Mathematical and computational models of the retina in health, development and disease

The retina confers upon us the gift of vision, enabling us to perceive the world in a manner unparalleled by any other tissue. Experimental and clinical studies have provided great insight into the physiology and biochemistry of the retina; however, there are questions which cannot be answered using these methods alone. Mathematical and computational techniques can provide complementary insight into this inherently complex and nonlinear system. They allow us to characterise and predict the behaviour of the retina, as well as to test hypotheses which are experimentally intractable. In this review, we survey some of the key theoretical models of the retina in the healthy, developmental and diseased states. The main insights derived from each of these modelling studies are highlighted, as are model predictions which have yet to be tested, and data which need to be gathered to inform future modelling work. Possible directions for future research are also discussed. Whilst the present modelling studies have achieved great success in unravelling the workings of the retina, they have yet to achieve their full potential. For this to happen, greater involvement with the modelling community is required, and stronger collaborations forged between experimentalists, clinicians and theoreticians. It is hoped that, in addition to bringing the fruits of current modelling studies to the attention of the ophthalmological community, this review will encourage many such future collaborations

Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or Cytosine arabinoside

Treatment of choroidal melanoma by chemotherapy is usually unsuccessful, with response rates of less than 1% reported for dacarbazine (DTIC)-containing regimens which show 20% or more response rates in skin melanoma. Recently, we reported the activity of several cytotoxic agents against primary choroidal melanoma in an ATP-based tumour chemosensitivity assay (ATP-TCA). In this study, we have used the same method to examine the sensitivity of choroidal melanoma to combinations suggested by our earlier study. Tumour material from 36 enucleated eyes was tested against a battery of single agents and combinations which showed some activity in the previous study. The combination of treosulfan with gemcitabine or cytosine arabinoside showed consistent activity in 70% and 86% of cases, respectively. Paclitaxel was also active, particularly in combination with treosulfan (47%) or mitoxantrone (33%). Addition of paclitaxel to the combination of treosulfan + cytosine analogue added little increased sensitivity. For treosulfan + cytosine arabinoside, further sequence and timing experiments showed that simultaneous administration gave the greatest suppression, with minor loss of inhibition if the cytosine analogue was given 24 h after the treosulfan. Administration of cytosine analogue 24 h before treosulfan produced considerably less inhibition at any concentration. While we have so far been unable to study metastatic tumour from choroidal melanoma patients, the combination of treosulfan with gemcitabine or cytosine arabinoside shows activity ex vivo against primary tumour tissue. Clinical trials are in progress. © 1999 Cancer Research Campaig

Intra- and inter-individual genetic differences in gene expression

Genetic variation is known to influence the amount of mRNA produced by a gene. Given that the molecular machines control mRNA levels of multiple genes, we expect genetic variation in the components of these machines would influence multiple genes in a similar fashion. In this study we show that this assumption is correct by using correlation of mRNA levels measured independently in the brain, kidney or liver of multiple, genetically typed, mice strains to detect shared genetic influences. These correlating groups of genes (CGG) have collective properties that account for 40-90% of the variability of their constituent genes and in some cases, but not all, contain genes encoding functionally related proteins. Critically, we show that the genetic influences are essentially tissue specific and consequently the same genetic variations in the one animal may up-regulate a CGG in one tissue but down-regulate the same CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. The implication of this study is that this class of genetic variation can result in complex inter- and intra-individual and tissue differences and that this will create substantial challenges to the investigation of phenotypic outcomes, particularly in humans where multiple tissues are not readily available.

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Validity, reliability and stability of the portable Cortex Metamax 3B gas analysis system

This study investigated the performance of the portable Cortex Metamax 3B (MM3B) automated gas analysis system during both simulated and human exercise using adolescents. Repeated measures using a Gas Exchange System Validator (GESV) across a range of simulated metabolic rates, showed the MM3B to be adequately reliable (both percentage errors, and percentage technical error of measurements <2%) for measuring expired ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2). Over a 3 h period, the MM3B was shown to be acceptably stable in measuring gas fractions, as well as VE, VO2, and VCO2 generated by the GESV, especially at moderate and high metabolic rates (drifts <2% and of minor physiological significance). Using eight healthy adolescents during rest, moderate, and vigorous cycle ergometry, the validity of the MM3B was tested against the primary criterion Douglas bag method (DBM) and a secondary criterion machine known to be accurate, the Jaeger Oxycon Pro system. No significant errors in VE were noted, yet the MM3B significantly overestimated both VO2 and VCO2 by approximately 10–17% at moderate and vigorous exercise as compared to the DBM and at all exercise levels compared to the Oxycon Pro. No significant differences were seen in any metabolic variable between the two criterion systems (DBM and Oxycon Pro). It is concluded the MM3B produces acceptably stable and reliable results, but is not adequately valid during moderate and vigorous exercise without some further correction of VO2 and VCO2

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial

Background: Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction (‘optical treatment’) followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching (‘dose’), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. Methods/design: A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. Discussion: This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Second primary malignancies after treatment for malignant lymphoma

To determine the incidence and possible causes of second primary malignancies after treatment for Hodgkin's and Non-Hodgkin's lymphoma (HL and NHL). A cohort of 3764 consecutive patients diagnosed with HL or NHL between January 1970 and July 2001 was identified using the Sheffield Lymphoma Group database. A search was undertaken for all patients diagnosed with a subsequent primary malignancy. Two matched controls were identified for each case. Odds ratios were calculated to detect and quantify any risk factors in the cases compared to their matched controls. Mean follow-up for the cohort was 5.2 years. A total of 68 patients who developed second cancers at least 6 months after their primary diagnosis were identified, giving a crude incidence of 1.89% overall: 3.21% among the patients treated for HL, 1.32% in those treated for NHL. Most common were bronchial, breast, colorectal and haematological malignancies. High stage at diagnosis almost reached statistical significance in the analysis of just the NHL patients (odds ratio=3.48; P=0.068) after adjustment for other factors. Treatment modality was not statistically significant in any analysis. High stage at diagnosis of NHL may be a risk factor for developing a second primary cancer

A new species of cryptic cyanobacteria isolated from the epidermis of a bottlenose dolphin and as a bioaerosol

Two cyanobacterial strains, one collected from an epidermal mat present on a dead bottlenose dolphin and the other as a bioaerosol 457 m (1500 ft) above the river, were recently analysed from the St. Johns River, Jacksonville, Florida, USA. Both samples had major phenotypic plasticity which confused morphological identification. Amplicon sequencing of the 16S rRNA gene from the isolates revealed that both samples were closely aligned (branch bootstrap support = 100%) with the recently erected genus Komarekiella. Whole genome sequencing and phylogenetic construction also supported the isolation of a new species of cyanobacteria branching from the Nostoc clade. A total evidence approach of molecular, genetic, and ecological examination of these strains supported the erection of a new species, Komarekiella delphini-convector. A prior study determined that the dolphin with the epidermal mat had low levels of microcystins/nodularins (MCs/NODs) in the hepatic tissue. To investigate whether these toxins originated from the epidermal mat, immunoassay (ELISA) and 2-methyl-3-methoxy-4-phenylbutyric acid (MMPB) techniques were conducted on the original mat and subsequent culture samples. The results from both analyses were not conclusive. Genome mining was conducted and revealed diverse biosynthetic capabilities of this species but could not support toxin-producing potential. Further analytical work is required to determine the pathogenic capacity of this epizoic species

Falls Assessment Clinical Trial (FACT): design, interventions, recruitment strategies and participant characteristics

<p>Abstract</p> <p>Background</p> <p>Guidelines recommend multifactorial intervention programmes to prevent falls in older adults but there are few randomised controlled trials in a real life health care setting. We describe the rationale, intervention, study design, recruitment strategies and baseline characteristics of participants in a randomised controlled trial of a multifactorial falls prevention programme in primary health care.</p> <p>Methods</p> <p>Participants are patients from 19 primary care practices in Hutt Valley, New Zealand aged 75 years and over who have fallen in the past year and live independently. Two recruitment strategies were used – waiting room screening and practice mail-out. Intervention participants receive a community based nurse assessment of falls and fracture risk factors, home hazards, referral to appropriate community interventions, and strength and balance exercise programme. Control participants receive usual care and social visits. Outcome measures include number of falls and injuries over 12 months, balance, strength, falls efficacy, activities of daily living, quality of life, and physical activity levels.</p> <p>Results</p> <p>312 participants were recruited (69% women). Of those who had fallen, 58% of people screened in the practice waiting rooms and 40% when screened by practice letter were willing to participate. Characteristics of participants recruited using the two methods are similar (p > 0.05). Mean age of all participants was 81 years (SD 5). On average participants have 7 medical conditions, take 5.5 medications (29% on psychotropics) with a median of 2 falls (interquartile range 1, 3) in the previous year.</p> <p>Conclusion</p> <p>The two recruitment strategies and the community based intervention delivery were feasible and successful, identifying a high risk group with multiple falls. Recruitment in the waiting room gave higher response rates but was less efficient than practice mail-out. Testing the effectiveness of an evidence based intervention in a 'real life' setting is important.</p> <p>Trial registration</p> <p>Australian Clinical Trials Register ID 12605000054617.</p