539 research outputs found

    Aetiology, Risk Factors, and Biomarkers in Systemic Sclerosis with Interstitial Lung Disease

    Get PDF
    Systemic sclerosis (SSc) is a complex, multi-organ, autoimmune disease. Lung fibrosis occurs in ~80% of patients with SSc; 25-30% develop progressive interstitial lung disease (ILD). The pathogenesis of fibrosis in SSc associated ILD (SSc-ILD) involves cellular injury, activation/differentiation of mesenchymal cells and morphological/biological changes in epithelial/endothelial cells. Risk factors for progressive SSc-ILD include older age, male sex, lung involvement on baseline high-resolution computed tomography, reduced diffusing capacity for carbon monoxide and reduced forced vital capacity. SSc-ILD is characterized by genetic risk architecture distinct from that associated with idiopathic pulmonary fibrosis (IPF). Presence of anti-Scl-70 antibodies and absence of anti-centromere antibodies indicate increased likelihood of progressive ILD. Elevated levels of serum Krebs von den Lungen-6 (KL6) and CRP are associated with SSc-ILD severity, although whether KL6 independently predicts SSc-ILD progression remains controversial. A promising prognostic indicator is serum chemokine (C-C motif) ligand 18. SSc-ILD shares similarities with IPF, although clear differences exist. Histologically, a non-specific interstitial pneumonia pattern is commonly observed in SSc-ILD, whereas IPF is defined by usual interstitial pneumonia. The course of SSc-ILD is variable, ranging from minor, stable disease to a progressive course, while all IPF patients experience progression of disease. Although appropriately treated SSc-ILD patients have better chances of stabilization and survival, a relentlessly progressive course, akin to IPF, is seen in a minority. Better understanding of cellular and molecular pathogenesis, genetic risk and distinctive features of SSc-ILD, and identification of robust prognostic biomarkers are needed for optimal disease management. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

    Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure

    Get PDF
    Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance “strength”) rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain—consequent to increased chemosensitivity and delay—the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = −0.68) oscillations (P < 0.001 for all, both groups combined). Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population

    Unusual tumours of the heart: diagnostic and prognostic implications

    Get PDF
    Metastases to the heart are extremely uncommon. We describe three unusual cases along with their management. A review of the current literature concerning cardiac secondaries is included

    Ectopic A-lattice seams destabilize microtubules

    Get PDF
    Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe

    Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

    Get PDF
    BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk

    Acute Drug Treatment in the Early C. elegans Embryo

    Get PDF
    Genetic and genome-wide RNAi approaches available in C. elegans, combined with tools for visualizing subcellular events with high-resolution, have led to increasing adoption of the early C. elegans embryo as a model for mechanistic and functional genomic analysis of cellular processes. However, a limitation of this system has been the impermeability of the embryo eggshell, which has prevented the routine use of small molecule inhibitors. Here, we present a method to permeabilize and immobilize embryos for acute inhibitor treatment in conjunction with live imaging. To identify a means to permeabilize the eggshell, we used a dye uptake assay to screen a set of 310 candidate genes defined by a combination of bioinformatic criteria. This screen identified 20 genes whose inhibition resulted in >75% eggshell permeability, and 3 that permeabilized embryos with minimal deleterious effects on embryo production and early embryonic development. To mount permeabilized embryos for acute drug addition in conjunction with live imaging, we combined optimized inhibition of one of these genes with the use of a microfabricated chamber that we designed. We demonstrate that these two developments enable the temporally controlled introduction of inhibitors for mechanistic studies. This method should also open new avenues of investigation by allowing profiling and specificity-testing of inhibitors through comparison with genome-wide phenotypic datasets

    Radio emission from Supernova Remnants

    Get PDF
    The explosion of a supernova releases almost instantaneously about 10^51 ergs of mechanic energy, changing irreversibly the physical and chemical properties of large regions in the galaxies. The stellar ejecta, the nebula resulting from the powerful shock waves, and sometimes a compact stellar remnant, constitute a supernova remnant (SNR). They can radiate their energy across the whole electromagnetic spectrum, but the great majority are radio sources. Almost 70 years after the first detection of radio emission coming from a SNR, great progress has been achieved in the comprehension of their physical characteristics and evolution. We review the present knowledge of different aspects of radio remnants, focusing on sources of the Milky Way and the Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief overview of theoretical background, analyze morphology and polarization properties, and review and critical discuss different methods applied to determine the radio spectrum and distances. The consequences of the interaction between the SNR shocks and the surrounding medium are examined, including the question of whether SNRs can trigger the formation of new stars. Cases of multispectral comparison are presented. A section is devoted to reviewing recent results of radio SNRs in the Magellanic Clouds, with particular emphasis on the radio properties of SN 1987A, an ideal laboratory to investigate dynamical evolution of an SNR in near real time. The review concludes with a summary of issues on radio SNRs that deserve further study, and analyzing the prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure

    In Vitro and In Vivo Activity of a Palladacycle Complex on Leishmania (Leishmania) amazonensis

    Get PDF
    Leishmaniasis is an important public health problem with an estimated annual incidence of 1.5 million of new human cases of cutaneous leishmaniasis and 500,000 of visceral leishmaniasis. Treatment of the diseases is limited by toxicity and parasite resistance to the drugs currently in use, validating the need to develop new leishmanicidal compounds. We evaluated the killing by the palladacycle complex DPPE 1.2 of Leishmania (Leishmania) amazonensis, an agent of human cutaneous leishmaniasis in the Amazon region, Brazil. DPPE 1.2 destroyed promastigotes of L. (L.) amazonensis in vitro at nanomolar concentrations, whereas intracellular amastigotes were killed at drug concentrations 10-fold less toxic than those displayed to macrophages. L. (L.) amazonensis-infected BALB/c mice treated by intralesional injection of DPPE 1.2 exhibited a significant decrease of foot lesion sizes and a 97% reduction of parasite burdens when compared to untreated controls. Additional experiments indicated the inhibition of the cathepsin B activity of L. (L.) amazonensis amastigotes by DPPE 1.2. Further studies are needed to explore the potential of DPPE 1.2 as an additional option for the chemotherapy of leishmaniasis
    corecore