lemierre's syndrome.

An increasingly reported entity, Lemierre's syndrome classically presents with a recent oropharyngeal infection, internal jugular vein thrombosis and the presence of anaerobic organisms such as Fusobacterium necrophorum. The authors report a normally fit and well 17-year-old boy who presented with severe sepsis following a 5-day history of a sore throat, myalgia and neck stiffness requiring intensive care admission. Blood cultures grew F. necrophorum and radiological investigations demonstrated left internal jugular vein, cavernous sinus and sigmoid sinus thrombus, left vertebral artery dissection and thrombus within the left internal carotid artery. Imaging also revealed two areas of acute ischaemia in the brain, consistent with septic emboli, skull base (clival) osteomyelitis and an extensive epidural abscess. The patient improved on meropenem and metronidazole and was warfarinised for his cavernous sinus thrombosis. He has an on-going left-sided hypoglossal (XIIth) nerve palsy.