Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study

Background Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/FLAIR-weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. Methods We included 20 consecutive adults with newly-diagnosed non-enhancing (seven diffuse astrocytomas, IDH-mutant; one oligodendroglioma, IDH-mutant and1p/19q-codeleted; one glioblastoma IDH-wildtype) or enhancing glioma (glioblastoma, nine IDH-wildtype and two IDH-mutant). Standardized pre-operative imaging (T1-, T2-, FLAIR-weighted and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multi-region stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by two neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. Results A total of 174 biopsies were obtained (63 from nine non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of Apparent Diffusion Coefficient (ADC) with [18F]FET PET (AUC, 95%CI: 0.89,0.79-0.99) detected tumor better than T1G MRI (0.56,0.39-0.72;P<.001) and [18F]FET PET (0.76,0.66-0.86;P=0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65-0.98) compared to 0.69 (0.56-0.81;P=0.019) for [18F]FET PET. Conclusion and relevance Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy

Impact of the population at risk of diabetes on projections of diabetes burden in the United States: an epidemic on the way

AIMS/HYPOTHESIS: The aim of this study was to make projections of the future diabetes burden for the adult US population based in part on the prevalence of individuals at high risk of developing diabetes. MATERIALS AND METHODS: Models were created from data in the nationally representative National Health and Nutrition Examination Survey (NHANES) II mortality survey (1976–1992), the NHANES III (1988–1994) and the NHANES 1999–2002. Population models for adults (>20 years of age) from NHANES III data were fitted to known diabetes prevalence in the NHANES 1999–2002 before making future projections. We used a multivariable diabetes risk score to estimate the likelihood of diabetes incidence in 10 years. Estimates of future diabetes (diagnosed and undiagnosed) prevalence in 2011, 2021, and 2031 were made under several assumptions. RESULTS: Based on the multivariable diabetes risk score, the number of adults at high risk of diabetes was 38.4 million in 1991 and 49.9 million in 2001. The total diabetes burden is anticipated to be 11.5% (25.4 million) in 2011, 13.5% (32.6 million) in 2021, and 14.5% (37.7 million) in 2031. Among individuals aged 30 to 39 years old who are not currently targeted for screening according to age, the prevalence of diabetes is expected to rise from 3.7% in 2001 to 5.2% in 2031. By 2031, 20.2% of adult Hispanic individuals are expected to have diabetes. CONCLUSIONS/INTERPRETATION: The prevalence of diabetes is projected to rise to substantially greater levels than previously estimated. Diabetes prevalence within the Hispanic community is projected to be potentially overwhelming. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00125-006-0528-5 and is accessible to authorized users

Spatial concordance of DNA methylation classification in diffuse glioma

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists

Molecular, morphological and acoustic identification of Eumops maurus and Eumops hansae (Chiroptera: Molossidae) with new reports from Central Amazonia

Eumops maurus and Eumops hansae are rarely captured Neotropical molossid bats for which information on taxonomy, natural history, and spatial distribution are scarce. This translates into a poor understanding of their ecology and limits the delimitation of useful characters for their identification. Here, we describe records of these two molossids from the Central Brazilian Amazon, providing data on their external and craniodental morphology, DNA barcode (COI) sequences complemented by acoustic data for the species. Morphological characters, DNA sequence data and phylogenetic relationships within the genus Eumops were consistent with those previously described for both species. Echolocation call characteristics did not differ significantly so as to be useful for separating E. maurus and E. hansae from other congeners. Our records are, respectively the first and the second for Central Amazonia as one individual previously attributed to Eumops amazonicus from Manaus may be considered a junior synonym for E. hansae. These new records increase the extent of the species’ known ranges, partially filling in previous existing gaps in their distribution in central South America. Our data further suggest that these molossid bats forage in a wider range of habitats than previously thought

Norovirus infections in children under 5 years of age hospitalized due to the acute viral gastroenteritis in northeastern Poland

The primary aim of this study was to evaluate the frequency and seasonality of norovirus infection in hospitalized Polish children under 5 years of age, and a secondary aim was to compare the clinical severity of norovirus and rotavirus disease. The prospective surveillance study was carried out from July 2009 through June 2010. Stool samples from 242 children hospitalized due to acute viral gastroenteritis were tested for rotavirus group A and adenovirus with commercial immunochromatographic test and for norovirus with EIA assay. Single norovirus infection was found in 35/242 (14.5%) patients and in a further 5 (2.1%) children as co-infection with rotavirus. Overall, norovirus was detected in 16.5% of stool specimens. Norovirus infections tended to peak from October to November and again from February to March. In autumn months and in February, the proportion of norovirus gastroenteritis cases was equal or even surpassed those of rotavirus origin. Both norovirus and rotavirus infections most commonly affected children between 12 and 23 months of age. The low-grade or no fever was significantly more common in children infected with norovirus (94.3%) compared to rotavirus cases (52.9%). Overall, norovirus gastroenteritis was less severe than rotavirus disease with regard to 20-point severity scale (p < 0.05). Noroviruses have emerged as a relevant cause of acute gastroenteritis in Polish children. There is a great need for introducing routine norovirus testing of hospitalized children with gastroenteritis

In Situ Enzyme Activity in the Dissolved and Particulate Fraction of the Fluid from Four Pitcher Plant Species of the Genus Nepenthes

The genus Nepenthes, a carnivorous plant, has a pitcher to trap insects and digest them in the contained fluid to gain nutrient. A distinctive character of the pitcher fluid is the digestive enzyme activity that may be derived from plants and dwelling microbes. However, little is known about in situ digestive enzymes in the fluid. Here we examined the pitcher fluid from four species of Nepenthes. High bacterial density was observed within the fluids, ranging from 7×106 to 2.2×108 cells ml−1. We measured the activity of three common enzymes in the fluid: acid phosphatases, β-d-glucosidases, and β-d-glucosaminidases. All the tested enzymes detected in the liquid of all the pitcher species showed activity that considerably exceeded that observed in aquatic environments such as freshwater, seawater, and sediment. Our results indicate that high enzyme activity within a pitcher could assist in the rapid decomposition of prey to maximize efficient nutrient use. In addition, we filtered the fluid to distinguish between dissolved enzyme activity and particle-bound activity. As a result, filtration treatment significantly decreased the activity in all enzymes, while pH value and Nepenthes species did not affect the enzyme activity. It suggested that enzymes bound to bacteria and other organic particles also would significantly contribute to the total enzyme activity of the fluid. Since organic particles are themselves usually colonized by attached and highly active bacteria, it is possible that microbe-derived enzymes also play an important role in nutrient recycling within the fluid and affect the metabolism of the Nepenthes pitcher plant

Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate

Background: Multi drug resistance (MDR) or cross-resistance to multiple classes of chemotherapeutic agents is a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are an important determinant of MDR. Therefore, there is an urgent need for development of novel compounds that are not substrates of P-glycoprotein and are effective against drug-resistant cancer. Methodology/Principal Findings: In this present study, we have synthesized a novel, redox active Fe (II) complex (chelate), iron N- (2-hydroxy acetophenone) glycinate (FeNG). The structure of the complex has been determined by spectroscopic means. To evaluate the cytotoxic effect of FeNG we used doxorubicin resistant and/or sensitive T lymphoblastic leukemia cells and show that FeNG kills both the cell types irrespective of their MDR phenotype. Moreover, FeNG induces apoptosis in doxorubicin resistance T lymphoblastic leukemia cell through mitochondrial pathway via generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyle-cysteine (NAC) could completely block ROS generation and, subsequently, abrogated FeNG induced apoptosis. Therefore, FeNG induces the doxorubicin resistant T lymphoblastic leukemia cells to undergo apoptosis and thus overcome MDR. Conclusion/Significance: Our study provides evidence that FeNG, a redox active metal chelate may be a promising ne

Adenoviral gene transfer of angiostatic ATF-BPTI inhibits tumour growth

BACKGROUND: The outgrowth of new vessels – angiogenesis – in the tumour mass is considered to be a limiting factor of tumour growth. To inhibit the matrix lysis that is part of the tumour angiogenesis, we employed the chimeric protein mhATF-BPTI, composed of the receptor binding part of the urokinase (ATF) linked to an inhibitor of plasmin (BPTI). METHODS: For delivery, recombinant adenovirus encoding the transgene of interest was injected intravenously or locally into the tumour. The anti tumour effect of this compound was compared to that of human endostatin and of mhATF alone in two different rat bronchial carcinomas growing either as subcutaneous implants or as metastases. RESULTS: Significant inhibition of the tumour growth and decrease of the number of lung metastasis was achieved when the concentration of mhATF-BPTI at the tumour site was above 400 of ng / g tissue. This concentration could be achieved via production by the liver, only if permissive to the recombinant adenovirus. When the tumour cells could be transduced, local delivery of the vector was enough to obtain a response. In the case of metastasis, the capacity of the lung tissue to concentrate the encoded protein was essential to reach the required therapeutic levels. Further, endostatin or mhATF could not reproduce the effects of mhATF-BPTI, at similar concentrations (mhATF) and even at 10-fold higher concentration (endostatin). CONCLUSION: The ATF-BPTI was shown to inhibit tumour growth of different rat lung tumours when critical concentration was reached. In these tumour models, endostatin or ATF induce almost no tumour response

Integrated high-content quantification of intracellular ROS levels and mitochondrial morphofunction

Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-contentmicroscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow, and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells