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Find video protocols related to scientific articles indexed in Pubmed.
Eradicating HIV-1 infection: seeking to clear a persistent pathogen.
Nat. Rev. Microbiol.
PUBLISHED: 11-18-2014
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Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART.
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One-unit versus two-unit cord-blood transplantation for hematologic cancers.
N. Engl. J. Med.
PUBLISHED: 10-30-2014
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Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation.
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Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study.
Ann. Rheum. Dis.
PUBLISHED: 10-30-2014
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We aimed to quantify the risk of major adverse cardiovascular events (MACE) among patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA) and psoriasis without known PsA compared with the general population after adjusting for traditional cardiovascular risk factors.
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Effect of Psoriasis Severity on Hypertension Control: A Population-Based Study in the United Kingdom.
JAMA Dermatol
PUBLISHED: 10-17-2014
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Hypertension is prevalent among patients with psoriasis. The effect of psoriasis and its severity on hypertension control is unknown.
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The quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells.
J. Virol.
PUBLISHED: 09-24-2014
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Central memory (TCM) CD4(+) T cells are the principal reservoir of latent HIV-1 infection that persists despite durable, successful antiretroviral therapy (ART). In a study that measured HIV DNA in 34 patients and replication-competent HIV in four patients, pools of resting and activated transitional memory (TTM) CD4(+) T cells were found to be a reservoir for HIV infection. As defective viruses account for the majority of integrated HIV DNA and do not reflect the actual frequency of latent, replication-competent proviral infection, we assessed the specific contribution of resting TTM cells to latent HIV infection. We measured the frequency of replication-competent HIV in purified resting memory cell subpopulations by a limiting dilution, quantitative viral outgrowth assay (QVOA). HIV was routinely detected within the resting central memory compartment, but was infrequently detected within the resting TTM compartment. These observations suggest that prolonged ART may limit persistent latent infection in the TTM compartment. Our results confirm the importance of latent infection within the TCM compartment, and again focus attention on these cells as the most important latent viral reservoir. While proliferation may drive expansion of detectable viral genomes in cells, the frequency of replication-competent HIV must be carefully assessed. Latent infection appears to wane within the transitional memory compartment in patients who have sustained successful viral suppression via ART, or were treated very early in infection.
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Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy - ACTG A5286.
J. Infect. Dis.
PUBLISHED: 09-11-2014
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?Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).
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Selective HDAC inhibition for the disruption of latent HIV-1 infection.
PLoS ONE
PUBLISHED: 08-19-2014
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Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small molecule inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small molecule HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymatic inhibition of HDAC3 with the selective small-molecule inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.
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Emerging strategies to deplete the HIV reservoir.
Curr. Opin. Infect. Dis.
PUBLISHED: 07-25-2014
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This review highlights recent studies undertaken to further advance the search for successful approaches to eradicate HIV infection.
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Framing expectations in early HIV cure research.
Trends Microbiol.
PUBLISHED: 07-03-2014
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Language used to describe clinical research represents a powerful opportunity to educate volunteers. In the case of HIV cure research there is an emerging need to manage expectations by using the term 'experiment'. Cure experiments are proof-of-concept studies designed to evaluate novel paradigms to reduce persistent HIV-1 reservoirs, without any expectation of medical benefit.
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Broadly-specific cytotoxic T cells targeting multiple HIV antigens are expanded from HIV+ patients: Implications for immunotherapy.
Mol. Ther.
PUBLISHED: 06-30-2014
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Antiretroviral therapy (ART) is unable to eradicate human immunodeficiency virus type (HIV-1) infection. Therefore, there is an urgent need to develop novel therapies for this disease to augment anti-HIV immunity. T cell therapy is appealing in this regard as T cells have the ability to proliferate, migrate, and their antigen specificity reduces the possibility of off-target effects. However, past human studies in HIV-1 infection that administered T cells with limited specificity, failed to provide ART-independent, long-term viral control. In this study, we sought to expand functional, broadly-specific cytotoxic T cells (HXTCs) from HIV-infected patients on suppressive ART as a first step towards developing cellular therapies for implementation in future HIV eradication protocols. Blood samples from 7 HIV+ patients on suppressive ART were used to derive HXTCs. Multi-antigen specificity was achieved by co-culturing T cells with antigen presenting cells pulsed with peptides representing Gag, Pol, and Nef. All but 2 lines were multi-specific for all three antigens. HXTCs demonstrated efficacy as shown by release of pro-inflammatory cytokines, specific lysis of antigen-pulsed targets, and the ability to suppress HIV replication in vitro. In conclusion we are able to generate broadly-specific cytotoxic T cell lines that simultaneously target multiple HIV antigens and show robust anti-viral function.Molecular Therapy (2014); doi:10.1038/mt.2014.207.
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Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches.
J. Am. Acad. Dermatol.
PUBLISHED: 06-04-2014
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Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence.
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Lower-extremity amputation risk is associated with variation in behavioral risk factor surveillance system responses.
Diabetes Care
PUBLISHED: 05-30-2014
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To determine whether regional variation in the rate of lower-extremity amputation (LEA) is associated with health behaviors.
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What's new in the literature: An update of new research since the original WHS diabetic foot ulcer guidelines in 2006.
Wound Repair Regen
PUBLISHED: 05-15-2014
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The objective of the paper was to update the diabetic foot ulcer guidelines that were previously published in 2006. We performed a key word search using MEDLINE and Cochrane reviews for publication between January 2006 and January 2012. Articles that fit the inclusion criteria were reviewed and the previous guidelines were updated.
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Translational challenges in targeting latent HIV infection and the CNS reservoir problem.
J. Neurovirol.
PUBLISHED: 04-16-2014
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Too controversial to discuss only a short time ago, achieving a cure for HIV infection has become a priority in HIV research. However, substantial challenges must be overcome. Among key hurdles to be surmounted is the definition of a reliable, validated model in which to test latency reversal agents (LRAs), as current primary cell models differ in their response to such agents. Animal models such as the HIV-infected humanized BLT mouse and SIV-infected macaque will be essential to study LRAs and to quantify their effects in anatomic reservoirs. Of several potential anatomic reservoirs, the central nervous system presents a significant obstacle, as it is known to harbor persistent HIV infection and is difficult to access for study and therapeutic intervention.
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Persistence of mild to moderate atopic dermatitis.
JAMA Dermatol
PUBLISHED: 04-04-2014
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Atopic dermatitis (AD) is a common illness of childhood.
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HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.
J. Infect. Dis.
PUBLISHED: 03-11-2014
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A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.
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Early therapy-related myeloid sarcoma and deletion of 9q22.32 to q31.1.
Pediatr Blood Cancer
PUBLISHED: 03-05-2014
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Survival following childhood neuroblastoma is improving with low rates of secondary myeloid neoplasms. We describe a 13-month-old male with intermediate risk neuroblastoma who developed an isolated scalp therapy-related myeloid sarcoma (t-MS). Developmental delays and two distinct malignancies prompted constitutional evaluation. Chromosomal microarray identified a 7.3 Mb deletion of 9q22.32 to 9q31.1. He remains in remission 11 months following hematopoietic cell transplant. Unusual presentations of rare diseases necessitate a multidisciplinary approach and adaptation of standardized protocols to accommodate increased risks imposed by genetic variants.
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How Might We Cure HIV?
Curr Infect Dis Rep
PUBLISHED: 02-25-2014
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Antiretroviral therapy (ART) does not eliminate HIV-1 from latently infected reservoirs, and this remains the critical obstacle to the eradication of infection. Although ART is effective in suppressing viral load, life-long ART is burdensome in many respects. Given expanding numbers of HIV-infected individuals on ART worldwide, there is an urgent need to examine the possibility that innovative therapies might eradicate infection, and obviate the need for life-long medical therapy for HIV-positive people around the world. Several approaches to eradicating the latent HIV reservoir and curing infection have been proposed and are under study. An initial strategy seeks to induce the expression of the latent integrated proviral genomes within resting CD4+ T cells, so that viral proteins or particles may be revealed and allow these cellular reservoirs to be cleared. The inducing agents that have been studied recently are inhibitors of histone deacetylase (HDAC) such as suberoylanilide hydroxamic acid (SAHA). Such induction of viral expression seems unlikely in itself to efficiently clear all latently infected cells. Therefore, it seems likely that parallel efforts to augment the HIV-specific immune response with specific immunotherapies or vaccination may be required. Recently, efforts to achieve immune augmentation by ex vivo expansion of viral specific cytotoxic T-cell lymphocytes derived from HIV-infected patients have yielded an augmented HIV-specific immune response in vivo, as have cellular vaccinations delivered by administration of dendritic cells. As HIV latency and the persistence of infection despite effective ART is multifactorial, the eradication of HIV infection may require multiple approaches.
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The reliability of teledermatology to triage inpatient dermatology consultations.
JAMA Dermatol
PUBLISHED: 02-14-2014
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Many hospitals do not have inpatient dermatologic consultative services, and most have reduced availability of services during off-hours. Dermatologists based in outpatient settings can find it challenging to determine the urgency with which they need to evaluate inpatients when consultations are requested. Teledermatology may provide a valuable mechanism for dermatologists to triage inpatient consultations and increase efficiency, thereby expanding access to specialized care for hospitalized patients.
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Microcircuit dynamics of map plasticity in barrel cortex.
Curr. Opin. Neurobiol.
PUBLISHED: 02-05-2014
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Functional reorganization of the whisker map in rodent barrel cortex has long served as a model for cortical plasticity following changes in sensory experience. Given the heterogeneity of neuronal response properties in neocortex, it has remained unclear how individual neurons in the cortical microcircuit are affected. Novel in vivo imaging and electrophysiology methods allow longitudinal recording of the same neurons' functional properties and therefore have the critical ability to resolve the direction and dynamics of change as plasticity progresses. Tracking sensory responsiveness before and after whisker trimming has uncovered diverse effects in individual neurons, suggesting that longitudinal recording will be essential for elucidating plasticity mechanisms within cortical microcircuits.
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Five-year malignancy incidence in patients with chronic pruritus: a population-based cohort study aimed at limiting unnecessary screening practices.
J. Am. Acad. Dermatol.
PUBLISHED: 01-28-2014
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The incidence of malignancy in patients with chronic pruritus and nondiseased skin is unknown.
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Global mortality from conditions with skin manifestations.
J. Am. Acad. Dermatol.
PUBLISHED: 01-27-2014
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Global Burden of Disease Study is a research database containing systematically compiled information from vital statistics and epidemiologic literature to inform research, public policy, and resource allocation.
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Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents.
J. Am. Acad. Dermatol.
PUBLISHED: 01-13-2014
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Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option.
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Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
J. Am. Acad. Dermatol.
PUBLISHED: 01-11-2014
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Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.
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HLA-B*57 elite suppressor and chronic progressor HIV-1 isolates replicate vigorously and cause CD4+ T cell depletion in humanized BLT mice.
J. Virol.
PUBLISHED: 01-03-2014
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Elite controllers or suppressors (ES) are HIV-1-infected patients who maintain undetectable viral loads without antiretroviral therapy. The mechanism of control remains unclear, but the HLA-B*57 allele is overrepresented in cohorts of these patients. However, many HLA-B*57 patients develop progressive disease, and some studies have suggested that infection with defective viruses may be the cause of the lack of high levels of virus replication and disease progression in ES. We therefore performed a comprehensive comparative in vivo and in vitro characterization of viruses isolated from well-defined ES. For this purpose, we first performed full-genome sequence analysis and in vitro fitness assays on replication-competent isolates from HLA-B*57 ES and HLA-B*57 chronic progressors (CPs). Under our experimental conditions, we found that isolates from ES and CPs can replicate in vitro. However, since inherently these assays involve the use of unnaturally in vitro-activated cells, we also investigated the replication competence and pathogenic potential of these HIV isolates in vivo using humanized BLT mice. The results from these analyses demonstrate that virus isolates from ES are fully replication competent in vivo and can induce peripheral and systemic CD4 T cell depletion. These results provide the first direct in vivo evidence that viral fitness does not likely determine clinical outcome in HLA-B*57 patients and that elite suppressors can control replication-competent, fully pathogenic viruses. A better understanding of the immunological bases of viral suppression in ES will serve to inform novel approaches to preventive and therapeutic HIV vaccine design.
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Simplification to abacavir/lamivudine + atazanavir maintains viral suppression and improves bone and renal biomarkers in ASSURE, a randomized, open label, non-inferiority trial.
PLoS ONE
PUBLISHED: 01-01-2014
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Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study's primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients.
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Network oscillations drive correlated spiking of ON and OFF ganglion cells in the rd1 mouse model of retinal degeneration.
PLoS ONE
PUBLISHED: 01-01-2014
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Following photoreceptor degeneration, ON and OFF retinal ganglion cells (RGCs) in the rd-1/rd-1 mouse receive rhythmic synaptic input that elicits bursts of action potentials at ? 10 Hz. To characterize the properties of this activity, RGCs were targeted for paired recording and morphological classification as either ON alpha, OFF alpha or non-alpha RGCs using two-photon imaging. Identified cell types exhibited rhythmic spike activity. Cross-correlation of spike trains recorded simultaneously from pairs of RGCs revealed that activity was correlated more strongly between alpha RGCs than between alpha and non-alpha cell pairs. Bursts of action potentials in alpha RGC pairs of the same type, i.e. two ON or two OFF cells, were in phase, while bursts in dissimilar alpha cell types, i.e. an ON and an OFF RGC, were 180 degrees out of phase. This result is consistent with RGC activity being driven by an input that provides correlated excitation to ON cells and inhibition to OFF cells. A2 amacrine cells were investigated as a candidate cellular mechanism and found to display 10 Hz oscillations in membrane voltage and current that persisted in the presence of antagonists of fast synaptic transmission and were eliminated by tetrodotoxin. Results support the conclusion that the rhythmic RGC activity originates in a presynaptic network of electrically coupled cells including A2s via a Na(+)-channel dependent mechanism. Network activity drives out of phase oscillations in ON and OFF cone bipolar cells, entraining similar frequency fluctuations in RGC spike activity over an area of retina that migrates with changes in the spatial locus of the cellular oscillator.
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Targeted cytotoxic therapy kills persisting HIV infected cells during ART.
PLoS Pathog.
PUBLISHED: 01-01-2014
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Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. For this purpose, we first characterized the impact of ART on HIV RNA levels in multiple organs of bone marrow-liver-thymus (BLT) humanized mice and found that antiretroviral drug penetration and activity was sufficient to reduce, but not eliminate, HIV production in each tissue tested. For targeted cytotoxic killing of these persistent vRNA(+) cells, we treated BLT mice undergoing ART with an HIV-specific immunotoxin. We found that compared to ART alone, this agent profoundly depleted productively infected cells systemically. These results offer proof-of-concept that targeted cytotoxic therapies can be effective components of HIV eradication strategies.
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An In-Depth Comparison of Latent HIV-1 Reactivation in Multiple Cell Model Systems and Resting CD4+ T Cells from Aviremic Patients.
PLoS Pathog.
PUBLISHED: 12-01-2013
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The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for "anti-latency" therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.
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Long-acting injectable antiretrovirals for HIV treatment and prevention.
Curr Opin HIV AIDS
PUBLISHED: 10-09-2013
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Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents.
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Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744.
Antimicrob. Agents Chemother.
PUBLISHED: 08-26-2013
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Dolutegravir (DTG) and GSK1265744 are HIV integrase inhibitors (INIs) in clinical development. The oral formulation of rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), has been approved for treatment-naive HIV infection. Long-acting depot injections of GSK1265744 and RPV are also being developed. This study evaluated the potential for drug interactions between RPV and these INIs. This phase 1, open-label, two-cohort, three-period, single-sequence crossover study evaluated oral coadministration of RPV with DTG or GSK1265744. Healthy subjects received DTG (50 mg every 24 h for 5 days) or GSK1265744 (30 mg every 24 h for 12 days) in period 1 followed by a washout, RPV (25 mg every 24 h for 11 or 12 days) in period 2, immediately followed by RPV (25 mg every 24 h) plus DTG (50 mg every 24 h) for 5 days or GSK1265744 (30 mg every 24 h) for 12 days in period 3. Steady-state pharmacokinetic (PK) parameters were estimated using noncompartmental analysis of data collected on the last day of each period. The combinations of RPV and DTG (n = 16) and of RPV and GSK1265744 (n = 11) were well tolerated; no grade 3 or 4 adverse events (AEs) or AE-related discontinuations were observed. The 90% confidence intervals for the area under the curve from time zero until the end of the dosage interval [AUC0-?] and maximum concentration of drug in serum (Cmax) geometric mean ratios were within 0.8 to 1.25. Following administration of DTG + RPV, DTG and RPV C? increased by 22% and 21%, respectively. Following administration of GSK1265744 + RPV, RPV C? decreased 8%. DTG and GSK1265744 can be administered with RPV without dosage adjustment for either agent. These results support coadministration of RPV with DTG or GSK1265744 as either oral or long-acting depot injection regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01467531.).
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Guidelines of care for the management of atopic dermatitis: Section 1. Diagnosis and assessment of atopic dermatitis.
J. Am. Acad. Dermatol.
PUBLISHED: 08-17-2013
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Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomes measures for assessment, and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed.
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HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model.
Retrovirology
PUBLISHED: 08-14-2013
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The major targets of HIV infection in humans are CD4+ T cells. CD4+ T cell depletion is a hallmark of AIDS. Previously, the SCID-hu thy/liv model was used to study the effect of HIV on thymopoeisis in vivo. However, these mice did not develop high levels of peripheral T cell reconstitution and required invasive surgery for infection and analysis. Here, we describe a novel variant of this model in which thy/liv implantation results in systemic reconstitution with human T cells in the absence of any other human hematopoietic lineages.
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Online correction of licking-induced brain motion during two-photon imaging with a tunable lens.
J. Physiol. (Lond.)
PUBLISHED: 08-12-2013
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Two-photon calcium imaging in awake, head-fixed animals enables the measurement of neuronal activity during behaviour. Often, licking for the retrieval of water reward is used as a measurable report of the animals decision during reward-driven behaviour. However, licking behaviour can induce severe motion artifacts that interfere with two-photon imaging of cellular activity. Here, we describe a simple method for the online correction of licking-induced focus shifts for two-photon calcium imaging of neocortical neurons in the head-fixed mouse. We found that licking causes a stereotyped drop of neocortical tissue, shifting neurons up to 20 ?m out of focus. Based on the measurement of licking with a piezo film sensor, we developed a feedback model, which provides a corrective signal for fast optical focus adjustments with an electrically tunable lens. Using online correction with this feedback model, we demonstrate a reduction of licking-related focus changes below 3 ?m, minimizing motion artifact contamination of cellular calcium signals. Focus correction with a tunable lens is a simple and effective method to improve the ability to monitor neuronal activity during reward-based behaviour.
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Low-frequency (<100 kHz), low-intensity (<100 mW/cm(2)) ultrasound to treat venous ulcers: a human study and in vitro experiments.
J. Acoust. Soc. Am.
PUBLISHED: 08-10-2013
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The purpose of this study was to examine whether low frequency (<100?kHz), low intensity (<100 mW/cm(2), spatial peak temporal peak) ultrasound can be an effective treatment of venous stasis ulcers, which affect 500?000 patients annually costing over $1 billion per year. Twenty subjects were treated with either 20 or 100?kHz ultrasound for between 15 and 45?min per session for a maximum of four treatments. Healing was monitored by changes in wound area. Additionally, two in vitro studies were conducted using fibroblasts exposed to 20?kHz ultrasound to confirm the ultrasounds effects on proliferation and cellular metabolism. Subjects receiving 20 kHz ultrasound for 15?min showed statistically faster (p?
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Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.
JAMA Dermatol
PUBLISHED: 08-09-2013
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Despite the growing literature on comorbidity risks in psoriasis, there remains a critical knowledge gap on the degree to which objectively measured psoriasis severity may affect the prevalence of major medical comorbidity.
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Effect of race on outcomes after allogeneic hematopoietic cell transplantation for severe aplastic anemia.
Am. J. Hematol.
PUBLISHED: 08-02-2013
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We compared outcomes after hematopoietic cell transplantation in patients of African American (n?=?84) and Caucasian (n?=?215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P?=?0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P?=?0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P?=?0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD. Am. J. Hematol., 2013. © 2013 Wiley Periodicals, Inc.
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Unexpected finding of delayed-onset seizures in HIV-positive, treatment-experienced subjects in the phase IIb evaluation of fosdevirine (GSK2248761).
Antivir. Ther. (Lond.)
PUBLISHED: 07-24-2013
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Fosdevirine (GSK2248761) is a non-nucleoside reverse transcriptase inhibitor with HIV-1 activity against common efavirenz-resistant strains. Two partially blind, randomized, phase IIb studies were initiated (1 in treatment-naïve; 1 in treatment-experienced subjects with HIV) to select a once-daily dose of fosdevirine for phase III trials.
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Genomics in clinical practice: lessons from the front lines.
Sci Transl Med
PUBLISHED: 07-19-2013
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The price of whole-genome and -exome sequencing has fallen to the point where these methods can be applied to clinical medicine. Here, we outline the lessons we have learned in converting a sequencing laboratory designed for research into a fully functional clinical program.
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The Global Burden of Skin Disease in 2010: An Analysis of the Prevalence and Impact of Skin Conditions.
J. Invest. Dermatol.
PUBLISHED: 07-05-2013
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The Global Burden of Disease (GBD) Study 2010 estimated the GBD attributable to 15 categories of skin disease from 1990 to 2010 for 187 countries. For each of the following diseases, we performed systematic literature reviews and analyzed resulting data: eczema, psoriasis, acne vulgaris, pruritus, alopecia areata, decubitus ulcer, urticaria, scabies, fungal skin diseases, impetigo, abscess, and other bacterial skin diseases, cellulitis, viral warts, molluscum contagiosum, and non-melanoma skin cancer. We used disability estimates to determine nonfatal burden. Three skin conditions, fungal skin diseases, other skin and subcutaneous diseases, and acne were in the top 10 most prevalent diseases worldwide in 2010, and eight fell into the top 50; these additional five skin problems were pruritus, eczema, impetigo, scabies, and molluscum contagiosum. Collectively, skin conditions ranged from the 2nd to 11th leading cause of years lived with disability at the country level. At the global level, skin conditions were the fourth leading cause of nonfatal disease burden. Using more data than has been used previously, the burden due to these diseases is enormous in both high- and low-income countries. These results argue strongly to include skin disease prevention and treatment in future global health strategies as a matter of urgency.Journal of Investigative Dermatology advance online publication, 21 November 2013; doi:10.1038/jid.2013.446.
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Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.
J. Allergy Clin. Immunol.
PUBLISHED: 07-01-2013
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Atopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African American subjects.
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Approach to diagnosing lower extremity ulcers.
Dermatol Ther
PUBLISHED: 06-08-2013
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Chronic leg ulcers (as differentiated from wound of the foot) are most often due to venous disease, arterial insufficiency (peripheral arterial disease), or a combination of both. Treatment modalities vary depending on the etiology of the ulcer, so it is important to make an appropriate diagnosis of the wound. Like for most medical illnesses, the determination of the etiology of these wounds is based on history, physical examination, and testing.
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Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study.
Arthritis Care Res (Hoboken)
PUBLISHED: 05-23-2013
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Rare but potentially life-threatening cutaneous adverse reactions have been associated with allopurinol, but population-based data on the incidence and mortality of such reactions are scarce.
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Change-point models to estimate the limit of detection.
Stat Med
PUBLISHED: 05-06-2013
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In many biological and environmental studies, measured data is subject to a limit of detection. The limit of detection is generally defined as the lowest concentration of analyte that can be differentiated from a blank sample with some certainty. Data falling below the limit of detection is left censored, falling below a level that is easily quantified by a measuring device. A great deal of interest lies in estimating the limit of detection for a particular measurement device. In this paper, we propose a change-point model to estimate the limit of detection by using data from an experiment with known analyte concentrations. Estimation of the limit of detection proceeds by a two-stage maximum likelihood method. Extensions are considered that allow for censored measurements and data from multiple experiments. A simulation study is conducted demonstrating that in some settings the change-point model provides less biased estimates of the limit of detection than conventional methods. The proposed method is then applied to data from an HIV pilot study. Copyright © 2013 John Wiley & Sons, Ltd.
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Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia.
Blood
PUBLISHED: 05-02-2013
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Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30?000 ng/mL and were elevated in IDH-mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG ?200 ng/mL (hazard ratio, 3.9; P = .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies.
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Epidemiology of foot ulceration and amputation: can global variation be explained?
Med. Clin. North Am.
PUBLISHED: 04-25-2013
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Amputation is a treatment, and not simply part of the natural history of foot disease. However, assessment of amputation incidence is the measure most frequently used to document an outcome reflecting the management of diabetic foot disease, mainly because the data are already captured in most health care systems. Nevertheless, interpretation of the results requires great care. Many centers have recorded decreases in the incidence of amputation in recent years and have concluded that this reflects improvement in clinical care. Although improvement in clinical care is clearly of a priority, it is important not to underestimate the extent to which the at-risk population (those with diabetes) may have changed as a result of changing criteria for the diagnosis of diabetes, as well as the increasing implementation of systematic and opportunistic screening. The incidence of amputation can be calculated and expressed in many ways, with different groups using different criteria for deciding both the numerator and the denominator, and studying populations that may differ in several different ways. Given that the incidence of amputation can also be influenced by a wide variety of clinical and social factors, it is not surprising that considerable variation exists between published studies from different countries. For these reasons it is currently difficult to make meaningful comparisons between data from different countries. On the other hand, the demonstration of wide variation within a single country or between countries or communities that have very similar populations, health care systems, and procedures for documenting amputation incidence is of greater interest. When 8- to 10-fold variation exists within similar health care systems, a risk as large as any published risk factor for amputation, it is essential that the reasons are explored. While race and social deprivation both make an important contribution to variation, another is likely to relate to aspects of the structure of care, including the training and beliefs of individual clinicians, patients’ access to care, preferences of patients, and the ability of a patient to understand the need for care and execute a care plan. This area of study requires further investigation.
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Axonal loss in murine peripheral nerves following exposure to recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge.
J Bone Joint Surg Am
PUBLISHED: 04-05-2013
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With the proven efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) to treat open tibial fractures and promote spine fusion, there has been an increase in its off-label use. Recent studies have shown that BMPs play a role in nerve development and regeneration. Little is known about changes that result when rhBMP-2 is used in the vicinity of peripheral nerves. The purpose of this study is to characterize changes in peripheral nerves following exposure to rhBMP-2-soaked collagen sponges.
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Herpes zoster vaccine effectiveness against incident herpes zoster and post-herpetic neuralgia in an older US population: a cohort study.
PLoS Med.
PUBLISHED: 04-01-2013
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Herpes zoster is common and has serious consequences, notably post-herpetic neuralgia (PHN). Vaccine efficacy against incident zoster and PHN has been demonstrated in clinical trials, but effectiveness has not been studied in unselected general populations unrestricted by region, full health insurance coverage, or immune status. Our objective was to assess zoster vaccine effectiveness (VE) against incident zoster and PHN in a general population-based setting.
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Reactivation of latent HIV-1 in central memory CD4+ T cells through TLR-1/2 stimulation.
Retrovirology
PUBLISHED: 03-18-2013
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Toll-like receptors (TLRs) are crucial for recognition of pathogen-associated molecular patterns by cells of the innate immune system. TLRs are present and functional in CD4+ T cells. Memory CD4+ T cells, predominantly central memory cells (TCM), constitute the main reservoir of latent HIV-1. However, how TLR ligands affect the quiescence of latent HIV within central memory CD4+ T cells has not been studied.
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Warm, Humid, and High Sun Exposure Climates Are Associated with Poorly Controlled Eczema: PEER (Pediatric Eczema Elective Registry) Cohort, 2004-2012.
J. Invest. Dermatol.
PUBLISHED: 03-18-2013
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Anecdotal reports of children experiencing eczema flares during winter and summer months along with global variation in eczema prevalence has fueled speculation that climate may modulate disease activity. The aim of this study was to determine whether long-term weather patterns affect the severity and persistence of eczema symptoms in children. We performed a prospective cohort study of US children (N=5,595) enrolled in PEER (Pediatric Eczema Elective Registry) between 2004 and 2012 to evaluate the effect of climate (daily temperature, daily sun exposure, daily humidity) on the severity of eczema symptoms. Odds ratios (ORs) were calculated for the patient-evaluated outcome of disease control. Multivariate logistic regression modeling adjusting for gender, race, income, and topical medication use demonstrated that higher temperature (OR=0.90, 95% confidence interval (CI): 0.87-0.93, P<0.001) and increased sun exposure (OR=0.93, 95% CI: 0.89-0.98, P=0.009) were associated with poorly controlled eczema. Higher humidity (OR=0.90, 95% CI: 0.812-0.997, P=0.04) was also associated with poorly controlled disease, but the statistical significance of this association was lost in our multivariate analysis (P=0.44).
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Combined approaches for HIV cure.
Curr Opin HIV AIDS
PUBLISHED: 03-01-2013
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A serious effort has begun to develop therapies that may be capable of eradicating established HIV infection in man. Because of the biological complexity of HIV infection that persists despite potent antiretroviral therapy, it is widely believed that if such therapies can be developed they will involve complex, multimodality approaches. We highlight some of the recent studies in this effort.
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Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
Diabetes Care
PUBLISHED: 02-19-2013
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Hyperbaric oxygen (HBO) is a device that is used to treat foot ulcers. The study goal was to compare the effectiveness of HBO with other conventional therapies administered in a wound care network for the treatment of a diabetic foot ulcer and prevention of lower-extremity amputation.
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Snapshots: chromatin control of viral infection.
Virology
PUBLISHED: 02-06-2013
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Like their cellular host counterparts, many invading viral pathogens must contend with, modulate, and utilize the host cells chromatin machinery to promote efficient lytic infection or control persistent-latent states. While not intended to be comprehensive, this review represents a compilation of conceptual snapshots of the dynamic interplay of viruses with the chromatin environment. Contributions focus on chromatin dynamics during infection, viral circumvention of cellular chromatin repression, chromatin organization of large DNA viruses, tethering and persistence, viral interactions with cellular chromatin modulation machinery, and control of viral latency-reactivation cycles.
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Successful autologous cord blood transplantation in a child with acquired severe aplastic anemia.
Pediatr Transplant
PUBLISHED: 01-25-2013
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Over 400 cases of pediatric SAA occur annually in the United States. A growing number of children with SAA may have had their stem cells harvested through cord blood collection. We describe a nine-yr-old male with SAA treated successfully with an autologous cord blood transplant following immunoablative chemotherapy. With the increasing number of people cryopreserving autologous cord blood, the use of autologous cord blood in the treatment of SAA might be considered as initial therapy. This case serves to discuss approaches to preparative therapy as well as the potential complications in this growing cohort of patients.
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Quality assessment of tissue specimens for studies of diabetic foot ulcers.
Exp. Dermatol.
PUBLISHED: 01-24-2013
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Diabetic foot ulcers (DFUs) represent an important clinical problem resulting in significant morbidity and mortality. Ongoing translational research studies strive to better understand molecular/cellular basis of DFU pathology that may lead to identification of novel treatment protocols. Tissue at the non-healing wound edge has been identified as one of major contributors to the DFU pathophysiology that provides important tool for translational and clinical investigations. To evaluate quality of tissue specimens and their potential use, we obtained 81 DFU specimens from 25 patients and performed histological analyses, immunohistochemistry and RNA quality assessments. We found that depth of the collected specimen is important determinant of research utility, and only specimens containing a full-thickness epidermis could be utilized for immunohistochemistry and RNA isolation. We showed that only two-thirds of collected specimens could be utilized in translational studies. This attrition rate is important for designs of future studies involving tissue specimen collection from DFU.
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Steady or changing? Long-term monitoring of neuronal population activity.
Trends Neurosci.
PUBLISHED: 01-21-2013
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Stability and flexibility are both hallmarks of brain function that allow animals to thrive in ever-changing environments. Investigating how a balance between these opposing features is achieved with a dynamic array of cellular and molecular constituents requires long-term tracking of activity from individual neurons. Here, we review in vivo chronic extracellular recording studies and recent long-term two-photon calcium-imaging investigations that address the question of stability and plasticity of neuronal population activity in the mammalian brain. Overall, spiking activity is heterogeneously distributed among neurons in local populations and largely remains stable for individual cells over time. Tuning properties appear more flexible and may be adaptively stabilized, possibly by neuromodulators, to encode reliably and specifically salient stimuli or behaviors.
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Asthma and frequency of wheeze: risk factors for the persistence of atopic dermatitis in children.
Ann. Allergy Asthma Immunol.
PUBLISHED: 01-16-2013
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Studies have examined the development of asthma in children with atopic dermatitis (AD); however, none have looked at the association of asthma or the frequency of wheeze with respect to persistence or difficulty in achieving AD clinical improvement in children.
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Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T-cell activation.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 01-15-2013
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Initiation of antiretroviral therapy during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T-cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful antiretroviral therapy, and maintained viral suppression through 96 weeks. Pretherapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and although this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, P = 0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.
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Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study.
Lancet
PUBLISHED: 01-08-2013
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Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1.
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Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom.
J. Invest. Dermatol.
PUBLISHED: 11-24-2011
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Increasing epidemiological evidence suggests independent associations between psoriasis and cardiovascular and metabolic disease. Our objective was to test the hypothesis that directly assessed psoriasis severity relates to the prevalence of metabolic syndrome and its components. A population-based, cross-sectional study was undertaken using computerized medical records from the Health Improvement Network Study population including individuals in the age group of 45-65 years with psoriasis and practice-matched controls. The diagnosis and extent of psoriasis were determined using provider-based questionnaires. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A total of 44,715 individuals were included: 4,065 with psoriasis and 40,650 controls. In all, 2,044 participants had mild psoriasis (?2% body surface area (BSA)), 1,377 had moderate psoriasis (3-10% BSA), and 475 had severe psoriasis (>10% BSA). Psoriasis was associated with metabolic syndrome, adjusted odds ratio (adj. OR 1.41, 95% confidence interval (CI) 1.31-1.51), varying in a "dose-response" manner, from mild (adj. OR 1.22, 95% CI 1.11-1.35) to severe psoriasis (adj. OR 1.98, 95% CI 1.62-2.43). Psoriasis is associated with metabolic syndrome and the association increases with increasing disease severity. Furthermore, associations with obesity, hypertriglyceridemia, and hyperglycemia increase with increasing disease severity independently of other metabolic syndrome components. These findings suggest that screening for metabolic disease should be considered for psoriasis, especially when it is severe.
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Chronic imaging of cortical sensory map dynamics using a genetically encoded calcium indicator.
J. Physiol. (Lond.)
PUBLISHED: 11-14-2011
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In vivo optical imaging can reveal the dynamics of large-scale cortical activity, but methods for chronic recording are limited. Here we present a technique for long-term investigation of cortical map dynamics using wide-field ratiometric fluorescence imaging of the genetically encoded calcium indicator (GECI) Yellow Cameleon 3.60. We find that wide-field GECI signals report sensory-evoked activity in anaesthetized mouse somatosensory cortex with high sensitivity and spatiotemporal precision, and furthermore, can be measured repeatedly in separate imaging sessions over multiple weeks. This method opens new possibilities for the longitudinal study of stability and plasticity of cortical sensory representations.
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Generation of HIV latency in humanized BLT mice.
J. Virol.
PUBLISHED: 10-19-2011
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Here we demonstrate that a combination of tenofovir, emtricitabine, and raltegravir effectively suppresses peripheral and systemic HIV replication in humanized BLT mice. We also demonstrate that antiretroviral therapy (ART)-treated humanized BLT mice harbor latently infected resting human CD4+ T cells that can be induced ex vivo to produce HIV. We observed that the levels of infected resting human CD4+ T cells present in BLT mice are within the range of those observed circulating in patients undergoing suppressive ART. These results demonstrate the potential of humanized BLT mice as an attractive model for testing the in vivo efficacy of novel HIV eradication strategies.
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Latent HIV-1 infection of resting CD4? T cells in the humanized Rag2?/? ?c?/? mouse.
J. Virol.
PUBLISHED: 10-19-2011
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Persistent human immunodeficiency virus type 1 (HIV-1) infection of resting CD4? T cells, unaffected by antiretroviral therapy (ART), provides a long-lived reservoir of HIV infection. Therapies that target this viral reservoir are needed to eradicate HIV-1 infection. A small-animal model that recapitulates HIV-1 latency in resting CD4? T cells may accelerate drug discovery and allow the rational design of nonhuman primate (NHP) or human studies. We report that in humanized Rag2?/? ?(c)?/? (hu-Rag2?/? ?(c)?/?) mice, as in humans, resting CD4? T cell infection (RCI) can be quantitated in pooled samples of circulating cells and tissue reservoirs (e.g., lymph node, spleen, bone marrow) following HIV-1 infection with the CCR5-tropic JR-CSF strain and suppression of viremia by ART. Replication-competent virus was recovered from pooled resting CD4? T cells in 7 of 16 mice, with a median frequency of 8 (range, 2 to 12) infected cells per million T cells, demonstrating that HIV-1 infection can persist despite ART in the resting CD4? T cell reservoir of hu-Rag2?/? ?(c)?/? mice. This model will allow rapid preliminary assessments of novel eradication approaches and combinatorial strategies that may be challenging to perform in the NHP model or in humans, as well as a rigorous analysis of the effect of these interventions in specific anatomical compartments.
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Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated.
J. Exp. Med.
PUBLISHED: 10-10-2011
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The initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after somatic mutations. Polyreactive gp41-binding antibodies were also isolated from uninfected individuals. These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non-HIV-1 antigens.
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Location, location, location: geographic clustering of lower-extremity amputation among Medicare beneficiaries with diabetes.
Diabetes Care
PUBLISHED: 09-20-2011
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OBJECTIVE Lower-extremity amputation (LEA) is common among persons with diabetes. The goal of this study was to identify geographic variation and the influence of location on the incidence of LEA among U.S. Medicare beneficiaries with diabetes. RESEARCH DESIGN AND METHODS We conducted a cohort study of beneficiaries of Medicare. The geographic unit of analysis was hospital referral regions (HRRs). Tests of spatial autocorrelation and geographically weighted regression were used to evaluate the incidence of LEA by HRRs as a function of geographic location in the U.S. Evaluated covariates covered sociodemographic factors, risk factors for LEA, diabetes severity, provider access, and cost of care. RESULTS Among persons with diabetes, the annual incidence per 1,000 of LEA was 5.0 in 2006, 4.6 in 2007, and 4.5 in 2008 and varied by the HRR. The incidence of LEA was highly concentrated in neighboring HRRs. High rates of LEA clustered in contiguous portions of Texas, Oklahoma, Louisiana, Arkansas, and Mississippi. Accounting for geographic location greatly improved our ability to understand the variability in LEA. Additionally, covariates associated with LEA per HRR included socioeconomic status, prevalence of African Americans, age, diabetes, and mortality rate associated with having a foot ulcer. CONCLUSIONS There is profound "region-correlated" variation in the rate of LEA among Medicare beneficiaries with diabetes. In other words, location matters and whereas the likelihood of an amputation varies dramatically across the U.S. overall, neighboring locations have unexpectedly similar amputation rates, some being uniformly high and others uniformly low.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.