Population-based detection of systolic and diastolic dysfunction with amino-terminal pro-B-type natriuretic peptide

Background: There is limited information regarding the clinical utility of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) for the detection of left ventricular (LV) dysfunction in the community. We evaluated predictors of circulating NT-proBN

Pro-inflammatory flagellin proteins of prevalent motile commensal bacteria are variably abundant in the intestinal microbiome of elderly humans

Peer reviewedPublisher PD

Semi-Quantitative Models for Identifying Potent and Selective Transthyretin Amyloidogenesis Inhibitors

Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration

Genotype-specific lesion growth rates in stargardt disease

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed bial-lelic ABCA4 mutations from five genotype groups: c.6079C \u3e T, c.[2588G \u3e C;5603A \u3e T], c.3113C \u3e T, c.5882G \u3e A and c.5603A \u3e T. Fundus autofluorescence (AF) 30◦ × 30◦ images were manually seg-mented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21–86) were recruited. Patients with c.3113C \u3e T or c.6079C \u3e T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p \u3c 0.001 and 0.14 to 0.21; p \u3c 0.001) respectively, as compared to those patients harbouring c.5882G \u3e A at 0.06 mm/year (95% CI 0.03–0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset

Sibling concordance in symptom onset and atrophy growth rates in Stargardt disease using ultra-widefield fundus autofluorescence

Purpose: To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point. Methods: In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test. Results: Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences (P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences (P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant (P = 0.44 for area GR and P = 0.61 for radius GR). Conclusion: There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation

Effect of room temperature transport vials on DNA quality and phylogenetic composition of faecal microbiota of elderly adults and infants

Background: Alterations in intestinal microbiota have been correlated with a growing number of diseases. Investigating the faecal microbiota is widely used as a non-invasive and ethically simple proxy for intestinal biopsies. There is an urgent need for collection and transport media that would allow faecal sampling at distance from the processing laboratory, obviating the need for same-day DNA extraction recommended by previous studies of freezing and processing methods for stool. We compared the faecal bacterial DNA quality and apparent phylogenetic composition derived using a commercial kit for stool storage and transport (DNA Genotek OMNIgene GUT) with that of freshly extracted samples, 22 from infants and 20 from older adults. Results: Use of the storage vials increased the quality of extracted bacterial DNA by reduction of DNA shearing. When infant and elderly datasets were examined separately, no differences in microbiota composition were observed due to storage. When the two datasets were combined, there was a difference according to a Wilcoxon test in the relative proportions of Faecalibacterium, Sporobacter, Clostridium XVIII, and Clostridium XlVa after 1 week's storage compared to immediately extracted samples. After 2 weeks' storage, Bacteroides abundance was also significantly different, showing an apparent increase from week 1 to week 2. The microbiota composition of infant samples was more affected than that of elderly samples by storage, with significantly higher Spearman distances between paired freshly extracted and stored samples (

Tumour-associated and non-tumour-associated microbiota in colorectal cancer

Objective: A signature that unifies the colorectal cancer (CRC) microbiota across multiple studies has not been identified. In addition to methodological variance, heterogeneity may be caused by both microbial and host response differences, which was addressed in this study. Design: We prospectively studied the colonic microbiota and the expression of specific host response genes using faecal and mucosal samples (‘ON’ and ‘OFF’ the tumour, proximal and distal) from 59 patients undergoing surgery for CRC, 21 individuals with polyps and 56 healthy controls. Microbiota composition was determined by 16S rRNA amplicon sequencing; expression of host genes involved in CRC progression and immune response was quantified by real-time quantitative PCR. Results: The microbiota of patients with CRC differed from that of controls, but alterations were not restricted to the cancerous tissue. Differences between distal and proximal cancers were detected and faecal microbiota only partially reflected mucosal microbiota in CRC. Patients with CRC can be stratified based on higher level structures of mucosal-associated bacterial co-abundance groups (CAGs) that resemble the previously formulated concept of enterotypes. Of these, Bacteroidetes Cluster 1 and Firmicutes Cluster 1 were in decreased abundance in CRC mucosa, whereas Bacteroidetes Cluster 2, Firmicutes Cluster 2, Pathogen Cluster and Prevotella Cluster showed increased abundance in CRC mucosa. CRC-associated CAGs were differentially correlated with the expression of host immunoinflammatory response genes. Conclusions: CRC-associated microbiota profiles differ from those in healthy subjects and are linked with distinct mucosal gene-expression profiles. Compositional alterations in the microbiota are not restricted to cancerous tissue and differ between distal and proximal cancers

Grass Species Flammability, Not Biomass, Drives Changes in Fire Behavior at Tropical Forest-Savanna Transitions

Forest-savanna mosaics are maintained by fire-mediated positive feedbacks; whereby forest is fire suppressive and savanna is fire promoting. Forest-savanna transitions therefore represent the interface of opposing fire regimes. Within the transition there is a threshold point at which tree canopy cover becomes sufficiently dense to shade out grasses and thus suppress fire. Prior to reaching this threshold, changes in fire behavior may already be occurring within the savanna. Such changes are neither empirically described nor their drivers understood. Fire behavior is largely driven by fuel flammability. Flammability can vary significantly between grass species and grass species composition can change near forest-savanna transitions. This study measured fire behavior changes at eighteen forest-savanna transition sites in a vegetation mosaic in Lopé National Park in Gabon, central Africa. The extent to which these changes could be attributed to changes in grass flammability was determined using species-specific flammability traits. Results showed simultaneous suppression of fire and grass biomass when tree canopy leaf area index (LAI) reached a value of 3, indicating that a fire suppression threshold existed within the forest-savanna transition. Fires became less intense and less hot prior to reaching this fire suppression threshold. These changes were associated with higher LAI values, which induced a change in the grass community, from one dominated by the highly flammable Anadelphia afzeliana to one dominated by the less flammable Hyparrhenia diplandra. Changes in fire behavior were not associated with changes in total grass biomass. This study demonstrated not only the presence of a fire suppression threshold but the mechanism of its action. Grass composition mediated fire-behavior within the savanna prior to reaching the suppression threshold, and grass species composition was mediated by tree canopy cover which was in turn mediated by fire-behavior. These findings highlight how biotic and abiotic controls interact and amplify each other in this mosaicked landscape to facilitate forest and savanna co-existence

Dogslife: A web-based longitudinal study of Labrador Retriever health in the UK

<p>Abstract</p> <p>Background</p> <p>Dogslife is the first large-scale internet-based longitudinal study of canine health. The study has been designed to examine how environmental and genetic factors influence the health and development of a birth cohort of UK-based pedigree Labrador Retrievers.</p> <p>Results</p> <p>In the first 12 months of the study 1,407 Kennel Club (KC) registered eligible dogs were recruited, at a mean age of 119 days of age (SD 69 days, range 3 days – 504 days). Recruitment rates varied depending upon the study team’s ability to contact owners. Where owners authorised the provision of contact details 8.4% of dogs were recruited compared to 1.3% where no direct contact was possible. The proportion of dogs recruited was higher for owners who transferred the registration of their puppy from the breeder to themselves with the KC, and for owners who were sent an e-mail or postcard requesting participation in the project. Compliance with monthly updates was highly variable. For the 280 dogs that were aged 400 days or more on the 30^th June 2011, we estimated between 39% and 45% of owners were still actively involved in the project. Initial evaluation suggests that the cohort is representative of the general population of the KC registered Labrador Retrievers eligible to enrol with the project. Clinical signs of illnesses were reported in 44.3% of Labrador Retrievers registered with Dogslife (median age of first illness 138 days), although only 44.1% of these resulted in a veterinary presentation (median age 316 days).</p> <p>Conclusions</p> <p>The web-based platform has enabled the recruitment of a representative population of KC registered Labrador Retrievers, providing the first large-scale longitudinal population-based study of dog health. The use of multiple different methods (e-mail, post and telephone) of contact with dog owners was essential to maximise recruitment and retention of the cohort.</p