A comparison of HFrEF vs HFpEF's clinical workload and cost in the first year following hospitalization and enrollment in a disease management program.

BACKGROUND: Admission with heart failure (HF) is a milestone in the progression of the disease, often resulting in higher intensity medical care and ensuing readmissions. Whilst there is evidence supporting enrolling patients in a heart failure disease management program (HF-DMP), not all reported HF-DMPs have systematically enrolled patients with HF with preserved ejection fraction (HFpEF) and there is a scarcity of literature differentiating costs based on HF-phenotype. METHODS: 1292 consenting, consecutive patients admitted with a primary diagnosis of HF were enrolled in a hospital based HF-DMP and categorized as HFpEF (EF≥45%) or HFrEF (EF<45%). Hospitalizations, primary care, medications, and DMP workload with associated costs were evaluated assessing DMP clinic-visits, telephonic contact, medication changes over 1year using a mixture of casemix and micro-costing techniques. RESULTS: The total average annual cost per patient was marginally higher in patients with HFrEF €13,011 (12,011, 14,078) than HFpEF, €12,206 (11,009, 13,518). However, emergency non-cardiovascular admission rates and average cost per patient were higher in the HFpEF vs HFrEF group (0.46 vs 0.31 per patient/12months) & €655 (318, 1073) vs €584 (396, 812). In the first 3months of the outpatient HF-DMP the HFrEF population cost more on average €791 (764, 819) vs €693 (660, 728). CONCLUSION: There are greater short-term (3-month) costs of HFrEF versus HFpEF as part of a HF-DMP following an admission. However, long-term (3-12month) costs of HFpEF are greater because of higher non-cardiovascular rehospitalisations. As HFpEF becomes the dominant form of HF, more work is required in HF-DMPs to address prevention of non-cardiovascular rehospitalisations and to integrate hospital based HF-DMPs into primary healthcare structures.

Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.

Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.

Particulate and non-particulate steroids in spinal epidurals: a systematic review and meta-analysis.

BACKGROUND: Steroids in transforaminal epidural injections are widely used to ease radicular pain in both cervical and lumbar radiculopathy. Concerns have been articulated about the use of particulate steroids for this intervention, as a number of case reports have been published linking them with post procedural paralysis, possibly due to spinal ischaemia secondary to a steroid particulate embolism. Non-particulate, or soluble steroids, are mooted as an alternative; however, their effectiveness relative to particulate steroids has not been conclusively proven. STUDY DESIGN: We review the evidence in the published literature regarding the efficacy of non-particulate steroids in epidural injections compared to particulate steroids, and synthesise it to gauge the qualitative outcomes from level one evidence (visual analogue scales, numerical pain scores and Oswestry Disability Index) from baseline to specified follow up. METHODS: The PRISMA guidelines were utilised for this review. An internet search was performed to collate the available literature from medical databases PubMed, EMBASE, Web of Science and the Cochrane library. We used a broad search term [epidural (and) steroid] to ensure a wide capture of articles. No limitations in terms of language or date of publication were implemented. The reference lists of articles included for full text review were searched for any additional primary or review publications. RESULTS: Four online libraries were searched, with a combined total of 11,353 titles reviewed, not excluding duplicates. Post title abstract and full text review, nine articles were identified as suitable for inclusion for qualitative synthesis. Four of these were suitable for quantitative synthesis, with a total of 300 participants, 147 in the particulate group and 153 in the non-particulate group. Using a random effects model, the pooled standard mean difference of VAS score diminution was not significant between groups (0.31 in favour of particulates, 95 % CI -0.68 to 1.30). From our qualitative synthesis, there was a trend for greater improvement in pain scores within the particulate group. The type of steroid used did not appear to have an effect on the disability score given by patients. CONCLUSION: Particulate steroids are not demonstrably better in relieving pain compared to their non-particulate counterparts. In view of the concerns over the safety profile of particulate steroids, it may be prudent to switch to non particulates, or at the very least the dangers and alternatives should be flagged with the patient group as part of a shared decision making process.

Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients.

Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic-regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co-existing psychiatric illness. In addition, global DNA methylation levels [5-methyl cytosine (5-mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non-attempters, assessed for DSM-IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3' UTR of the DNMT3B gene was associated with SA compared with a non-attempter control group (P = 0.001; Chi-squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t-test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients.

Freedom from Echinococcus multilocularis: an Irish perspective.

Echinococcus multilocularis, an emerging zoonotic disease is extending its geographical distribution within the European Union (EU). At present, five member states including Ireland are considered free. Previous EU regulations on importing domestic pets allowed these countries to maintain national rules that required all dogs be treated with an anti-cestode compound before entry. The controls on the movement of pet animals within the EU were recently reviewed by the European Commission and it was decided that the five countries had to demonstrate freedom from E. multilocularis before they could continue with the mandatory tapeworm treatment. The intestines of 220, 307 and 216 foxes were examined, using the sedimentation and counting technique, for the presence of E. multilocularis in 2003, 2009 and 2010 respectively. There was no evidence of the parasite in the foxes. These data together with the negative results from 130 foxes examined by other workers during 1999 and 2000 (Wolfe et al., 2001) were used to estimate the probability of freedom using scenario trees. The result of the model suggested that the probability that Ireland was free from E. multilocularis in 2010 was high, 0.98 (95% confidence interval, 0.94-1.00), thus justifying the retention of the mandatory tapeworm treatment for dogs entering the country from other EU member states.

The prevalence and distribution of Alaria alata, a potential zoonotic parasite, in foxes in Ireland.

The digenean trematode Alaria alata, an intestinal parasite of wild canids is widely distributed in Europe. The recent finding of the mesocercarial life cycle stage in the paratenic wild boar host suggests that it may potentially infect humans Mohl et al. (Parasitol Res 105:1-15, 2009). Over 500 foxes were examined during a wildlife survey for zoonotic diseases in 2009 and 2010. The prevalence of A. alata ranged from 21% to 26% in 2009 and 2010, and the intensity of infection varied, with the majority of foxes having between one and ten trematodes, but a small number of animals had parasitic burdens greater than 500. The location of foxes was geo-referenced and mapped using a geographic information system. The results of the spatial analysis suggest that A. alata may have a limited distribution being confined mainly to areas of pasture especially in the central plain and north Munster. Hot spot analysis indicated a clustering and that the level of parasitism was greatest in foxes from those areas where the prevalence of infection was highest.

Spatial distribution of risk factors for Cryptosporidium spp. transport in an Irish catchment.

Cryptosporidium spp. has become a major public health concern in many parts of the globe, including Ireland, as a result of recent reported waterborne outbreaks of Cryptosporidiosis. Continuous monitoring of Cryptosporidium spp. in water supplies is not feasible, so a risk-forecasting approach is required. This study reports a globally applicable approach for evaluating the spatial variation in relative risk of contaminating surface water by Cryptosporidium spp. based on a risk potential index (RPI) as an indicator of the potential pollution of surface water. The RPI is predicted by readily available data on land use, rainfall, soil type, slope, soil moisture deficit, and distance from water course. A small catchment in County Meath, Ireland, was chosen to illustrate the analysis of the approach. Data for the study area were digitized and rectified using surveyed ground control points to capture each of the RPI factors, field boundaries, and land use. The six parameters were classified and assigned a relative risk score out of 5. A Geographic Information Systems overlay analysis then was used to calculate a cumulative relative risk score for each month of the year. The analysis indicated that April and June experienced a relatively low risk of Cryptosporidium spp. transport compared with other months of the year. June had the least risk, because more than 98% of the catchment was estimated to be of low or moderate risk (RPI ranges = 0 to 2). December had the highest risk of Cryptosporidium spp. transport, because approximately 20% of the catchment area had a moderately high to very high risk (RPI ranges = 2 to 5). The study also made an attempt to reduce the risk of contaminating surface water by alternative land-use practice and relocating the field boundaries. The study demonstrated a semi-quantitative and readily implemented method for using spatial risk assessment for planning land management to reduce the risk of surface water contamination by Cryptosporidium spp. from agricultural sources. The approach could be used in any catchment with similar hydrological characteristics subject to a surface water pathogen contamination risk from grazing livestock.

Control of cryptosporidiosis in neonatal calves: use of halofuginone lactate in two different calf rearing systems.

To date there is no effective treatment for bovine cryptosporidiosis. This study describes the use of halofuginone lactate in preventing cryptosporidiosis in naturally infected neonatal calves on a dairy farm with a high prevalence of infection. The animals were kept in two different calf rearing systems. A randomized double-blind trial was carried out with 32 naturally infected calves, divided into four groups. The two prophylactic halofuginone lactate treated groups were kept in either individual or group pens. Similarly, the animals receiving the placebo were housed in either individual pens or together in a large pen. A total of ten faecal samples were collected periodically during the 28 days study from each calf and tested for the presence of Cryptosporidium spp. using microscopic and molecular methods. Generalized estimating equations models were used to determine if the effects of the various treatments and/or rearing systems on the presence of diarrhoea and infection were statistically significant. Further analysis (classification trees models) was carried out to explore possible risk factors for cryptosporidiosis and interactions between treatments and rearing systems. Halofuginone lactate was shown to be effective in reducing clinical signs of cryptosporidiosis and environmental contamination. However, the treatment did not delay the onset of diarrhoea and did not reduce the risk of infection amongst calves reared together in a highly contaminated environment. The use of halofuginone lactate in combination with good hygienic measures, such as rearing animals in clean individual pens, was the most effective method to reduce the risk of cryptosporidiosis amongst 7-13 days old calves. It was concluded that the control of the parasite could be achieved by the combination of using effective preventive drugs, such as halofuginone lactate and good animal husbandry procedures.

Anisakid larvae in Atlantic salmon (Salmo salar L.) grilse and post-smolts: molecular identification and histopathology.

The molecular identification and histopathology are described for the parasitic larvae of a nematode species present in the abdominal cavity of Atlantic salmon ( Salmo salar ) grilse caught in fish traps on their natal river in the west of Ireland and post-smolts collected during experimental trawls on the continental shelf edge of the northeast Atlantic Ocean. Larvae in the adult and juvenile salmon were identified as Anisakis simplex sensu stricto by PCR amplification and RFLP and sequencing of the ITS gene and PCR amplification and sequencing of the cox2 gene. Parasitic nematode larvae in the grilse were either encapsulated in the abdominal mesentery associated with the pyloric ceca or on the serosal surface of the liver and in the vent region. In some fish, larvae were found in the parenchyma of the liver and muscularis circularis of the intestine. In general, the larvae induced a limited cellular response apart from the occurrence of focal melanin macrophage aggregates and individual eosinophilic granular cells in the connective tissue capsule. Melanin macrophage aggregates were also present among the hepatocytes adjacent to encapsulated larvae in the liver. The reaction to the parasites was more severe in the wall of the intestine. Encapsulated nematode larvae caused displacement, vacuolation, and necrosis of the circular muscle fibers. The stratum compactum was also disrupted with focal areas of degeneration. Overall, the intestinal wall had a hypercellular appearance with extensive cellular infiltration comprising eosinophilic granular cells, macrophages, lymphocytes, and fibrocytes. The post-smolts were caught in May during the early oceanic phase of their life cycle. In these fish, A. simplex sensu stricto larvae were found lying free on the serosal surface of the intestine and liver without any apparent histologic changes. This is the earliest in the marine migration of Atlantic salmon that A. simplex sensu stricto infection has been recorded.

The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer.

It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype. A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many processes including apoptosis. To date, studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast, colon and stomach, with only limited data available on prostate cancer. Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer. The most significant advances have involved the discovery of apoptotic gene targets of methylation, including XAF1, (fragile histidine triad (FHIT ), cellular retinol binding protein 1 (CRBP1), decoy receptor 1(DCR1), decoy receptor 2 (DCR2 ), target of methylation-induced silenceing 1 (TMS1), TNF receptor superfamily, member 6 (FAS), Reprimo (RPRM) and GLI pathogenesis-related 1 (GLIPR1). These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers. We also introduce the concept of an 'apoptotic methylation signature' for prostate cancer and evaluate its potential in a diagnostic, prognostic and therapeutic setting.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Study on the prevalence of Toxoplasma gondii and Neospora caninum and molecular evidence of Encephalitozoon cuniculi and Encephalitozoon (Septata) intestinalis infections in red foxes (Vulpes vulpes) in rural Ireland.

Thoracic fluid (pleural fluid and clotted blood) from 206 foxes were examined for antibodies to Toxoplasma gondii and 220 thoracic fluid samples were tested for Neospora caninum antibodies using indirect immunofluorescent antibody tests (IFAT). A total of 115 (56%) and six (3%) foxes had antibodies to T. gondii and N. caninum, respectively. The brains from 148 foxes were examined for histological lesions and pathological changes suggestive of parasitic encephalitis were observed in 33 (22%). Two thirds of these foxes had antibodies to T. gondii and one fox had antibodies to both T. gondii and N. caninum. PCR assays carried out on DNA extracted from the 33 brains with histological lesions were negative for N. caninum but one of the brains was positive for T. gondii. Microsporidian DNA was also amplified from the brains of two of these foxes. Sequencing these amplicons revealed 100% homology with Encephalitozoon (Septata) intestinalis in one fox and Encephalitozoon cuniculi in the second fox. This is the first report of Encephalitozoon infections in wildlife in Ireland.

A study of helminth parasites in culled cows from Ireland.

The objective of this study was to determine the prevalence and intensity of gastrointestinal nematode, lungworm and liver fluke infection in culled cows in Ireland. Abomasa, colorectal contents and livers were collected from 30 to 68 culled beef and dairy cows during autumn 2002 and summer 2003, respectively. Ostertagia ostertagi were found in the abomasa of only three (10%) cows sampled in autumn and in 38 (57%) cows examined in summer. The majority of positive animals had low burdens of O. ostertagi but a few individuals in the group sampled during the summer had a moderate infection (5000-10,000 adult worms). A proportion of the cows in the summer group were also co-infected with small numbers of Trichostrongylus axei. Cooperia oncophora predominated in the recoveries from the larval cultures although O. ostertagi were also recovered. The overall prevalence of Dictyocaulus viviparus was 14%, based on larval identification in faecal samples. Liver fluke, or varying degrees of pathology attributable to Fasciola hepatica, were present in 65% of the livers. The results of this study extend those of previous workers, which were largely limited to dairy cows alone and which focussed on gastrointestinal nematodes and did not include simultaneous infections with lungworm and liver fluke. It was concluded, from the level of polyparasitism evident in this study, that adult cattle should be considered in preventative approaches to bovine helminthosis.

Maturational changes in airway smooth muscle shortening and relaxation. Implications for asthma.

Greater airway responsiveness in healthy juveniles is considered a factor in the higher asthma prevalence at a young age compared with adults. Several studies on the contractile response of airway smooth muscle (ASM) from birth to adulthood have addressed the hypothesis that a maturation of ASM plays a role in juvenile airway hyperresponsiveness. Maturation of distinct ASM properties, i.e. force generation, shortening, and relaxation, has been reported, although the majority of the studies have focused on maturation of maximum force and/or sensitivity to contractile agonists. However, in most animal species maturation of the ability to generate force does not correlate with maturation of airway responsiveness. Ontogenesis of ASM shortening has been less extensively studied and the existing reports emphasize an increase during maturation of tissue passive forces opposing shortening. ASM spontaneous relaxation has been very minimally investigated. We have recently demonstrated that the ability of ASM to spontaneously relax during stimulation is sharply reduced in juvenile airway tissue. It remains to be determined the role of these ASM properties in the onset of childhood asthma and whether specific alterations are induced by the occurrence of obstructive airway diseases in young individuals.

Multiple forms of formamidopyrimidine-DNA glycosylase produced by alternative splicing in Arabidopsis thaliana.

Formamidopyrimidine-DNA glycosylase (FPG) catalyzes the initial steps in the repair of DNA containing oxidized purines. Two cDNA clones from Arabidopsis thaliana encoding homologs of bacterial FPG have previously been described. We now report that there are at least five additional variants of FPG mRNA in Arabidopsis, each apparently produced from the same gene (AtMMH) by alternative splicing. Thus, AtMMH, like at least four other genes in the base excision repair pathway of human cells, produces multiple forms of protein product through alternative splicing. The variant forms of Arabidopsis FPG may be localized in different locations in the cells, may have different preferences for oxidized substrates, and/or may recruit different proteins that guide the subsequent steps of base excision repair.

Epidemiological studies of human and animal Salmonella typhimurium DT104 and DT104b isolates in Ireland.

A total of 122 human and animal Salmonella Typhimurium DT104 isolates and 6 epidemiologically related DT104b isolates from human and animal products were analysed by pulsed-field gel electrophoresis (PFGE). Genomic DNA was subjected to macrorestriction with three enzymes, SpeI, SfiI and XbaI. A total of 14 restriction fragment length polymorphism (RFLP) profiles were identified when the PFGE patterns from the three enzymes were combined. The majority of isolates (81.2%) exhibited the same RFLP profile. Six animal DT104 isolates, susceptible to enrofloxacin and resistant to naladixic acid, were identified from the antibiotic susceptibility test. Four of these isolates had a different PFGE profile from the common RFLP. In addition, 4 of the 6 isolates were geographically clustered in one region. It was concluded that there was one predominant strain of S. Typhimurium DT104 in Ireland and that the potential and selection pressures for emergence of fluoroquinolone-resistant isolates were present.

Alternative forms of formamidopyrimidine-DNA glycosylase from Arabidopsis thaliana.

Formamidopyrimidine-DNA glycosylase (FPG) catalyzes the initial steps in the repair of DNA containing oxidized purines. Two complementary DNA clones encoding homologs of bacterial FPG, designated Atfpg-1 and Atfpg-2, have been isolated from Arabidopsis thaliana. They are products of alternative splicing of the transcript of a single gene. Proteins encoded by both clones, AtFPG-1 and AtFPG-2, engineered to contain oligohistidine sequences on their C-terminal ends, were expressed in Escherichia coli and purified, and their activities were assayed. Both proteins cleaved DNA that contained apurinic sites, indicating that they have abasic lyase activity. AtFPG-1, but not AtFPG-2, showed significant cleavage of a double-stranded oligonucleotide that contained 8-oxo-guanine, indicating that the structural differences between the two proteins influence their enzymatic activities. However, both proteins were able to cleave the same sites in DNA that was treated with visible light in the presence of methylene blue.