Coronary artery anomalies and variants: technical feasibility of assessment with coronary MR angiography at 3 T.

The purpose of this study was to prospectively use a whole-heart three-dimensional (3D) coronary magnetic resonance (MR) angiography technique specifically adapted for use at 3 T and a parallel imaging technique (sensitivity encoding) to evaluate coronary arterial anomalies and variants (CAAV). This HIPAA-compliant study was approved by the local institutional review board, and informed consent was obtained from all participants. Twenty-two participants (11 men, 11 women; age range, 18-62 years) were included. Ten participants were healthy volunteers, whereas 12 participants were patients suspected of having CAAV. Coronary MR angiography was performed with a 3-T MR imager. A 3D free-breathing navigator-gated and vector electrocardiographically-gated segmented k-space gradient-echo sequence with adiabatic T2 preparation pulse and parallel imaging (sensitivity encoding) was used. Whole-heart acquisitions (repetition time msec/echo time msec, 4/1.35; 20 degrees flip angle; 1 x 1 x 2-mm acquired voxel size) lasted 10-12 minutes. Mean examination time was 41 minutes +/- 14 (standard deviation). Findings included aneurysms, ectasia, arteriovenous fistulas, and anomalous origins. The 3D whole-heart acquisitions developed for use with 3 T are feasible for use in the assessment of CAAV.

Neuromotor development in children. Part 3: motor performance in 3- to 5-year-olds.

AIM: The aim of this cross-sectional study was to provide normative data (ordinal scores and timed performances) for gross and fine motor tasks in typically developing children between 3 and 5 years of age using the Zurich Neuromotor Assessment (ZNA). METHOD: Typically developing children (n=101; 48 males, 53 females) between 3 and 5 years of age were enrolled from day-care centres in the greater Zurich area and tested using a modified version of the ZNA; the tests were recorded digitally on video. Intraobserver reliability was assessed on the videos of 20 children by one examiner. Interobserver reliability was assessed by two examiners. Test-retest reliability was performed on an additional 20 children. The modelling approach summarized the data with a linear age effect and an additive term for sex, while incorporating informative missing data in the normative values. Normative data for adaptive motor tasks, pure motor tasks, and static and dynamic balance were calculated with centile curves (for timed performance) and expected ordinal scores (for ordinal scales). RESULTS: Interobserver, intraobserver, and test-retest reliability of tasks were moderate to good. Nearly all tasks showed significant age effects, whereas sex was significant only for stringing beads and hopping on one leg. INTERPRETATION: These results indicate that timed performance and ordinal scales of neuromotor tasks can be reliably measured in preschool children and are characterized by developmental change and high interindividual variability.

New developments in laboratory monitoring of HIV-1 infection.

The laboratory tests currently available to the clinician for day-to-day management of HIV infection are generally limited to the measurement of the viral load and of the CD4 cell count. More recently, analysis of drug resistance and of plasma drug levels have been added to the monitoring armamentarium. There are, however, numerous other techniques currently available to researchers that may in the future be incorporated into clinical routine. These include the analysis of human and viral genetic determinants of disease evolution, detailed analyses of immune recovery and reserve, pharmacogenetic determinants of treatment response, and toxicity. These approaches may in the future provide highly individualized disease management.

Identification of a Poor-Prognosis BRAF-Mutant-Like Population of Patients With Colon Cancer.

PURPOSE Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications. Materials and METHODS A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression-based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors. Results A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class. CONCLUSION A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.

Maintenance of biodiversity in vineyard-dominated landscapes: a case study on larval salamanders

Alteration of natural habitats as a result of agricultural intensification is detrimental for wildlife. There is, however, growing evidence that land use and management can be wildlife friendly. In Europe, agricultural areas cover two-thirds of the land and therefore play a major role in maintaining biodiversity. Agricultural land use is very intense in vineyard-dominated landscapes but there are no refuges for wildlife in the form of ecological compensation areas. In our study, we assessed spatial variation in abundance of salamander (Salamandra salamandra) larvae in relation to land use and stream characteristics in vineyard-dominated landscapes. Abundance of larval salamanders depended positively on weirs, amount of riparian vegetation along the streams and environment-friendly agricultural practice in the vineyards. Surprisingly, road density also had positive effects, presumably through indirect effects (stone walls along roads may serve as refugia). Thus, abundance is determined by characteristics of both the aquatic and terrestrial habitats. Our results suggest that fire salamanders can persist in landscapes dominated by intensive agriculture like viticulture, indicate wildlife-friendly management options and highlight that man-made habitat can be valuable for wildlife.

Management of faecal incontinence and constipation in adults with central neurological diseases.

BACKGROUND: People with neurological disease have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine dividing line between the two conditions, with any management intended to ameliorate, one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical with a limited research base. OBJECTIVES: To determine the effects of management strategies for faecal incontinence and constipation in people with neurological diseases affecting the central nervous system. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Trials Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE and all reference lists of relevant articles. Date of the most recent searches: May 2000. SELECTION CRITERIA: All randomised or quasi-randomised trials evaluating any types of conservative, or surgical measure for the management of faecal incontinence and constipation in people with neurological diseases were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction have also been considered. DATA COLLECTION AND ANALYSIS: All three reviewers assessed the methodological quality of eligible trials and two reviewers independently extracted data from included trials using a range of pre-specified outcome measures. MAIN RESULTS: Only seven trials were identified by the search strategy and all were small and of poor quality. Oral medications for constipation were the subject of four trials. Cisapride does not seem to have clinically useful effects in people with spinal cord injuries (two trials). Psyllium was associated with increased stool frequency in people with Parkinson's disease but not altered colonic transit time (one trial). Some rectal preparations to initiate defecation produced faster results than others (one trial). Different time schedules for administration of rectal medication may produce different bowel responses (one trial). Mechanical evacuation may be more effective than oral or rectal medication (one trial). The clinical significance of any of these results is difficult to interpret. REVIEWER'S CONCLUSIONS: It is not possible to draw any recommendation for bowel care in people with neurological diseases from the trials included in this review. Bowel management for these people must remain empirical until well-designed controlled trials with adequate numbers and clinically relevant outcome measures become available.

HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass.

BACKGROUND: Acute kidney injury (AKI) is common in patients undergoing cardiac surgery among whom it is associated with poor outcomes, prolonged hospital stays and increased mortality. Statin drugs can produce more than one effect independent of their lipid lowering effect, and may improve kidney injury through inhibition of postoperative inflammatory responses. OBJECTIVES: This review aimed to look at the evidence supporting the benefits of perioperative statins for AKI prevention in hospitalised adults after surgery who require cardiac bypass. The main objectives were to 1) determine whether use of statins was associated with preventing AKI development; 2) determine whether use of statins was associated with reductions in in-hospital mortality; 3) determine whether use of statins was associated with reduced need for RRT; and 4) determine any adverse effects associated with the use of statins. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared administration of statin therapy with placebo or standard clinical care in adult patients undergoing surgery requiring cardiopulmonary bypass and reporting AKI, serum creatinine (SCr) or need for renal replacement therapy (RRT) as an outcome were eligible for inclusion. All forms and dosages of statins in conjunction with any duration of pre-operative therapy were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: All authors extracted data independently and assessments were cross-checked by a second author. Likewise, assessment of study risk of bias was initially conducted by one author and then by a second author to ensure accuracy. Disagreements were arbitrated among authors until consensus was reached. Authors from two of the included studies provided additional data surrounding post-operative SCr as well as need for RRT. Meta-analyses were used to assess the outcomes of AKI, SCr and mortality rate. Data for the outcomes of RRT and adverse effects were not pooled. Adverse effects taken into account were those reported by the authors of included studies. MAIN RESULTS: We included seven studies (662 participants) in this review. All except one study was assessed as being at high risk of bias. Three studies assessed atorvastatin, three assessed simvastatin and one investigated rosuvastatin. All studies collected data during the immediate perioperative period only; data collection to hospital discharge and postoperative biochemical data collection ranged from 24 hours to 7 days. Overall, pre-operative statin treatment was not associated with a reduction in postoperative AKI, need for RRT, or mortality. Only two studies (195 participants) reported postoperative SCr level. In those studies, patients allocated to receive statins had lower postoperative SCr concentrations compared with those allocated to no drug treatment/placebo (MD 21.2 µmol/L, 95% CI -31.1 to -11.1). Adverse effects were adequately reported in only one study; no difference was found between the statin group compared to placebo. AUTHORS' CONCLUSIONS: Analysis of currently available data did not suggest that preoperative statin use is associated with decreased incidence of AKI in adults after surgery who required cardiac bypass. Although a significant reduction in SCr was seen postoperatively in people treated with statins, this result was driven by results from a single study, where SCr was considered as a secondary outcome. The results of the meta-analysis should be interpreted with caution; few studies were included in subgroup analyses, and significant differences in methodology exist among the included studies. Large high quality RCTs are required to establish the safety and efficacy of statins to prevent AKI after cardiac surgery.

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification.

PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

Avaliação da dissimilaridade genética em genótipos de bananeira (Musa spp.) via marcadores RAPD

A bananicultura possui grande importância econômica e social. A UENF, por meio do Laboratório de Melhoramento Genético Vegetal iniciou um trabalho de introdução de cultivares de bananeira. Foram introduzidas cultivares com procedência da Embrapa Mandioca e Fruticultura e Embrapa Amazônia Ocidental. O objetivo deste trabalho foi realizar um estudo de diversidade genética entre 21 cultivares e obter a correta identificação de possíveis genótipos introduzidos na UENF. Foram avaliados os seguintes genótipos: Fhia 18, Prata-Anã, UENF 1526, Pacovan, Caipira, Maçã, UENF 1527, Nanicão, Thap Maeo, UENF 1528, UENF 1529, Grande Naine, Ambrósia, Bucaneiro, Calipso, PV42-68, PV42-85, PV42-142, ST12-31, Calcutta e BB da França. A análise de divergência genética foi feita com base na caracterização molecular, utilizando-se da técnica RAPD. Para serem obtidas marcas moleculares RAPD, foram utilizados 31 "primers", gerando um total de 94 marcas totais. Os resultados mostraram que os marcadores moleculares RAPD foram eficazes em revelar a existência de diversidade genética entre os 21 genótipos de bananeira. Na interpretação das análises moleculares, foi utilizado o complemento aritmético do Índice de Jaccard. Com base nas análises de agrupamento hierárquicas UPGMA e o método de otimização de Tocher, essa diversidade pôde ser observada pela presença de genótipos similares e divergentes.

Stability of cognitive performance in children with mild intellectual disability.

AIM: Longitudinal studies that have examined cognitive performance in children with intellectual disability more than twice over the course of their development are scarce. We assessed population and individual stability of cognitive performance in a clinical sample of children with borderline to mild non-syndromic intellectual disability. METHOD: Thirty-six children (28 males, eight females; age range 3-19y) with borderline to mild intellectual disability (Full-scale IQ [FSIQ] 50-85) of unknown origin were examined in a retrospective clinical case series using linear mixed models including at least three assessments with standardized intelligence tests. RESULTS: Average cognitive performance remained remarkably stable over time (high population stability, drop of only 0.38 IQ points per year, standard error=0.39, p=0.325) whereas individual stability was at best moderate (intraclass correlation of 0.58), indicating that about 60% of the residual variation in FSIQ scores can be attributed to between-child variability. Neither sex nor socio-economic status had a statistically significant impact on FSIQ. INTERPRETATION: Although intellectual disability during childhood is a relatively stable phenomenon, individual stability of IQ is only moderate, likely to be caused by test-to-test reliability (e.g. level of child's cooperation, motivation, and attention). Therefore, clinical decisions and predictions should not rely on single IQ assessments, but should also consider adaptive functioning and previous developmental history.

Lipid anchoring of Arabidopsis phototropin 1 to assess the functional significance of receptor internalization: should I stay or should I go?

The phototropin 1 (phot1) blue light receptor mediates a number of adaptive responses, including phototropism, that generally serve to optimize photosynthetic capacity. Phot1 is a plasma membrane-associated protein, but upon irradiation, a fraction is internalized into the cytoplasm. Although this phenomenon has been reported for more than a decade, its biological significance remains elusive. Here, we use a genetic approach to revisit the prevalent hypotheses regarding the functional importance of receptor internalization. Transgenic plants expressing lipidated versions of phot1 that are permanently anchored to the plasma membrane were used to analyse the effect of internalization on receptor turnover, phototropism and other phot1-mediated responses. Myristoylation and farnesylation effectively prevented phot1 internalization. Both modified photoreceptors were found to be fully functional in Arabidopsis, rescuing phototropism and all other phot1-mediated responses tested. Light-mediated phot1 turnover occurred as in the native receptor. Furthermore, our work does not provide any evidence of a role of phot1 internalization in the attenuation of receptor signalling during phototropism. Our results demonstrate that phot1 signalling is initiated at the plasma membrane. They furthermore indicate that release of phot1 into the cytosol is not linked to receptor turnover or desensitization.

Identifying the index lesion with template prostate mapping biopsies.

PURPOSE: The natural history of prostate cancer might be driven by the index lesion. We determined the percent of men in whom the index lesion could be defined using transperineal template prostate mapping biopsies. MATERIALS AND METHODS: Included in study were consecutive men undergoing transperineal template prostate mapping biopsies with biopsies grouped into 20 zones. Men with clinically significant disease in only 1 prostate area were considered to have an identifiable index lesion. We evaluated the impact of using 2 definitions of clinically significant disease (Gleason grade pattern 4 and/or lesion volume 0.5 cc or greater) and 2 clustering rules (stringent and tolerant) to define the index lesion. RESULTS: Included in study were 391 men with a median age of 62 years (IQR 58-67) and a median prostate specific antigen of 6.9 ng/ml (IQR 4.8-10.0). Of the men 269 (69%) were previously diagnosed with prostate cancer. By deploying a median of 1.2 cores per ml (IQR 0.9-1.7) cancer was diagnosed in 82.9% of the men (324 of 391) with a median of 6 positive cores (IQR 2-9), a median maximum cancer core length of 5 mm (IQR 3-8) and a total cancer core length per zone of 7 mm (IQR 3-13). Insignificant disease was found in 26.3% to 42.9% of cases. When a stringent spatial relationship was used to define individual lesions, 44.4% to 54.6% of patients had 1 index lesion and 12.7% to 19.1% had more than 1 area with clinically significant disease. These proportions changed to 46.6% to 59.2% and 10.5% to 14.5%, respectively, when less stringent spatial clustering was applied. CONCLUSIONS: Transperineal template prostate mapping biopsies enable the index lesion to be localized in most men with clinically significant disease. This information may be important to select appropriate candidates for targeted therapy and to plan a tailored treatment strategy in men undergoing radical therapy.

Fluorine MR Imaging of Inflammation in Atherosclerotic Plaque in Vivo.

PURPOSE: To preliminarily test the hypothesis that fluorine 19 ((19)F) magnetic resonance (MR) imaging enables the noninvasive in vivo identification of plaque inflammation in a mouse model of atherosclerosis, with histologic findings as the reference standard. MATERIALS AND METHODS: The animal studies were approved by the local animal ethics committee. Perfluorocarbon (PFC) emulsions were injected intravenously in a mouse model of atherosclerosis (n = 13), after which (19)F and anatomic MR imaging were performed at the level of the thoracic aorta and its branches at 9.4 T. Four of these animals were imaged repeatedly (at 2-14 days) to determine the optimal detection time. Repeated-measures analysis of variance with a Tukey test was applied to determine if there was a significant change in (19)F signal-to-noise ratio (SNR) of the plaques and liver between the time points. Six animals were injected with a PFC emulsion that also contained a fluorophore. As a control against false-positive results, wild-type mice (n = 3) were injected with a PFC emulsion, and atherosclerotic mice were injected with a saline solution (n = 2). The animals were sacrificed after the last MR imaging examination, after which high-spatial-resolution ex vivo MR imaging and bright-field and immunofluorescent histologic examination were performed. RESULTS: (19)F MR signal was detected in vivo in plaques in the aortic arch and its branches. The SNR was found to significantly increase up to day 6 (P < .001), and the SNR of all mice at this time point was 13.4 ± 3.3. The presence of PFC and plaque in the excised vessels was then confirmed both through ex vivo (19)F MR imaging and histologic examination, while no signal was detected in the control animals. Immunofluorescent histologic findings confirmed the presence of PFC in plaque macrophages. CONCLUSION: (19)F MR imaging allows the noninvasive in vivo detection of inflammation in atherosclerotic plaques in a mouse model of atherosclerosis and opens up new avenues for both the early detection of vulnerable atherosclerosis and the elucidation of inflammation mechanisms in atherosclerosis.