Further investigation of confirmed urinary tract infection (UTI) in children under five years: a systematic review.

Background: Further investigation of confirmed UTI in children aims to prevent renal scarring and future complications. Methods: We conducted a systematic review to determine the most effective approach to the further investigation of confirmed urinary tract infection (UTI) in children under five years of age. Results: 73 studies were included. Many studies had methodological limitations or were poorly reported. Effectiveness of further investigations: One study found that routine imaging did not lead to a reduction in recurrent UTIs or renal scarring. Diagnostic accuracy: The studies do not support the use of less invasive tests such as ultrasound as an alternative to renal scintigraphy, either to rule out infection of the upper urinary tract (LR- = 0.57, 95%CI: 0.47, 0.68) and thus to exclude patients from further investigation or to detect renal scarring (LR+ = 3.5, 95% CI: 2.5, 4.8). None of the tests investigated can accurately predict the development of renal scarring. The available evidence supports the consideration of contrast-enhanced ultrasound techniques for detecting vesico-ureteric reflux (VUR), as an alternative to micturating cystourethrography (MCUG) (LR+ = 14.1, 95% CI: 9.5, 20.8; LR- = 0.20, 95%CI: 0.13, 0.29); these techniques have the advantage of not requiring exposure to ionising radiation. Conclusion: There is no evidence to support the clinical effectiveness of routine investigation of children with confirmed UTI. Primary research on the effectiveness, in terms of improved patient outcome, of testing at all stages in the investigation of confirmed urinary tract infection is urgently required

Effect of pathology type and severity on the distribution of MRI signal intensities within the degenerated nucleus pulposus: application to idiopathic scoliosis and spondylolisthesis

<p>Abstract</p> <p>Background</p> <p>Disc degeneration is characterized by a loss of cellularity, degradation of the extracellular matrix, and, as a result, morphological changes and biomechanical alterations. We hypothesized that the distribution of the MR signal intensity within the nucleus zone of the intervertebral disc was modified according to the pathology and the severity of the pathology. The objective of this study was to propose new parameters characterizing the distribution of the signal intensity within the nucleus zone of lumbar intervertebral discs, and to quantify these changes in patients suffering from spondylolisthesis or idiopathic scoliosis.</p> <p>Methods</p> <p>A retrospective study had been performed on T2-weighted MR images of twenty nine patients suffering from spondylolisthesis and/or scoliosis. The high intensity zone of the nucleus pulposus was semi-automatically detected. The distance "DX" between the center weighted by the signal intensity and the geometrical center was quantified. The sum of the signal intensity on the axis perpendicular to the longitudinal axis of the disc was plotted for each position of the longitudinal axis allowing defining the maximum sum "SM" and its position "PSM".</p> <p>Results</p> <p>"SM" was clearly higher and "PSM" was more shifted for scoliosis than for spondylolisthesis. A two-way analysis of variance showed that the differences observed on "DX" were not attributed to the pathology nor its severity, the differences observed on "SM" were attributed to the pathology but not to its severity, and the differences observed on "PSM" were attributed to both the pathology and its severity.</p> <p>Conclusions</p> <p>The technique proposed in this study showed significant differences in the distribution of the MR signal intensity within the nucleus zone of intervertebral discs due to the pathology and its severity. The dependence of the "PSM" parameter to the severity of the pathology suggests this parameter as a predictive factor of the pathology progression. This new technique should be useful for the early diagnosis of intervertebral disc pathologies as it highlights abnormal patterns in the MRI signal for low severity of the pathology.</p

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Explosive volcanism on the ultraslow-spreading Gakkel ridge, Arctic Ocean

Author Posting. © Nature Publishing Group, 2008. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 453 (2008): 1236-1238, doi:10.1038/nature07075.Roughly 60% of the Earth’s outer surface is comprised of oceanic crust formed by volcanic processes at mid-ocean ridges (MORs). Although only a small fraction of this vast volcanic terrain has been visually surveyed and/or sampled, the available evidence suggests that explosive eruptions are rare on MORs, particularly at depths below the critical point for steam (3000 m). A pyroclastic deposit has never been observed on the seafloor below 3000 m, presumably because the volatile content of mid-ocean ridge basalts is generally too low to produce the gas fractions required to fragment a magma at such high hydrostatic pressure. We employed new deep submergence technologies during an International Polar Year expedition to the Gakkel Ridge in the Arctic Basin at 85°E, to acquire the first-ever photographic images of ‘zero-age’ volcanic terrain on this remote, ice-covered MOR. Our imagery reveals that the axial valley at 4000 m water depth is blanketed with unconsolidated pyroclastic deposits, including bubble wall fragments (limu o Pele), covering a large area greater than 10 km2. At least 13.5 wt% CO2 is required to fragment magma at these depths, which is ~10x greater than the highest values measured to-date in a MOR basalt. These observations raise important questions regarding the accumulation and discharge of magmatic volatiles at ultra-slow spreading rates on the Gakkel Ridge (6- 14 mm yr-1, full-rate), and demonstrate that large-scale pyroclastic activity is possible along even the deepest portions of the global MOR volcanic system.This research was funded by the National Aeronautics and Space Administration, the National Science Foundation, and the Woods Hole Oceanographic Institution

A study protocol for the evaluation of occupational mutagenic/carcinogenic risks in subjects exposed to antineoplastic drugs: a multicentric project

<p>Abstract</p> <p>Background</p> <p>Some industrial hygiene studies have assessed occupational exposure to antineoplastic drugs; other epidemiological investigations have detected various toxicological effects in exposure groups labeled with the job title. In no research has the same population been studied both environmentally and epidemiologically. The protocol of the epidemiological study presented here uses an integrated environmental and biological monitoring approach. The aim is to assess in hospital nurses preparing and/or administering therapy to cancer patients the current level of occupational exposure to antineoplastic drugs, DNA and chromosome damage as cancer predictive effects, and the association between the two.</p> <p>Methods/Design</p> <p>About 80 healthy non-smoking female nurses, who job it is to prepare or handle antineoplastic drugs, and a reference group of about 80 healthy non-smoking female nurses not occupationally exposed to chemicals will be examined simultaneously in a cross-sectional study. All the workers will be recruited from five hospitals in northern and central Italy after their informed consent has been obtained.</p> <p>Evaluation of surface contamination and dermal exposure to antineoplastic drugs will be assessed by determining cyclophosphamide on selected surfaces (wipes) and on the exposed nurses' clothes (pads). The concentration of unmetabolized cyclophosphamide as a biomarker of internal dose will be measured in end-shift urine samples from exposed nurses.</p> <p>Biomarkers of effect and susceptibility will be assessed in exposed and unexposed nurses: urinary concentration of 8-hydroxy-2-deoxyguanosine; DNA damage detected using the single-cell microgel electrophoresis (comet) assay in peripheral white blood cells; micronuclei and chromosome aberrations in peripheral blood lymphocytes. Genetic polymorphisms for enzymes involved in metabolic detoxification (i.e. glutathione <it>S</it>-transferases) will also be analysed.</p> <p>Using standardized questionnaires, occupational exposure will be determined in exposed nurses only, whereas potential confounders (medicine consumption, lifestyle habits, diet and other non-occupational exposures) will be assessed in both groups of hospital workers.</p> <p>Statistical analysis will be performed to ascertain the association between occupational exposure to antineoplastic drugs and biomarkers of DNA and chromosome damage, after taking into account the effects of individual genetic susceptibility, and the presence of confounding exposures.</p> <p>Discussion</p> <p>The findings of the study will be useful in updating prevention procedures for handling antineoplastic drugs.</p

Identification of β-Secretase (BACE1) Substrates Using Quantitative Proteomics

β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease with a lumenal active site that sheds the ectodomains of membrane proteins through juxtamembrane proteolysis. BACE1 has been studied principally for its role in Alzheimer's disease as the β-secretase responsible for generating the amyloid-β protein. Emerging evidence from mouse models has identified the importance of BACE1 in myelination and cognitive performance. However, the substrates that BACE1 processes to regulate these functions are unknown, and to date only a few β-secretase substrates have been identified through candidate-based studies. Using an unbiased approach to substrate identification, we performed quantitative proteomic analysis of two human epithelial cell lines stably expressing BACE1 and identified 68 putative β-secretase substrates, a number of which we validated in a cell culture system. The vast majority were of type I transmembrane topology, although one was type II and three were GPI-linked proteins. Intriguingly, a preponderance of these proteins are involved in contact-dependent intercellular communication or serve as receptors and have recognized roles in the nervous system and other organs. No consistent sequence motif predicting BACE1 cleavage was identified in substrates versus non-substrates. These findings expand our understanding of the proteins and cellular processes that BACE1 may regulate, and suggest possible mechanisms of toxicity arising from chronic BACE1 inhibition

Interaction of microtubules and actin during the post-fusion phase of exocytosis

Exocytosis is the intracellular trafficking step where a secretory vesicle fuses with the plasma membrane to release vesicle content. Actin and microtubules both play a role in exocytosis; however, their interplay is not understood. Here we study the interaction of actin and microtubules during exocytosis in lung alveolar type II (ATII) cells that secrete surfactant from large secretory vesicles. Surfactant extrusion is facilitated by an actin coat that forms on the vesicle shortly after fusion pore opening. Actin coat compression allows hydrophobic surfactant to be released from the vesicle. We show that microtubules are localized close to actin coats and stay close to the coats during their compression. Inhibition of microtubule polymerization by colchicine and nocodazole affected the kinetics of actin coat formation and the extent of actin polymerisation on fused vesicles. In addition, microtubule and actin cross-linking protein IQGAP1 localized to fused secretory vesicles and IQGAP1 silencing influenced actin polymerisation after vesicle fusion. This study demonstrates that microtubules can influence actin coat formation and actin polymerization on secretory vesicles during exocytosis