Disseminated Microsporidiosis Due to Encephalitozoon hellem: Pulmonary Colonization, Microhematuria, and Mild Conjunctivitis in a Patient with AIDS

Four genera of microsporidia have been associated with disease in humans, which predominantly affects immunocompromised persons. Systemic infection with a newly characterized microsporidian species, Encephalitozoon hellem, was recently reported in a patient with AIDS. This article describes a second patient with AIDS and disseminated E. hellem infection. In this case the parasite was detected in sputum, urine, and conjunctival swab specimens. Apart from recurrent mild conjunctivitis and asymptomatic microhematuria, the patient had no findings or symptoms that could be related to this parasite. Specifically, no microsporidian-associated pulmonary pathology was documented. Detection of E. hellem in the patient's sputum may have epidemiological implications in that this finding suggests transmission of microsporidia by the aerosol route. Because the patient died of unrelated complications, it remains unknown whether he was an asymptomatic carrier of microsporidia or whether microhematuria heralded early microsporidian disease, with the onset of cellular damage in the urinary trac

Integrating Murine Gene Expression Studies to Understand Obstructive Lung Disease due to Chronic Inhaled Endotoxin

Rationale: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. Methods: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. Results: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. Conclusions: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development

Double-stranded RNA-activated protein kinase PKR of fishes and amphibians: Varying the number of double-stranded RNA binding domains and lineage-specific duplications

BackgroundDouble-stranded (ds) RNA, generated during viral infection, binds and activates the mammalian anti-viral protein kinase PKR, which phosphorylates the translation initiation factor eIF2alpha leading to the general inhibition of protein synthesis. Although PKR-like activity has been described in fish cells, the responsible enzymes eluded molecular characterization until the recent discovery of goldfish and zebrafish PKZ, which contain Z-DNA-binding domains instead of dsRNA-binding domains (dsRBDs). Fish and amphibian PKR genes have not been described so far.ResultsHere we report the cloning and identification of 13 PKR genes from 8 teleost fish and amphibian species, including zebrafish, demonstrating the coexistence of PKR and PKZ in this latter species. Analyses of their genomic organization revealed up to three tandemly arrayed PKR genes, which are arranged in head-to-tail orientation. At least five duplications occurred independently in fish and amphibian lineages. Phylogenetic analyses reveal that the kinase domains of fish PKR genes are more closely related to those of fish PKZ than to the PKR kinase domains of other vertebrate species. The duplication leading to fish PKR and PKZ genes occurred early during teleost fish evolution after the divergence of the tetrapod lineage. While two dsRBDs are found in mammalian and amphibian PKR, one, two or three dsRBDs are present in fish PKR. In zebrafish, both PKR and PKZ were strongly upregulated after immunostimulation with some tissue-specific expression differences. Using genetic and biochemical assays we demonstrate that both zebrafish PKR and PKZ can phosphorylate eIF2alpha in yeast.ConclusionConsidering the important role for PKR in host defense against viruses, the independent duplication and fixation of PKR genes in different lineages probably provided selective advantages by leading to the recognition of an extended spectrum of viral nucleic acid structures, including both dsRNA and Z-DNA/RNA, and perhaps by altering sensitivity to viral PKR inhibitors. Further implications of our findings for the evolution of the PKR family and for studying PKR/PKZ interactions with viral gene products and their roles in viral infections are discussed

Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism

INTRODUCTION: Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17β-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved. METHODS: Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined. RESULTS: Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action. CONCLUSION: We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects

An ecological study of regional variation in work injuries among young workers

<p>Abstract</p> <p>Background</p> <p>The investigation of geographic variation in occupational injuries has received little attention. Young workers 15 to 24 years are of particular concern because they consistently show elevated occupational injury rates compared to older workers. The present study sought to: (a) to describe the geographic variation of work injuries; (b) to determine whether geographic variation remained after controlling for relevant demographic and job characteristics; (c) to identify the region-level factors that correlate with the geographic variation.</p> <p>Methods</p> <p>Using workers compensation claims and census data, we estimated claim rates per 100 full-time equivalents for 15 to 24 year olds in 46 regions in Ontario. A total of 21 region-level indicators were derived primarily from Census and Labour Force Survey data to reflect social and material deprivation of the region as well as demographic and employment characteristics of youth living in those areas.</p> <p>Results</p> <p>Descriptive findings showed substantial geographic variation in young worker injury rates, even after controlling for several job and demographic variables. Region-level characteristics such as greater residential stability were associated with low work injury rates. Also, regions with the lowest claim rates tended to have proportionally fewer cuts and burns than high-claim-rate regions.</p> <p>Conclusion</p> <p>The finding of substantial geographic variation in youth claim rates even after controlling for demographic and job factors can aid in targeting prevention resource. The association between region-level indicators such as residential stability and youth work injury suggests that work injury prevention strategies can be integrated with other local economic development measures. The findings partially support the notion that work safety measures may be unevenly distributed with respect to regional socio-economic factors.</p

EXACT: EXercise or Advice after ankle fraCTure. Design of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Ankle fractures are common. Management of ankle fractures generally involves a period of immobilisation followed by rehabilitation to reduce pain, stiffness, weakness and swelling. The effects of a rehabilitation program are still unclear. However, it has been shown that important components of rehabilitation programs may not confer additional benefits over exercise alone. The primary aim of this trial is to determine the effectiveness and cost-effectiveness of an exercise-based rehabilitation program after ankle fracture, compared to advice alone.</p> <p>Methods/Design</p> <p>A pragmatic randomised trial will be conducted. Participants will be 342 adults with stiff, painful ankles after ankle fracture treated with immobilisation. They will be randomly allocated using a concealed randomisation procedure to either an <it>Advice </it>or <it>Rehabilitation </it>group. Participants in the <it>Advice </it>group will receive verbal and written advice about exercise at the time of removal of immobilisation. Participants in the <it>Rehabilitation </it>group will be provided with a 4-week rehabilitation program that is designed, monitored and progressed by a physiotherapist, in addition to verbal and written advice. Outcomes will be measured by a blinded assessor at 1, 3 and 6 months. The primary outcomes will be activity limitation and quality-adjusted life years.</p> <p>Discussion</p> <p>This pragmatic trial will determine if a rehabilitation program reduces activity limitation and improves quality of life, compared to advice alone, after immobilisation for ankle fracture.</p