HTLV-1 Integration into Transcriptionally Active Genomic Regions Is Associated with Proviral Expression and with HAM/TSP

Human T-lymphotropic virus type 1 (HTLV-1) causes leukaemia or chronic inflammatory disease in ∼5% of infected hosts. The level of proviral expression of HTLV-1 differs significantly among infected people, even at the same proviral load (proportion of infected mononuclear cells in the circulation). A high level of expression of the HTLV-1 provirus is associated with a high proviral load and a high risk of the inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). But the factors that control the rate of HTLV-1 proviral expression remain unknown. Here we show that proviral integration sites of HTLV-1 in vivo are not randomly distributed within the human genome but are associated with transcriptionally active regions. Comparison of proviral integration sites between individuals with high and low levels of proviral expression, and between provirus-expressing and provirus non-expressing cells from within an individual, demonstrated that frequent integration into transcription units was associated with an increased rate of proviral expression. An increased frequency of integration sites in transcription units in individuals with high proviral expression was also associated with the inflammatory disease HAM/TSP. By comparing the distribution of integration sites in human lymphocytes infected in short-term cell culture with those from persistent infection in vivo, we infer the action of two selective forces that shape the distribution of integration sites in vivo: positive selection for cells containing proviral integration sites in transcriptionally active regions of the genome, and negative selection against cells with proviral integration sites within transcription units

Multi-detector row computed tomography (MDCT) and magnetic resonance imaging (MRI) in the evaluation of the mandibular invasion by squamous cell carcinomas (SCC) of the oral cavity. Correlation with pathological data

<p>Abstract</p> <p>Background</p> <p>To retrospectively compare the diagnostic accuracy of magnetic resonance imaging (MRI) and multidetector-row computed tomography (MDCT) in the assessment of the mandibular invasion by squamous cell carcinoma (SCC) having histopathological exams as standard of reference.</p> <p>Materials and methods</p> <p>Institutional review board approval with a waiver of informed patient consent was obtained. Of the 147 patients selected from our database who underwent surgical excision of a tumour arising into the oral cavity, thirty-six patients (26 men, 10 women; mean age, 56 years; range, 30-75 years) with hystologically proven SCC who performed both a preoperative MRI and MDCT, composed our final study population.</p> <p>Images were qualitatively analyzed in consensus by two expert radiologist in head and neck imaging. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were assessed for both MRI and MDCT.</p> <p>Differences in sensitivity, specificity, positive and negative predictive values were calculated at a statistical significance of p < .05.</p> <p>Results</p> <p>The sensitivity, the specificity and the accuracy of MRI and MDCT in the detection of the mandibular involvement were respectively 93%, 82%, 86% and 79%, 82%, 81%, while the positive predictive value (PPV) and negative predictive value (NPV) were respectively 76%, 95% and 73%, 86%. There wasn't any statistically significant difference in overall diagnostic accuracy between MRI and MDCT in the evaluation of mandibular tumour invasion (p > .05).</p> <p>Conclusion</p> <p>MRI showed to have a higher sensitivity compare to MDCT in the assessment of mandibular involvement from SCC arising in the oral cavity although none statistically significant differences were noted.</p

Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users

Background: Falls are a serious problem in the elderly, and have recently been described as cardiovascular-mediated side effects of beta-blocker eye drops. Therefore, we investigated the possible association between the long-term use of beta-blockers, prostaglandins and their combinations in eye drops, and falls, dizziness and orthostatic hypotension in older patients. Methods: All participants were long-term users of eye drops containing beta-blockers, prostaglandins or their combinations. They underwent a structured falls interview and blood pressure measurement for testing of orthostatic hypotension. The odds ratio for presence of orthostatic hypotension or a positive falls history according to use of beta-blocker eye drops was calculated with a binary logistic regression analysis. The main outcome measures were a positive falls history and the presence of orthostatic hypotension. Results: In total, 148 of 286 subjects participated. After adjustment for age, gender, and use of fall-risk-increasing drugs other than beta-blocker eye drops, we found no significant difference in fall risk [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.268-1.327] between patients using ophthalmic beta-blockers or a combination of ophthalmic beta-blockers and prostaglandins, and patients using ophthalmic prostaglandins only. Although prevalence of orthostatic hypotension was higher in the beta-blocker group (OR: 1.67; 95% CI: 0.731-3.793) compared to the prostaglandin group, this was a non-significant difference. Conclusions: In our study, we did not find a significant association between long-term use of beta-blockers eye drops and falls, dizziness or orthostatic hypotension in older ophthalmic outpatients, compared to long-term use of prostaglandin eye drops

Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection

Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV) integrates preferentially within active transcription units, whereas murine leukemia virus (MLV) integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN) coding region into HIV (to make HIVmIN) caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN) further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag) displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I–hypersensitive sites (i.e., +/− 1 kb), and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins

Association between risk factors for injurious falls and new benzodiazepine prescribing in elderly persons

<p>Abstract</p> <p>Background</p> <p>Benzodiazepines are frequently prescribed to elderly patients' despite concerns about adverse effects leading to injurious falls. Previous studies have not investigated the extent to which patients with pre-existing risk factors for falls are prescribed benzodiazepines. The objective of this study is to assess if some of the risk factors for falls are associated with new benzodiazepine prescriptions in elderly persons.</p> <p>Methods</p> <p>Using provincial administrative databases, elderly Quebec residents were screened in 1989 for benzodiazepine use and non-users were followed for up to 5 years. Logistic regression models were used to evaluate potential predictors of new benzodiazepine use among patient baseline characteristics.</p> <p>Results</p> <p>In the 252,811 elderly patients who had no benzodiazepine prescription during the baseline year (1989), 174,444 (69%) never filled a benzodiazepine prescription and 78,367 (31%) filled at least one benzodiazepine prescription. In the adjusted analysis, several risk factors for falls were associated with statistically significant increases in the risk of receiving a new benzodiazepine prescription including the number of prescribing physicians seen at baseline (OR: 1.12; 95% CI 1.11–1.13), being female (OR: 1.20; 95% CI 1.18–1.22) or a diagnosis of arthritis (OR: 1.11; 95% CI 1.09–1.14), depression (OR: 1.42; 95% CI 1.35–1.49) or alcohol abuse (OR: 1.24; 95% CI 1.05–1.46). The strongest predictor for starting a benzodiazepine was the use of other medications, particularly anti-depressants (OR: 1.85; 95% CI 1.75–1.95).</p> <p>Conclusion</p> <p>Patients with pre-existing conditions that increase the risk of injurious falls are significantly more likely to receive a new prescription for a benzodiazepine. The strength of the association between previous medication use and new benzodiazepine prescriptions highlights an important medication safety issue.</p

The Pine River Statement: Human Health Consequences of DDT Use

Objectives: Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. Data sources and extraction: We conducted a PubMed search in October 2008 and retrieved 494 studies. Data synthesis: Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. Conclusions: Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDT.Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. Data sources and extraction We conducted a PubMed search in October 2008 and retrieved 494 studies. Data synthesis Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. Conclusions Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDThttp://dx.doi.org/10.1289/ehp.1174

Accounting for Diffusion in Agent Based Models of Reaction-Diffusion Systems with Application to Cytoskeletal Diffusion

Diffusion plays a key role in many biochemical reaction systems seen in nature. Scenarios where diffusion behavior is critical can be seen in the cell and subcellular compartments where molecular crowding limits the interaction between particles. We investigate the application of a computational method for modeling the diffusion of molecules and macromolecules in three-dimensional solutions using agent based modeling. This method allows for realistic modeling of a system of particles with different properties such as size, diffusion coefficients, and affinity as well as the environment properties such as viscosity and geometry. Simulations using these movement probabilities yield behavior that mimics natural diffusion. Using this modeling framework, we simulate the effects of molecular crowding on effective diffusion and have validated the results of our model using Langevin dynamics simulations and note that they are in good agreement with previous experimental data. Furthermore, we investigate an extension of this framework where single discrete cells can contain multiple particles of varying size in an effort to highlight errors that can arise from discretization that lead to the unnatural behavior of particles undergoing diffusion. Subsequently, we explore various algorithms that differ in how they handle the movement of multiple particles per cell and suggest an algorithm that properly accommodates multiple particles of various sizes per cell that can replicate the natural behavior of these particles diffusing. Finally, we use the present modeling framework to investigate the effect of structural geometry on the directionality of diffusion in the cell cytoskeleton with the observation that parallel orientation in the structural geometry of actin filaments of filopodia and the branched structure of lamellipodia can give directionality to diffusion at the filopodia-lamellipodia interface

Neuregulin 1 Type III/ErbB Signaling Is Crucial for Schwann Cell Colonization of Sympathetic Axons

Analysis of Schwann cell (SC) development has been hampered by the lack of growing axons in many commonly used in vitro assays. As a consequence, the molecular signals and cellular dynamics of SC development along peripheral axons are still only poorly understood. Here we use a superior cervical ganglion (SCG) explant assay, in which axons elongate after treatment with nerve growth factor (NGF). Migration as well as proliferation and apoptosis of endogenous SCG-derived SCs along sympathetic axons were studied in these cultures using pharmacological interference and time-lapse imaging. Inhibition of ErbB receptor tyrosine kinases leads to reduced SC proliferation, increased apoptosis and thereby severely interfered with SC migration to distal axonal sections and colonization of axons. Furthermore we demonstrate that SC colonization of axons is also strongly impaired in a specific null mutant of an ErbB receptor ligand, Neuregulin 1 (NRG1) type III. Taken together, using a novel SC development assay, we demonstrate that NRG1 type III serves as a critical axonal signal for glial ErbB receptors that drives SC development along sympathetic axons