Visual fields in patients who have undergone vitrectomy for complications of diabetic retinopathy. A prospective study

BACKROUND: To determine the extent of visual field loss in patients who had required a pars plana vitrectomy secondary to complications of proliferative diabetic retinopathy. METHODS: Patients that had undergone a vitrectomy on at least one eye for treatment of either vitreous haemorrhage or tractional retinal detachment were selected for study. ETDRS acuity and Humphrey binocular Esterman visual field testing were performed and compared to the minimum standards for safe driving as defined by the Royal College of Ophthalmologists in 1999. In addition to this Goldman kinetic visual fields using a III4e and V4e stimulus size and central 24-2 threshold test with the SITA-fast strategy were performed on the vitrectomised eye. RESULTS: 20 patients (n = 20) were recruited. Mean visual acuity in the eye being tested was 0.20 (Snellen 6/9.5). Results from the Humphrey field analyzer showed a mean number of abnormal stimulus locations of 71.2% (p < 0.005). 70% of patients had sufficient binocular acuity to drive and of these 71.4% were shown not to have a minimum visual field for safe driving on binocular Esterman field analysis. CONCLUSION: Vitrectomy potentially allows retention/restoration of good visual acuity in patients with complications of proliferative diabetic retinopathy. However patients may be suffering from unrecognized visual impairment consequent upon extensive visual field loss which in over two thirds of patients may be sufficiently severe to preclude safe driving

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Optimising experimental design for high-throughput phenotyping in mice: a case study

To further the functional annotation of the mammalian genome, the Sanger Mouse Genetics Programme aims to generate and characterise knockout mice in a high-throughput manner. Annually, approximately 200 lines of knockout mice will be characterised using a standardised battery of phenotyping tests covering key disease indications ranging from obesity to sensory acuity. From these findings secondary centres will select putative mutants of interest for more in-depth, confirmatory experiments. Optimising experimental design and data analysis is essential to maximise output using the resources with greatest efficiency, thereby attaining our biological objective of understanding the role of genes in normal development and disease. This study uses the example of the noninvasive blood pressure test to demonstrate how statistical investigation is important for generating meaningful, reliable results and assessing the design for the defined research objectives. The analysis adjusts for the multiple-testing problem by applying the false discovery rate, which controls the number of false calls within those highlighted as significant. A variance analysis finds that the variation between mice dominates this assay. These variance measures were used to examine the interplay between days, readings, and number of mice on power, the ability to detect change. If an experiment is underpowered, we cannot conclude whether failure to detect a biological difference arises from low power or lack of a distinct phenotype, hence the mice are subjected to testing without gain. Consequently, in confirmatory studies, a power analysis along with the 3Rs can provide justification to increase the number of mice used

Microstructure and biomechanical characteristics of bone substitutes for trauma and orthopaedic surgery

Abstract. BACKGROUND: Many (artificial) bone substitute materials are currently available for use in orthopaedic trauma surgery. Objective data on their biological and biomechanical characteristics, which determine their clinical application, is mostly lacking. The aim of this study was to investigate structural and in vitro mechanical properties of nine bone substitute cements registered for use in orthopaedic trauma surgery in the Netherlands. METHODS: Seven calcium phosphate cements (BoneSource®, Calcibon®, ChronOS®, Eurobone®, HydroSet™, Norian SRS®, and Ostim®), one calcium sulphate cement (MIIG® X3), and one bioactive glass cement (Cortoss®) were tested. Structural characteristics were measured by micro-CT scanning. Compression strength and stiffness were determined following unconfined compression tests. RESULTS: Each bone substitute had unique characteristics. Mean total porosity ranged from 53% (Ostim®) to 0.5% (Norian SRS®). Mean pore size exceeded 100 μm only in Eurobone® and Cortoss® (162.2 ± 107.1 μm and 148.4 ± 70.6 μm, respectively). However, 230 μm pores were found in Calcibon®, Norian SRS®, HydroSet™, and MIIG® X3. Connectivity density ranged from 27/cm3 for HydroSet™ to 0.03/cm3 for Calcibon®. The ultimate compression strength was highest in Cortoss® (47.32 MPa) and lowest in Ostim® (0.24 MPa). Young's Modulus was highest in Calcibon® (790 MPa) and lowest in Ostim® (6 MPa). CONCLUSIONS: The bone substitutes tested display a wide range in structural properties and compression strength, indicating that they will be suitable for different clinical indications. The data outlined here will help surgeons to select the most suitable products currently available for specific clinical indications

Detection of copy number variations in rice using array-based comparative genomic hybridization

<p>Abstract</p> <p>Background</p> <p>Copy number variations (CNVs) can create new genes, change gene dosage, reshape gene structures, and modify elements regulating gene expression. As with all types of genetic variation, CNVs may influence phenotypic variation and gene expression. CNVs are thus considered major sources of genetic variation. Little is known, however, about their contribution to genetic variation in rice.</p> <p>Results</p> <p>To detect CNVs, we used a set of NimbleGen whole-genome comparative genomic hybridization arrays containing 718,256 oligonucleotide probes with a median probe spacing of 500 bp. We compiled a high-resolution map of CNVs in the rice genome, showing 641 CNVs between the genomes of the rice cultivars 'Nipponbare' (from <it>O. sativa </it>ssp. <it>japonica</it>) and 'Guang-lu-ai 4' (from <it>O. sativa </it>ssp. <it>indica</it>). The CNVs identified vary in size from 1.1 kb to 180.7 kb, and encompass approximately 7.6 Mb of the rice genome. The largest regions showing copy gain and loss are of 37.4 kb on chromosome 4, and 180.7 kb on chromosome 8. In addition, 85 DNA segments were identified, including some genic sequences. Contracted genes greatly outnumbered duplicated ones. Many of the contracted genes corresponded to either the same genes or genes involved in the same biological processes; this was also the case for genes involved in disease and defense.</p> <p>Conclusion</p> <p>We detected CNVs in rice by array-based comparative genomic hybridization. These CNVs contain known genes. Further discussion of CNVs is important, as they are linked to variation among rice varieties, and are likely to contribute to subspecific characteristics.</p

Genomics in neurodevelopmental disorders: an avenue to personalized medicine

Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g., autism spectrum disorder, intellectual disability) remains a great challenge. Recent advancements in genomics, such as whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that have been discovered, the etiological variability and the heterogeneous clinical presentation, the need for genotype — along with phenotype- based diagnosis of individual patients has become a requisite. In this review we look at recent advancements in genomic analysis and their translation into clinical practice

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference