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  • 1
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aims : To evaluate the morphological features of 11 cases of breast ductal carcinoma in situ (DCIS) with spindle cells and to propose an approach to distinguish it from benign mimics. The association with neuroendocrine differentiation was also investigated.Methods : Cases of breast DCIS with a spindle cell component diagnosed in the Department of Pathology, Singapore General Hospital, between June 1996 and January 2003, were included in the study. The histological characteristics were documented, and immunohistochemistry for neuroendocrine markers, hormone receptors, cerbB2, smooth muscle actin (SMA) and high-molecular-weight (HMW) cytokeratins, was carried out. Electron microscopy was carried out on reprocessed paraffin-embedded material in three cases.Results : Of 11 women diagnosed with DCIS with spindle cells, four presented with nipple discharge, six with a breast lump, while one was discovered to have a screen detected density. The tumour size ranged from 3 to 41 mm. The proportion of spindle cells varied from 10% to 80% of the in-situ tumour cell population. Nuclear grade was low in seven cases and intermediate in four. Necrosis was observed in two cases. Architectural pattern was papillary in six cases, and mixed in the rest. Microinvasion was present in two cases, with possible microinvasion in another two. Immunohistochemistry for neuroendocrine markers synaptophysin and chromogranin showed positive reactivity for at least one marker in all but three cases; one of these latter cases demonstrated ultrastructural neurosecretory granules. Oestrogen and progesterone receptors were expressed in 10 and nine cases, respectively, while cerbB2 was positive in only one case. HMW cytokeratin immunoprofile revealed a general lack of immunostaining within the abnormal cell population; likewise, no positivity for SMA of the cellular proliferation was detected.Conclusions : Almost all DCIS lesions with spindle cells disclose neuroendocrine differentiation. Although the distinction from benign florid usual hyperplasia may pose a diagnostic histological problem, the presence of diffuse neuroendocrine expression, in conjunction with the pattern of HMW keratin profile on immunohistochemistry, supports an in-situ neoplastic process. The absence of SMA immunostaining, in conjunction with negative reactivity for cytokeratins 5/6 and 14, makes the possibility of a myoepithelial proliferation unlikely.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 128 (1985), S. 554-562 
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0196-9781
    Keywords: Analgesia ; Intestinal transit ; Kentsin ; Opioid receptors
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Nuclear Inst. and Methods in Physics Research, B 59-60 (1991), S. 705-708 
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 109 (1981), S. 69-81 
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The hypothesis that, in the case of clonal or low-density cultures, cells which do not readily proliferate are those that do not produce an extracellular matrix (ECM), while those that proliferate actively are cells that have retained their ability to produce it, has been tested using low-density vascular endothelial cell cultures maintained on either plastic or ECM-coated dishes and exposed to various combinations of media and sera.Proliferation of low-density vascular endothelial cell cultures seeded on plastic and exposed to DMEM, RPMI-1640, or medium 199 plus thymidine is a function of the batch of calf serum used to supplement the various media. In all three cases, such cultures proliferated at a slow rate and fibroblast growth factor (FGF) greatly accelerated their proliferation. In contrast, when similar cultures were seeded on ECM-coated dishes, they actively proliferated regardless of the batch of calf serum to which they were exposed. FGF was no longer required in order for cultures to be come confluent. In the case of cultures exposed to RPMI-1640 or medium 199 plus thymidine, it was even toxic.When cultures were exposed to either medium 199 or Waymouth medium, cells did not proliferate, regardless of the substrate (either plastic or ECM) upon which they were maintained and of the batch of serum to which they were exposed. Addition of FGF to such media had no effect. It is therefore likely that nutrient limitations in both of these media restrict the ability of low-density vascular endothelial cells to respond to the mitogenic stimuli provided by either serum of FGF. These restrictions cannot be relieved by maintaining cells on ECM-coated dishes, and modifications of the nutrient composition of both media is required in order to allow cells to respond to either FGF or serum when maintained on plastic or to serum alone when maintained on ECM.These results suggest that, when low-density cell cultures are maintained on plastic and exposed to an adequate medium, their proliferation will be a function of both serum and FGF. When maintained on ECM, their proliferation will depend only on serum. It is therefore possible that the inability of serum to stimulate optimal cell proliferation when cells are maintained on plastic results from an inability of the cells to produce an ECM, and that FGF could induce such production.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2013-01-15
    Description: Background— Although aortic root pathology has been described in patients with tetralogy of Fallot, the scope of the problem remains poorly defined. We sought to determine the prevalence and predictors of aortic root dilatation in adults with repaired tetralogy of Fallot. Methods and Results— A multicenter cross-sectional study was conducted with standardized reassessment of echocardiographic parameters in 474 adults (≥18 years) with surgically repaired tetralogy of Fallot or pulmonary atresia with ventricular septal defect. The aortic root was measured in a parasternal long-axis view, in diastole, at the level of the sinus of Valsalva. Prevalence and predictors of an absolute diameter ≥40 mm and of an observed-to-expected ratio 〉1.5 were assessed. The aortic root dimension was ≥40 mm in 28.9% (95% confidence interval, 26.9%–30.9%). In multivariate analyses, the only independently associated factor was male sex (odds ratio, 4.48; 95% confidence interval, 1.55–12.89; P =0.006). The prevalence of an observed-to-expected aortic root dimension ratio 〉1.5 was 6.6% (95% confidence interval, 5.3%–7.9%). It was associated with pulmonary atresia and moderate or severe aortic regurgitation in univariate analyses, but no independent predictor was identified. The side of the aortic arch was not associated with aortic root dimension. The prevalence of moderate or severe aortic regurgitation was 3.5% (95% confidence interval, 2.7%–4.2%). Conclusions— Although nearly one third of adults with repaired tetralogy of Fallot have an aortic root diameter ≥40 mm, the prevalence of a dilated aortic root, when defined by an indexed ratio of observed-to-expected values, is low. Similarly, moderate or severe aortic regurgitation is uncommon.
    Keywords: Clinical Studies, Pediatric and congenital heart disease, including cardiovascular surgery, Epidemiology
    Electronic ISSN: 1524-4539
    Topics: Medicine
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  • 7
    Publication Date: 2021-02-08
    Description: Background: Complex multicellularity requires elaborate developmental mechanisms, often based on the versatility of heterodimeric transcription factor (TF) interactions. Homeobox TFs in the TALE superclass are deeply embedded in the gene regulatory networks that orchestrate embryogenesis. Knotted-like homeobox (KNOX) TFs, homologous to animal MEIS, have been found to drive the haploid-to-diploid transition in both unicellular green algae and land plants via heterodimerization with other TALE superclass TFs, demonstrating remarkable functional conservation of a developmental TF across lineages that diverged one billion years ago. Here, we sought to delineate whether TALE-TALE heterodimerization is ancestral to eukaryotes. Results: We analyzed TALE endowment in the algal radiations of Archaeplastida, ancestral to land plants. Homeodomain phylogeny and bioinformatics analysis partitioned TALEs into two broad groups, KNOX and non-KNOX. Each group shares previously defined heterodimerization domains, plant KNOX-homology in the KNOX group and animal PBC-homology in the non-KNOX group, indicating their deep ancestry. Protein-protein interaction experiments showed that the TALEs in the two groups all participated in heterodimerization. Conclusions: Our study indicates that the TF dyads consisting of KNOX/MEIS and PBC-containing TALEs must have evolved early in eukaryotic evolution. Based on our results, we hypothesize that in early eukaryotes, the TALE heterodimeric configuration provided transcription-on switches via dimerization-dependent subcellular localization, ensuring execution of the haploid-to-diploid transition only when the gamete fusion is correctly executed between appropriate partner gametes. The TALE switch then diversified in the several lineages that engage in a complex multicellular organization. © 2018 The Author(s).
    Type: Article , PeerReviewed
    Format: text
    Format: text
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  • 8
    Publication Date: 2015-09-11
    Description: Rationale: Thousands of mutations across 〉50 genes have been implicated in inherited cardiomyopathies. However, options for sequencing this rapidly evolving gene set are limited because many sequencing services and off-the-shelf kits suffer from slow turnaround, inefficient capture of genomic DNA, and high cost. Furthermore, customization of these assays to cover emerging targets that suit individual needs is often expensive and time consuming. Objective: We sought to develop a custom high throughput, clinical-grade next-generation sequencing assay for detecting cardiac disease gene mutations with improved accuracy, flexibility, turnaround, and cost. Methods and Results: We used double-stranded probes (complementary long padlock probes), an inexpensive and customizable capture technology, to efficiently capture and amplify the entire coding region and flanking intronic and regulatory sequences of 88 genes and 40 microRNAs associated with inherited cardiomyopathies, congenital heart disease, and cardiac development. Multiplexing 11 samples per sequencing run resulted in a mean base pair coverage of 420, of which 97% had 〉20 x coverage and 〉99% were concordant with known heterozygous single nucleotide polymorphisms. The assay correctly detected germline variants in 24 individuals and revealed several polymorphic regions in miR-499. Total run time was 3 days at an approximate cost of $100 per sample. Conclusions: Accurate, high-throughput detection of mutations across numerous cardiac genes is achievable with complementary long padlock probe technology. Moreover, this format allows facile insertion of additional probes as more cardiomyopathy and congenital heart disease genes are discovered, giving researchers a powerful new tool for DNA mutation detection and discovery.
    Keywords: Clinical genetics, Myocardial cardiomyopathy disease, Genetics of cardiovascular disease
    Print ISSN: 0009-7330
    Electronic ISSN: 1524-4571
    Topics: Medicine
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  • 9
    Publication Date: 2015-12-17
    Description: Nature Reviews Nephrology 12, 6 (2016). doi:10.1038/nrneph.2015.190 Authors: Michael Joannidis & Lui G. Forni Fluid therapy with saline is considered by some to confer a notable risk of acute kidney injury and mortality. However, data from the SPLIT trial — the first large, randomized controlled trial to compare saline to a 'balanced' solution — do not indicate any marked signal of harm in critically ill patients.
    Topics: Medicine
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  • 10
    Publication Date: 2015-08-15
    Description: The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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