Sequential extracellular matrix-focused and baited-global cluster analysis of serial transcriptomic profiles identifies candidate modulators of renal tubulointerstitial fibrosis in murine adriamycin-induced nephropathy

Transcriptome analysis using microarray technology represents a powerful unbiased approach for delineating pathogenic mechanisms in disease. Here molecular mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring changes in the renal transcriptome in a glomerular disease-dependent model of TIF ( adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with sequential primary biological function-focused and secondary

Children's serial recall errors: Implications for theories of short-term memory development

Three experiments examined developmental changes in serial recall of lists of 6 letters, with errors classified as movements, omissions, intrusions, or repetitions. In Experiments 1 and 2, developmental differences between groups of children aged from 7 to 11 years and adults were found in the pattern of serial recall errors. The errors of older participants were more likely to be movements than were those of younger participants, who made more intrusions and omissions. The number of repetition errors did not change with age, and this finding is interpreted in terms of a developmentally invariant postoutput response inhibition process. This interpretation was supported by the findings of Experiment 3, which measured levels of response inhibition in 7-, 9-, and 11-year-olds by comparing recall of lists with and without repeated items. Response inhibition remained developmentally invariant, although older children showed greater response facilitation (improved correct recall of adjacent repeated items). Group differences in the patterns of other errors are accounted for in terms of developmental changes in levels of output forgetting and changes in the efficiency of temporal encoding processes, (C) 2000 Academic Press.

PCR amplification of short tandem repeat sequences allows serial studies of chimaerism/engraftment following BMT in rodents

Animal models of bone marrow transplantation (BMT) allow evaluation of new experimental treatment strategies. One potential strategy involves the treatment of donor marrow with ultra-violet B light to allow transplantation across histocompatibility boundaries without an increase in graft rejection or graft-versus-host disease. A major requirement for a new experimental protocol, particularly if it involves manipulation of the donor marrow, is that the manipulated marrow gives rise to long-term multilineage engraftment. DNA based methodologies are now routinely used by many centres to evaluate engraftment and degree of chimaerism post-BMT in humans. We report the adaptation of this methodology to the serial study of engraftment in rodents. Conditions have been defined which allow analysis of serial tail vein samples using PCR of short tandem repeat sequences (STR-PCR). These markers have been used to evaluate the contribution of ultraviolet B treated marrow to engraftment following BMT in rodents without compromising the health of the animals under study. Chimaerism data from sequential tail vein samples and bone marrow from selected sacrificed animals showed excellent correlation, thus confirming the validity of this approach in analysing haemopoietic tissue. Thus the use of this assay may facilitate experimental studies in animal BMT.

Probed serial recall in Williams syndrome: Lexical influences on phonological short-term memory

Williams syndrome is a genetic disorder that, it has been claimed, results in an unusual pattern of linguistic strengths and weaknesses. The current study investigated the hypothesis that there is a reduced influence of lexical knowledge on phonological short-term memory in Williams syndrome. Fourteen children with Williams syndrome and 2 vocabulary la matched control groups, 20 typically developing children and 13 children with learning difficulties, were tested on 2 probed serial-recall tasks. On the basis of previous findings, it was predicted that children with Williams syndrome would demonstrate (a) a reduced effect of lexicality on the recall of list items, (b) relatively poorer recall of list items compared with recall of serial order, and (c) a reduced tendency to produce lexicalization errors in the recall of nonwords. in fact, none of these predictions were supported. Alternative explanations for previous findings and implications for accounts of language development in Williams syndrome are discussed.

Quantification of all-ceramic crown margin surface profile from try-in to 1-week post-cementation

To use profilometry to assess the margin surface profile of all-ceramic crowns (ACC’s) at try-in and 1-week after cementation with dual-cured resin (DC, RelyX ARC, 3 M ESPE, St. Paul, MN, USA), self-adhesive dual-cured resin (SADC, RelyX Unicem, 3 M ESPE), light-cured resin (LC, RelyX Veneer, 3 M ESPE) or chemically cured resin-modified glass ionomer (RMGI, RelyX Luting Plus, 3 M ESPE) luting cement. Methods: Forty, sound, extracted, human, premolar teeth underwent a standardised preparation for ACC’s. IPS Empress (Ivoclar-Vivadent, Liechtenstein) crowns of standard dimensions were fabricated and 10 luted with each cement and stored in water for 7 days. Three groups of serial profiles were taken, the first of the tooth preparation, the second of the crown margins at try-in and lastly of the crown margins after cementation and 7 days water storage. Results: There were no significant differences in the crown margin surface profile between the four cement groups at try-in. The change in crown margin position between try-in and post-cementation was significantly greater for DC than for LC and RMGI. SADC was not significantly different to the other cements. There were no significant differences in the crown margin extensions between the four cement groups, however most of the IPS Empress ACC’s in this study were underextended but this was not statistically significant. Conclusions: IPS Empress ACC’s seated more fully with LC and RMGI than with DC cement

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms:a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Progression of left atrial volume index in a population at risk for heart failure:a substudy of the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) trial

AIMS: Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre-heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation.

METHODS AND RESULTS: This was a prospective substudy within the framework of the STOP-HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow-up time between assessments was 15 ± 6 months. 'Progressors' (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m(2) (and baseline LAVI between 20 and 34 mL/m(2)). This cut-off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta-blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 'Progressors' matched to 30 'Non-progressors'. For 'Progressors', relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05).

CONCLUSION: Accelerated LAVI increase was found to occur in up to 14% of all pre-HF patients undergoing serial echocardiograms over a relatively short follow-up period. In a randomly selected subcohort of 'Progressors', changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at-risk group.

Before the “Comics:” On the Seriality of Graphic Narratives during the Nineteenth Century

While the connection between seriality and comics in the twentieth century has frequently been a subject of study, far less attention has been paid to the role of serialisation in the previous century, when the language of comics gradually developed in the illustrated and satirical press. This article discusses a heterogeneous group of graphic narratives published in various European countries between the 1830s and the 1880s, before a new generation of comic magazines influenced by American newspaper strips transformed this emerging field into the autonomous medium of comics. Serial works flourished during this period and included diverse modes, such as series of “graphic novels,” the use of recurring characters, the serialisation of picture stories in humour periodicals, and the use of graphic narratives as a regular feature in the illustrated news magazines. By providing a panoramic survey of various types of serial texts, the article suggests that the hybrid nature of these graphic narratives and the publishing strategies applied to them can be better understood if considered in relation to the larger context of nineteenth-century print culture, rather than in comparison with the future of the medium.

The effectiveness of physical activity interventions in socio-economically disadvantaged communities: A systematic review.

OBJECTIVE: Interventions to increase levels of physical activity (PA) in socio-economically disadvantaged communities are needed but little is known about their effectiveness. This review examines the effectiveness of interventions designed to increase PA in these communities and the theoretical frameworks and components used. METHODS: Five databases were searched for papers published in English between January 2000 and December 2010 that reported outcomes of PA interventions in socio-economically disadvantaged communities. Studies targeting individuals with pre-existing disease and not reporting a measure of free-living PA were excluded. Two reviewers independently extracted data and evaluated quality of evidence against pre-defined criteria. RESULTS: Of 478 publications identified, 27 were included. We found that group-based interventions were effective for adults but not for children; evidence for the effectiveness of interventions targeting individuals was insufficient; limited evidence suggested that community-wide interventions produced small changes in PA. Interventions underpinned by any theoretical framework, compared to none, were more likely to be effective. Several effective interventions included education, PA and social support components. CONCLUSION: Compared to other approaches, multi-component adult group-based interventions with theoretical frameworks are most effective in increasing PA in socio-economically disadvantaged communities. More robust evaluations of interventions targeting individuals in these 'hard-to-reach' communities are required. Copyright © 2012. Published by Elsevier Inc.

Surveillance for ocular hypertension: An evidence synthesis and economic evaluation

OBJECTIVES: To determine effective and efficient monitoring criteria for ocular hypertension [raised intraocular pressure (IOP)] through (i) identification and validation of glaucoma risk prediction models; and (ii) development of models to determine optimal surveillance pathways.

DESIGN: A discrete event simulation economic modelling evaluation. Data from systematic reviews of risk prediction models and agreement between tonometers, secondary analyses of existing datasets (to validate identified risk models and determine optimal monitoring criteria) and public preferences were used to structure and populate the economic model.

SETTING: Primary and secondary care.

PARTICIPANTS: Adults with ocular hypertension (IOP > 21 mmHg) and the public (surveillance preferences).

INTERVENTIONS: We compared five pathways: two based on National Institute for Health and Clinical Excellence (NICE) guidelines with monitoring interval and treatment depending on initial risk stratification, 'NICE intensive' (4-monthly to annual monitoring) and 'NICE conservative' (6-monthly to biennial monitoring); two pathways, differing in location (hospital and community), with monitoring biennially and treatment initiated for a ≥ 6% 5-year glaucoma risk; and a 'treat all' pathway involving treatment with a prostaglandin analogue if IOP > 21 mmHg and IOP measured annually in the community.

MAIN OUTCOME MEASURES: Glaucoma cases detected; tonometer agreement; public preferences; costs; willingness to pay and quality-adjusted life-years (QALYs).

RESULTS: The best available glaucoma risk prediction model estimated the 5-year risk based on age and ocular predictors (IOP, central corneal thickness, optic nerve damage and index of visual field status). Taking the average of two IOP readings, by tonometry, true change was detected at two years. Sizeable measurement variability was noted between tonometers. There was a general public preference for monitoring; good communication and understanding of the process predicted service value. 'Treat all' was the least costly and 'NICE intensive' the most costly pathway. Biennial monitoring reduced the number of cases of glaucoma conversion compared with a 'treat all' pathway and provided more QALYs, but the incremental cost-effectiveness ratio (ICER) was considerably more than £30,000. The 'NICE intensive' pathway also avoided glaucoma conversion, but NICE-based pathways were either dominated (more costly and less effective) by biennial hospital monitoring or had a ICERs > £30,000. Results were not sensitive to the risk threshold for initiating surveillance but were sensitive to the risk threshold for initiating treatment, NHS costs and treatment adherence.

LIMITATIONS: Optimal monitoring intervals were based on IOP data. There were insufficient data to determine the optimal frequency of measurement of the visual field or optic nerve head for identification of glaucoma. The economic modelling took a 20-year time horizon which may be insufficient to capture long-term benefits. Sensitivity analyses may not fully capture the uncertainty surrounding parameter estimates.

CONCLUSIONS: For confirmed ocular hypertension, findings suggest that there is no clear benefit from intensive monitoring. Consideration of the patient experience is important. A cohort study is recommended to provide data to refine the glaucoma risk prediction model, determine the optimum type and frequency of serial glaucoma tests and estimate costs and patient preferences for monitoring and treatment.

FUNDING: The National Institute for Health Research Health Technology Assessment Programme.

The quality of reporting of diagnostic accuracy studies in glaucoma using the Heidelberg retina tomograph

PURPOSE. Scanning laser tomography with the Heidelberg retina tomograph (HRT; Heidelberg Engineering, Heidelberg, Germany) has been proposed as a useful diagnostic test for glaucoma. This study was conducted to evaluate the quality of reporting of published studies using the HRT for diagnosing glaucoma. METHODS. A validated Medline and hand search of English-language articles reporting on measures of diagnostic accuracy of the HRT for glaucoma was performed. Two reviewers selected and appraised the papers independently. The Standards for Reporting of Diagnostic Accuracy (STARD) checklist was used to evaluate the quality of each publication. RESULTS. A total of 29 articles were included. Interobserver rating agreement was observed in 83% of items (? = 0.76). The number of STARD items properly reported ranged from 5 to 18. Less than a third of studies (7/29) explicitly reported more than half of the STARD items. Descriptions of key aspects of the methodology were frequently missing. For example, the design of the study (prospective or retrospective) was reported in 6 of 29 studies, and details of participant sampling (e.g., consecutive or random selection) were described in 5 of 29 publications. The commonest description of diagnostic accuracy was sensitivity and specificity (25/29) followed by area under the ROC curve (13/29), with 9 of 29 publications reporting both. CONCLUSIONS. The quality of reporting of diagnostic accuracy tests for glaucoma with HRT is suboptimal. The STARD initiative may be a useful tool for appraising the strengths and weaknesses of diagnostic accuracy studies. Copyright © Association for Research in Vision and Ophthalmology.

The quality of reporting of diagnostic accuracy studies published in ophthalmic journals

Aim: To evaluate the quality of reporting of all diagnostic studies published in five major ophthalmic journals in the year 2002 using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative parameters. Methods: Manual searching was used to identify diagnostic studies published in 2002 in five leading ophthalmic journals, the American Journal of Ophthalmology (AJO), Archives of Ophthalmology (Archives), British Journal of Ophthalmology (BJO), Investigative Ophthalmology and Visual Science (IOVS), and Ophthalmology. The STARD checklist of 25 items and flow chart was used to evaluate the quality of each publication. Results: A total of 16 publications were included (AJO = 5, Archives = 1, BJO = 2, IOVS = 2, and Ophthalmology = 6). More than half of the studies (n = 9) were related to glaucoma diagnosis. Other specialties included retina (n = 4) cornea (n = 2), and neuro-ophthalmology (n = 1). The most common description of diagnostic accuracy was sensitivity and specificity values, published in 13 articles. The number of fully reported items in evaluated studies ranged from eight to 19. Seven studies reported more than 50% of the STARD items. Conclusions: The current standards of reporting of diagnostic accuracy tests are highly variable. The STARD initiative may be a useful tool for appraising the strengths and weaknesses of diagnostic accuracy studies.

The Quality of Reporting of Diagnostic Accuracy Studies of Optical Coherence Tomography in Glaucoma

Objective: To evaluate the quality of reporting of diagnostic accuracy studies using optical coherence tomography (OCT) in glaucoma. Design: Descriptive series of published studies. Participants: Published studies reporting a measure of the diagnostic accuracy of OCT for glaucoma. Methods: Review of English language papers reporting measures of diagnostic accuracy of OCT for glaucoma. Papers were identified from a Medline literature search performed in June 2006. Articles were appraised using the 25 items provided by the Standards for Reporting of Diagnostic Accuracy (STARD) initiative. Each item was recorded as full, partially, or not reported. Main Outcome Measures: Degree of compliance with the STARD guidelines. Results: Thirty papers were appraised. Eight papers (26.7%) fully reported more than half of the STARD items. The lowest number of fully reported items in a study was 5 and the highest was 17. Descriptions of key aspects of methodology frequently were missing. For example, details of participant sampling (e.g., consecutive or random selection) were described in only 8 (26.7%) of 30 publications. Measures of statistical uncertainty were reported in 18 (60%) of 30 publications. No single STARD item was fully reported by all the papers. Conclusions: The standard of reporting of diagnostic accuracy studies in glaucoma using OCT was suboptimal. It is hoped that adoption of the STARD guidelines will lead to an improvement in reporting of diagnostic accuracy studies, enabling clearer evidence to be produced for the usefulness of OCT for the diagnosis of glaucoma. © 2007 American Academy of Ophthalmology.