Systemic sclerosis in a patient with pityriasis rubra pilaris

Pityriasis rubra pilaris (PRP) is a rare, chronic erythematous squamous disorder of unknown etiology. It has been found in association with several autoimmune diseases, including thyroiditis, myositis, myasthenia gravis and vitiligo. Herein we report a case of systemic sclerosis in a patient with classic adult pityriasis rubra pilaris. A 38 year old woman with classic adult type 1 pityriasis rubra pilaris (PRP) developed progressive skin thickening of the trunk, face, upper and lower extremities after 2 years of PRP treatment with topical emollients and steroids. Clinical examination and immunological findings were consistent with SSc. Co-existence of these two rare conditions is documented for the first time

An analysis of protein patterns present in the saliva of diabetic patients using pairwise relationship and hierarchical clustering

Molecular diagnosis is based on the quantification of RNA, proteins, or metabolites whose concentration can be correlated to clinical situations. Usually, these molecules are not suitable for early diagnosis or to follow clinical evolution. Large-scale diagnosis using these types of molecules depends on cheap and preferably noninvasive strategies for screening. Saliva has been studied as a noninvasive, easily obtainable diagnosis fluid, and the presence of serum proteins in it enhances its use as a systemic health status monitoring tool. With a recently described automated capillary electrophoresis-based strategy that allows us to obtain a salivary total protein profile, it is possible to quantify and analyze patterns that may indicate disease presence or absence. The data of 19 persons with diabetes and 58 healthy donors obtained by capillary electrophoresis were transformed, treated, and grouped so that the structured values could be used to study individuals’ health state. After Pairwise Relationships and Hierarchical Clustering analysis were observed that amplitudes of protein peaks present in the saliva of these individuals could be used as differentiating parameters between healthy and unhealthy people. It indicates that these characteristics can serve as input for a future computational intelligence algorithm that will aid in the stratification of individuals that manifest changes in salivary proteins.info:eu-repo/semantics/acceptedVersio

Unilateral optic neuropathy following subdural hematoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Unilateral optic neuropathy is commonly due to a prechiasmatic affliction of the anterior visual pathway, while losses in visual hemifields result from the damage to brain hemispheres. Here we report the unusual case of a patient who suffered from acute optic neuropathy following hemispherical subdural hematoma. Although confirmed up to now only through necropsy studies, our case strongly suggests a local, microcirculatory deficit identified through magnetic resonance imaging <it>in vivo</it>.</p> <p>Case presentation</p> <p>A 70-year-old Caucasian German who developed a massive left hemispheric subdural hematoma under oral anticoagulation presented with acute, severe visual impairment on his left eye, which was noticed after surgical decompression. Neurologic and ophthalmologic examinations indicated sinistral optic neuropathy with visual acuity reduced nearly to amaurosis. Ocular pathology such as vitreous body hemorrhage, papilledema, and central retinal artery occlusion were excluded. An orbital lesion was ruled out by means of orbital magnetic resonance imaging. However, cerebral diffusion-weighted imaging and T2 maps of magnetic resonance imaging revealed a circumscribed ischemic lesion within the edematous, slightly herniated temporomesial lobe within the immediate vicinity of the affected optic nerve. Thus, the clinical course and morphologic magnetic resonance imaging findings suggest the occurrence of pressure-induced posterior ischemic optic neuropathy due to microcirculatory compromise.</p> <p>Conclusion</p> <p>Although lesions of the second cranial nerve following subdural hematoma have been reported individually, their pathogenesis was preferentially proposed from autopsy studies. Here we discuss a dual, pressure-induced and secondarily ischemic pathomechanism on the base of <it>in vivo </it>magnetic resonance imaging diagnostics which may remain unconsidered by computed tomography.</p

Local spatial regression models : a comparative analysis on soil contamination

Spatial data analysis focuses on both attribute and locational information. Local analyses deal with differences across space whereas global analyses deal with similarities across space. This paper addresses an experimental comparative study to analyse the spatial data by some weighted local regression models. Five local regression models have been developed and their estimation capacities have been evaluated. The experimental studies showed that integration of objective function based fuzzy clustering to geostatistics provides some accurate and general models structures. In particular, the estimation performance of the model established by combining the extended fuzzy clustering algorithm and standard regional dependence function is higher than that of the other regression models. Finally, it could be suggested that the hybrid regression models developed by combining soft computing and geostatistics could be used in spatial data analysis

Beyond R0 : demographic models for variability of lifetime reproductive output

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 6 (2011): e20809, doi:10.1371/journal.pone.0020809.The net reproductive rate measures the expected lifetime reproductive output of an individual, and plays an important role in demography, ecology, evolution, and epidemiology. Well-established methods exist to calculate it from age- or stage-classified demographic data. As an expectation, provides no information on variability; empirical measurements of lifetime reproduction universally show high levels of variability, and often positive skewness among individuals. This is often interpreted as evidence of heterogeneity, and thus of an opportunity for natural selection. However, variability provides evidence of heterogeneity only if it exceeds the level of variability to be expected in a cohort of identical individuals all experiencing the same vital rates. Such comparisons require a way to calculate the statistics of lifetime reproduction from demographic data. Here, a new approach is presented, using the theory of Markov chains with rewards, obtaining all the moments of the distribution of lifetime reproduction. The approach applies to age- or stage-classified models, to constant, periodic, or stochastic environments, and to any kind of reproductive schedule. As examples, I analyze data from six empirical studies, of a variety of animal and plant taxa (nematodes, polychaetes, humans, and several species of perennial plants).Supported by National Science Foundation Grant DEB-0816514 and by a Research Award from the Alexander von Humboldt Foundation

EspA Acts as a Critical Mediator of ESX1-Dependent Virulence in Mycobacterium tuberculosis by Affecting Bacterial Cell Wall Integrity

Mycobacterium tuberculosis (Mtb) requires the ESX1 specialized protein secretion system for virulence, for triggering cytosolic immune surveillance pathways, and for priming an optimal CD8+ T cell response. This suggests that ESX1 might act primarily by destabilizing the phagosomal membrane that surrounds the bacterium. However, identifying the primary function of the ESX1 system has been difficult because deletion of any substrate inhibits the secretion of all known substrates, thereby abolishing all ESX1 activity. Here we demonstrate that the ESX1 substrate EspA forms a disulfide bonded homodimer after secretion. By disrupting EspA disulfide bond formation, we have dissociated virulence from other known ESX1-mediated activities. Inhibition of EspA disulfide bond formation does not inhibit ESX1 secretion, ESX1-dependent stimulation of the cytosolic pattern receptors in the infected macrophage or the ability of Mtb to prime an adaptive immune response to ESX1 substrates. However, blocking EspA disulfide bond formation severely attenuates the ability of Mtb to survive and cause disease in mice. Strikingly, we show that inhibition of EspA disulfide bond formation also significantly compromises the stability of the mycobacterial cell wall, as does deletion of the ESX1 locus or individual components of the ESX1 system. Thus, we demonstrate that EspA is a major determinant of ESX1-mediated virulence independent of its function in ESX1 secretion. We propose that ESX1 and EspA play central roles in the virulence of Mtb in vivo because they alter the integrity of the mycobacterial cell wall

Networked T Cell Death following Macrophage Infection by Mycobacterium tuberculosis

<div><h3>Background</h3><p>Depletion of T cells following infection by <em>Mycobacterium tuberculosis</em> (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised.</p> <h3>Methodology/Principal Findings</h3><p>We found that lymphopenia (<1.5×10⁹ cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from <em>Mycobacterium bovis</em> Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system.</p> <h3>Conclusions</h3><p>Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.</p> </div

Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death

Survival within macrophages is a central feature of Mycobacterium tuberculosis pathogenesis. Despite significant advances in identifying new immunological parameters associated with mycobacterial disease, some basic questions on the intracellular fate of the causative agent of human tuberculosis in antigen-presenting cells are still under debate. To get novel insights into this matter, we used a single-cell fluorescence resonance energy transfer (FRET)-based method to investigate the potential cytosolic access of M. tuberculosis and the resulting cellular consequences in an unbiased, quantitative way. Analysis of thousands of THP-1 macrophages infected with selected wild-type or mutant strains of the M. tuberculosis complex unambiguously showed that M. tuberculosis induced a change in the FRET signal after 3 to 4 days of infection, indicating phagolysosomal rupture and cytosolic access. These effects were not seen for the strains M. tuberculosisΔRD1 or BCG, both lacking the ESX-1 secreted protein ESAT-6, which reportedly shows membrane-lysing properties. Complementation of these strains with the ESX-1 secretion system of M. tuberculosis restored the ability to cause phagolysosomal rupture. In addition, control experiments with the fish pathogen Mycobacterium marinum showed phagolysosomal translocation only for ESX-1 intact strains, further validating our experimental approach. Most importantly, for M. tuberculosis as well as for M. marinum we observed that phagolysosomal rupture was followed by necrotic cell death of the infected macrophages, whereas ESX-1 deletion- or truncation-mutants that remained enclosed within phagolysosomal compartments did not induce such cytotoxicity. Hence, we provide a novel mechanism how ESX-1 competent, virulent M. tuberculosis and M. marinum strains induce host cell death and thereby escape innate host defenses and favor their spread to new cells. In this respect, our results also open new research directions in relation with the extracellular localization of M. tuberculosis inside necrotic lesions that can now be tackled from a completely new perspective

Contrasting Transcriptional Responses of a Virulent and an Attenuated Strain of Mycobacterium tuberculosis Infecting Macrophages

Along with the recent identification of single nucleotide polymorphisms in H37Ra when compared to H37Rv, our demonstration of differential expression of PhoP-regulated and ESX-1 region-related genes during macrophage infection further highlights the significance of these genes in the attenuation of H37Ra