Streptococcus bovis bacteraemia: an evaluation of the long-term effect on cardiac outcomes

Introduction: Streptococcus bovis can lead to bacteraemia, septicaemia, and ultimately endocarditis. The objective of this study was to evaluate the long-term implications of S. bovis endocarditis on cardiac morbidity and mortality. 

Methods: A retrospective cohort study was performed between January 2000 and March 2009 to assess all patients diagnosed with S. bovis bacteraemia from the Belfast Health and Social Care Trust. The primary end-point for cardiac investigations was the presence of endocarditis. Secondary end-points included referral for cardiac surgery and overall mortality. 

Results: Sixty-one positive S. bovis blood cultures from 43 patients were included. Following echocardiography, seven patients were diagnosed with infective endocarditis (16.3 % of total patients); four patients (9.3 %) had native valve involvement while three (7.0 %) had prosthetic valve infection. Five of these seven patients had more than one positive S. bovis culture (71.4 %). Three had significant valve dysfunction that warranted surgical repair/replacement, one of whom was unfit for surgery. There was a 100 % recurrence rate amongst the valve replacement patients (n = 2) and six patients with endocarditis had colorectal pathology. Patients with endocarditis had similar long-term survival as those with non-endocarditic bacteraemia (57.1 % alive vs. 50 % of non-endocarditis patients, p = 0.73). 

Conclusion: Streptococcus bovis endocarditis patients tended to have pre-existing valvular heart disease and those with prosthetic heart valves had higher surgical intervention and relapse rates. These patients experienced a higher rate of co-existing colorectal pathology but currently have reasonable long-term outcomes. This may suggest that they represent a patient population that merits consideration for an early surgical strategy to maximise long-term results, however, further evaluation is warranted. © 2013 The Japanese Association for Thoracic Surgery.

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS: Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment.

METHODS AND RESULTS: This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries.

CONCLUSION: Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

Clinical Outcomes in 3343 Children and Adults with Rheumatic Heart Disease from 14 Low and Middle Income Countries: 2-Year Follow-up of the Global Rheumatic Heart Disease Registry (the REMEDY study)

BACKGROUND: -There are few contemporary data on the mortality and morbidity associated with rheumatic heart disease (RHD) or information on their predictors. We report the two year follow-up of individuals with RHD from 14 low and middle income countries in Africa and Asia.

METHODS: -Between January 2010 and November 2012, we enrolled 3343 patients from 25 centers in 14 countries and followed them for two years to assess mortality, congestive heart failure (CHF), stroke or transient ischemic attack (TIA), recurrent acute rheumatic fever (ARF), and infective endocarditis (IE).

RESULTS: -Vital status at 24 months was known for 2960 (88.5%) patients. Two thirds were female. Although patients were young (median age 28 years, interquartile range 18 to 40), the two year case fatality rate was high (500 deaths, 16.9%). Mortality rate was 116.3/1000 patient-years in the first year and 65.4/1000 patient-years in the second year. Median age at death was 28.7 years. Independent predictors of death were severe valve disease (hazard ratio (HR) 2.36, 95% confidence interval (CI) 1.80-3.11), CHF (HR 2.16, 95% CI 1.70-2.72), New York Heart Association functional class III/IV (HR 1.67, 95% CI 1.32-2.10), atrial fibrillation (AF) (HR 1.40, 95% CI 1.10-1.78) and older age (HR 1.02, 95% CI 1.01-1.02 per year increase) at enrolment. Post-primary education (HR 0.67, 95% CI 0.54-0.85) and female sex (HR 0.65, 95%CI 0.52-0.80) were associated with lower risk of death. 204 (6.9%) had new CHF (incidence, 38.42/1000 patient-years), 46 (1.6%) had a stroke or TIA (8.45/1000 patient-years), 19 (0.6%) had ARF (3.49/1000 patient-years), and 20 (0.7%) had IE (3.65/1000 patient-years). Previous stroke and older age were independent predictors of stroke/TIA or systemic embolism. Patients from low and lower-middle income countries had significantly higher age- and sex-adjusted mortality compared to patients from upper-middle income countries. Valve surgery was significantly more common in upper-middle income than in lower-middle- or low-income countries.

CONCLUSIONS: -Patients with clinical RHD have high mortality and morbidity despite being young; those from low and lower-middle income countries had a poorer prognosis associated with advanced disease and low education. Programs focused on early detection and treatment of clinical RHD are required to improve outcomes.

Anti-infective photodynamic biomaterials for the prevention of intraocular lens-associated infectious endophthalmitis

Bacterial attachment onto intraocular lenses (IOLs) during cataract extraction and IOL implantation is a prominent aetiological factor in the pathogenesis of infectious endophthalmitis. Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) have shown that photosensitizers are effective treatments for cancer, and in the photoinactivation of bacteria, viruses, fungi and parasites, in the presence of light. To date, no method of localizing the photocytotoxic effect of a photosensitizer at a biomaterial surface has been demonstrated. Here we show a method for concentrating this effect at a material surface to prevent bacterial colonization by attaching a porphyrin photosensitizer at, or near to, that surface, and demonstrate the principle using IOL biomaterials. Anionic hydrogel copolymers were shown to permanently bind a cationic porphyrin through electrostatic interactions as a thin surface layer. The mechanical and thermal properties of the materials showed that the porphyrin acts as a surface cross-linking agent, and renders surfaces more hydrophilic. Importantly, Staphylococcus epidermidis adherence was reduced by up to 99.0 ± 0.42% relative to the control in intense light conditions and 91.7± 5.99% in the dark. The ability to concentrate the photocytotoxic effect at a surface, together with a significant dark effect, provides a platform for a range of light-activated anti-infective biomaterial technologies.

Non-nematode-derived double-stranded RNAs induce profound phenotypic changes in Meloidogyne incognita and Globodera pallida infective juveniles

Nine non-nematode-derived double-stranded RNAs (dsRNAs), designed for use as controls in RNA interference (RNAi) screens of neuropeptide targets, were found to induce aberrant phenotypes and an unexpected inhibitory effect on motility of root knot nematode Meloidogyne incognita J2s following 24 h soaks in 0.1 mg/ml dsRNA; a simple soaking procedure which we have found to elicit profound knockdown of neuronal targets in Globodera pallida J2s. We have established that this inhibitory phenomenon is both time- and concentration-dependent, as shorter 4 h soaks in 0.1 mg/ml dsRNA had no negative impact on M. incognita J2 stage worms, yet a 10-fold increase in concentration to 1 mg/ml for the same 4 h time period had an even greater qualitative and quantitative impact on worm phenotype and motility. Further, a 10-fold increase of J2s soaked in 0.1 mg/ml dsRNA did not significantly alter the observed phenotypic aberration, which suggests that dsRNA uptake of the soaked J2s is not saturated under these conditions. This phenomenon was not initially observed in potato cyst nematode G. pallida J2s, which displayed no aberrant phenotype, or diminution of migratory activity in response to the same 0.1 mg/ml dsRNA 24 h soaks. However, a 10-fold increase in dsRNA to 1 mg/ml was found to elicit comparable irregularity of phenotype and inhibition of motility in G. pallida, to that initially observed in M. incognita following a 24 h soak in 0.1 mg/ml dsRNA. Again, a 10-fold increase in the number of G. pallida J2s soaked in the same volume of 1 mg/ml dsRNA preparation did not significantly affect the observed phenotypic deviation. We do not observe any global impact on transcript abundance in either M. incognita or G. pallida J2s following 0.1 mg/ml dsRNA soaks, as revealed by reverse transcriptase-PCR and quantitative PCR data. This study aims to raise awareness of a phenomenon which we observe consistently and which we believe signifies a more expansive deficiency in our knowledge and understanding of the variables inherent to RNAi-based investigation.

Short interfering RNA-mediated gene silencing in Globodera pallida and Meloidogyne incognita infective stage juveniles

The analysis of gene function through RNA interference (RNAi)-based reverse genetics in plant parasitic nematodes (PPNs) remains inexplicably reliant on the use of long double-stranded RNA (dsRNA) silencing triggers; a practice inherently disadvantageous due to the introduction of superfluous dsRNA sequence. increasing chances of aberrant or off-target gene silencing through interactions between nascent short interfering RNAs (siRNAs) and non-cognate mRNA targets. Recently, we have shown that non-nematode, long dsRNAs have a propensity to elicit profound impacts on the phenotype and migrational abilities of both root knot and cyst nematodes. This study presents, to our knowledge for the first time, gene-specific knockdown of FMRFamide-like peptide (flp) transcripts, using discrete 21 bp siRNAs in potato cyst nematode Globodera pallida, and root knot nematode Meloidogyne incognita infective (J2) stage juveniles. Both knockdown at the transcript level through quantitative (q)PCR analysis and functional data derived from migration assay, indicate that siRNAs targeting certain areas of the FMRFamide-like peptide (FLP) transcripts are potent and specific in the silencing of gene function. In addition, we present a method of manipulating siRNA activity through the management of strand thermodynamics. Initial evaluation of strand thermodynamics as a determinant of RNA-induced Silencing Complex (RISC) strand selection (inferred from knockdown efficacy) in the siRNAs presented here suggested that the purported influence of 5' stand stability on guide incorporation may be somewhat promiscuous. However, we have found that on strategically incorporating base mismatches in the sense strand of a G. pallida-specific siRNA we could specifically increase or decrease the knockdown of its target (specific to the antisense strand), presumably through creating more favourable thermodynamic profiles for incorporation of either the sense (non-target-specific) or antisense (target-specific) strand into a cleavage-competent RISC. Whilst the efficacy of similar approaches to siRNA modification has been demonstrated in the context of Drosophila whole-cell lysate preparations and in mammalian cell cultures, it remained to be seen how these sense strand mismatches may impact on gene silencing in vivo, in relation to different targets and in different sequence contexts. This work presents the first application of such an approach in a whole organism; initial results show promise. (C) 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Bacteriophages as anti-infective agents: recent developments and regulatory challenges.

The biennial meeting on 'Exploiting Bacteriophages for Bioscience, Biotechnology and Medicine', held in London, UK, on 20 January 2012, and chaired by George Salmond (University of Cambridge, UK) hosted over 50 participants representing 13 countries. The highly multidisciplinary meeting covered a diverse range of topics, reflecting the current expansion of interest in this field, including the use of bacteriophages as the source of biochemical reagents for molecular biology, bacteriophages for the treatment of human and animal diseases, bacteriophage-based diagnostics and therapeutic delivery technologies and necessity for, and regulatory challenges associated with, robust clinical trials of phage-based therapeutics. This report focuses on a number of presentations from the meeting relating to cutting-edge research on bacteriophages as anti-infective agents.

Photosensitisers - the progression from photodynamic therapy to anti-infective surfaces

Introduction: The application of light as a stimulus in pharmaceutical systems and the associated ability to provide precise spatiotemporal control over location, wavelength and intensity, allowing ease of external control independent of environmental conditionals, has led to its increased use. Of particular note is the use of light with photosensitisers.

Areas covered: Photosensitisers are widely used in photodynamic therapy to cause a cidal effect towards cells on irradiation due to the generation of reactive oxygen species. These cidal effects have also been used to treat infectious diseases. The effects and benefits of photosensitisers in the treatment of such conditions are still being developed and further realised, with the design of novel delivery strategies. This review provides an overview of the realisation of the pharmaceutically relevant uses of photosensitisers, both in the context of current research and in terms of current clinical application, and looks to the future direction of research.

Expert opinion: Substantial advances have been and are being made in the use of photosensitisers. Of particular note are their antimicrobial applications, due to absence of resistance that is so frequently associated with conventional treatments. Their potency of action and the ability to immobilise to polymeric supports is opening a wide range of possibilities with great potential for use in healthcare infection prevention strategies.