Mancheño-Corvo, P; Martín-Duque, P
Cancer is a multigenic disorder involving mutations of both tumor suppressor genes and oncogenes. A large body of preclinical data, however, has suggested that cancer growth can be arrested or reversed by treatment with gene transfer vectors that carry a single growth inhibitory or pro-apoptotic gene or a gene that can recruit immune responses against the tumor. Many of these gene transfer vectors are modified viruses. The ability for the delivery of therapeutic genes, made them desirable for engineering virus vector systems. The viral vectors recently in laboratory and clinical use are based on RNA and DNA viruses processing very different genomic structures and host ranges. Particular viruses have been selected as gene delivery vehicles because of their capacities to carry foreign genes and their ability to efficiently deliver these genes associated with efficient gene expression. These are the major reasons why viral vectors derived from retroviruses, adenovirus, adeno-associated virus, herpesvirus and poxvirus are employed in more than 70% of clinical gene therapy trials worldwide. Because these vector systems have unique advantages and limitations, each has applications for which it is best suited. Retroviral vectors can permanently integrate into the genome of the infected cell, but require mitotic cell division for transduction. Adenoviral vectors can efficiently deliver genes to a wide variety of dividing and nondividing cell types, but immune elimination of infected cells often limits gene expression in vivo. Herpes simplex virus can deliver large amounts of exogenous DNA; however, cytotoxicity and maintenance of transgene expression remain as obstacles. AAV also infects many non-dividing and dividing cell types, but has a limited DNA capacity. This review discusses current and emerging virusbased genetic engineering strategies for the delivery of therapeutic molecules or several approaches for cancer treatment.
Okui, N; Kitamura, Y; Kobayashi, N; Sakuma, R; Ishikawa, T; Kitamura, T
Acquired immune deficiency syndrome (AIDS) is resistant to all current therapy. Gene therapy is an attractive alternative or additive to current, unsatisfactory AIDS therapy. To develop an antiviral molecule targeting viral integrase (HIV IN), we generated a single-chain antibody, termed scAb, which interacted with human immunodeficiency virus type 1 (HIV-1) IN and inhibited virus replication at the integration step when expressed intracellularly. To reduce infectivity from within the virus particles, we made expression plasmids (pC-scAbE-Vpr, pC-scAbE-CA, and pC-scAbE-WXXF), which expressed the anti-HIV IN scAb fused to the N-terminus of HIV-1-associated accessory protein R (Vpr), capsid protein (CA), and specific binding motif to Vpr (WXXF), respectively. All fusion proteins were tagged with a nine-amino acid peptide derived from influenza virus hemagglutinin (HA) at the C terminus. The fusion molecules, termed scAbE-Vpr, scAbE-CA, and scAbE-WXXF, interacted specifically with HIV IN immobilized on a nitrocellulose membrane. Immunoblot analysis showed that scAbE-Vpr, scAbE-CA, and scAbE-WXXF were incorporated into the virions produced by cotransfection of 293T cells with HIV-1 infectious clone DNA (pLAI) and pC-scAbE-Vpr, pC-scAbE-WXXF. A multinuclear activation galactosidase indicator (MAGI) assay revealed that the virions released from 293T cells cotransfected with pLAI and pC-scAbE-Vpr, pC-scAbE-WXXF had as little 1000-fold of the infectivity of the control wild-type virions, which were produced from the 293T cells transfected with pLAI alone. Furthermore, the virions produced from the 293T cells cotransfected with pLAI and an scAb expression vector (pC-scAb) showed only 1% of the infectivity of the control HIV-1 in a MAGI assay, although scAb was not incorporated into the virions. In either instance, the total quantity of the progeny virions released from the transfected 293T cells and the patterns of the virion proteins were hardly affected by the presence of
The FDA has approved talimogene laherparepvec, or T-VEC, to treat surgically unresectable skin and lymph node lesions in patients with advanced melanoma. T-VEC is the first oncolytic viral therapy to gain regulatory endorsement, based on data from the OPTiM study. ©2016 American Association for Cancer Research.
Full Text Available Oncolytic viruses have made their mark on the cancer world as a potential therapeutic option, with the possible advantages of reduced side effects and strengthened treatment efficacy due to higher tumor selectivity. Results have been so promising, that oncolytic viral treatments have now been approved for clinical trials in several countries. However, clinical studies may benefit from the ability to noninvasively and serially identify sites of viral targeting via molecular imaging in order to provide safety, efficacy, and toxicity information. Furthermore, molecular imaging of oncolytic viral therapy may provide a more sensitive and specific diagnostic technique to detect tumor origin and, more importantly, presence of metastases. Several strategies have been investigated for molecular imaging of viral replication broadly categorized into optical and deep tissue imaging, utilizing several reporter genes encoding for fluorescence proteins, conditional enzymes, and membrane protein and transporters. Various imaging methods facilitate molecular imaging, including computer tomography, magnetic resonance imaging, positron emission tomography, single photon emission CT, gamma-scintigraphy, and photoacoustic imaging. In addition, several molecular probes are used for medical imaging, which act as targeting moieties or signaling agents. This review will explore the preclinical and clinical use of in vivo molecular imaging of replication-competent oncolytic viral therapy.
James A. Hutchinson
Full Text Available Recent introduction of all-oral direct-acting antiviral (DAA treatment has revolutionized care of patients with chronic hepatitis C virus (HCV infection. Regrettably, the high cost of DAA treatment is burdensome for healthcare systems and may be prohibitive for some patients who would otherwise benefit. Understanding how patient-related factors influence individual responses to DAA treatment may lead to more efficient prescribing. In this observational study, patients with chronic HCV infection were comprehensively monitored by flow cytometry to identify pretreatment immunological variables that predicted HCV RNA negativity within 4 weeks of commencing DAA treatment. Twenty-three patients [genotype 1a (n = 10, 1b (n = 9, and 3 (n = 4] were treated with daclatasvir plus sofosbuvir (SOF (n = 15, ledipasvir plus SOF (n = 4, or ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir (n = 4. DAA treatment most prominently altered the distribution of CD8+ memory T cell subsets. Knowing only pretreatment frequencies of CD3+ and naive CD8+ T cells allowed correct classification of 83% of patients as “fast” (HCV RNA-negative by 4 weeks or “slow” responders. In a prospective cohort, these parameters correctly classified 90% of patients. Slow responders exhibited higher frequencies of CD3+ T cells, CD8+ TEM cells, and CD5high CD27− CD57+ CD8+ chronically activated T cells, which is attributed to bystander hyperactivation of virus-non-specific CD8+ T cells. Taken together, non-specific, systemic CD8+ T cell activation predicted a longer time to viral clearance. This discovery allows pretreatment identification of individuals who may not require a full 12-week course of DAA therapy; in turn, this could lead to individualized prescribing and more efficient resource allocation.
Patel, Hema; Platt, Robert W; Pekeles, Gary S; Ducharme, Francine M
In previously well infants hospitalized with acute viral bronchiolitis, the effectiveness of repeated nebulized therapy with epinephrine (EPI) was compared with treatment with albuterol (ALB) or saline placebo (PLAC). In this randomized, double-blind, parallel-group, controlled trial, infants received study nebulizations every 1 to 6 hours and were assessed twice daily by the research team. The primary outcome was length of hospital stay (LOS). Secondary outcomes included the time from admission until the infant had normal hydration, oxygenation, and minimal respiratory distress. A total of 149 infants were randomized; 50 were allocated to receive racemic EPI, 51 were given ALB, and 48 received PLAC. Baseline characteristics and pre-enrollment symptoms, signs, and therapy were similar between groups. There were no group differences in the primary outcome measure, mean LOS (hours)(+/- SD): EPI = 59.8 (62), ALB = 61.4 (54), and PLAC = 63.3 (47); P =.95 by intent-to-treat analysis. Group differences were not statistically significant in any of the secondary outcomes. There were no group differences in the effectiveness of therapy for infants hospitalized with bronchiolitis. Based on these results, we do not recommend routine use of either nebulized EPI or ALB in this patient group.
Cinnamon L. Hardee
Full Text Available Uses of viral vectors have thus far eclipsed uses of non-viral vectors for gene therapy delivery in the clinic. Viral vectors, however, have certain issues involving genome integration, the inability to be delivered repeatedly, and possible host rejection. Fortunately, development of non-viral DNA vectors has progressed steadily, especially in plasmid vector length reduction, now allowing these tools to fill in specifically where viral or other non-viral vectors may not be the best options. In this review, we examine the improvements made to non-viral DNA gene therapy vectors, highlight opportunities for their further development, address therapeutic needs for which their use is the logical choice, and discuss their future expansion into the clinic
Alton, Eric W F W; Armstrong, David K; Ashby, Deborah; Bayfield, Katie J; Bilton, Diana; Bloomfield, Emily V; Boyd, A Christopher; Brand, June; Buchan, Ruaridh; Calcedo, Roberto; Carvelli, Paula; Chan, Mario; Cheng, Seng H; Collie, D David S; Cunningham, Steve; Davidson, Heather E; Davies, Gwyneth; Davies, Jane C; Davies, Lee A; Dewar, Maria H; Doherty, Ann; Donovan, Jackie; Dwyer, Natalie S; Elgmati, Hala I; Featherstone, Rosanna F; Gavino, Jemyr; Gea-Sorli, Sabrina; Geddes, Duncan M; Gibson, James S R; Gill, Deborah R; Greening, Andrew P; Griesenbach, Uta; Hansell, David M; Harman, Katharine; Higgins, Tracy E; Hodges, Samantha L; Hyde, Stephen C; Hyndman, Laura; Innes, J Alastair; Jacob, Joseph; Jones, Nancy; Keogh, Brian F; Limberis, Maria P; Lloyd-Evans, Paul; Maclean, Alan W; Manvell, Michelle C; McCormick, Dominique; McGovern, Michael; McLachlan, Gerry; Meng, Cuixiang; Montero, M Angeles; Milligan, Hazel; Moyce, Laura J; Murray, Gordon D; Nicholson, Andrew G; Osadolor, Tina; Parra-Leiton, Javier; Porteous, David J; Pringle, Ian A; Punch, Emma K; Pytel, Kamila M; Quittner, Alexandra L; Rivellini, Gina; Saunders, Clare J; Scheule, Ronald K; Sheard, Sarah; Simmonds, Nicholas J; Smith, Keith; Smith, Stephen N; Soussi, Najwa; Soussi, Samia; Spearing, Emma J; Stevenson, Barbara J; Sumner-Jones, Stephanie G; Turkkila, Minna; Ureta, Rosa P; Waller, Michael D; Wasowicz, Marguerite Y; Wilson, James M; Wolstenholme-Hogg, Paul
Summary Background Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. Methods We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Findings Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Interpretation Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of
Elalfy, Mohsen S; Nugent, Diane
Immune thrombocytopenia (ITP) might be preceded by silent or overt viral infections. Similarly, anti-viral drugs and viral vaccines could also trigger ITP and might play a central role in its pathogenesis. The seasonal nature of childhood ITP suggests that viral infections might initiate immune responses that increase the predisposition and occurrence of ITP. Active cytomegalovirus or Epstein-Barr virus should be considered in differential diagnosis when thrombocytopenia is associated with lymphadenopathy, especially with splenomegaly. This review will focus on the specific association of ITP in association with viral disease and vaccinations, and will discuss the effectiveness of current therapies in light of our current understanding of viral-associated ITP. Copyright © 2016 Elsevier Inc. All rights reserved.
Full Text Available Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV replication in elite controllers (EC remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC and viremic noncontrollers (HN on highly active antiretroviral therapy (HAART. Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1, a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of
Sologub, T V; Shul'diakov, A A; Romantsov, M G; Zhekalov, A N; Petlenko, S V; Erofeeva, M K; Maksakova, V L; Isakov, V A; Zarubaev, V V; Gatsan, V V; Kovalenko, A L
Data on the study of the efficacy of the tablets of cycloferon, an early inductor of types 1 and 2 interferon, in the treatment of influenza and acute respiratory tract viral infections in adults are presented. The study enrolled 522 patients with moderate influenza of type A (H1N1) verified in 61% of the patients and type A (H3N2) verified in 7.5% of the cases. The patients were randomized with the envelope procedure. In the patients treated with cycloferon the intensity and period of the fever were stopped earlier and averaged from 1.8 to 3 days vs. 5 days in the reference group (symptomatic therapy). The improvement signs in the general state of the patients treated with cycloferon were noted on the 2nd day. The influenza complication as pneumonia was recorded in 2.2% of the patients treated with cycloferon, whereas in the patients under the symptomatic therapy the complications as bronchitis, pneumonia, angina were stated in 21.4% of the cases. For urgent prophylaxis of the influenza and respiratory tract viral infections (epidemiologic study) a group of 3717 subjects randomized with the table of random numbers was observed. 2080 patients were treated with cycloferon and 1637 patients were under the symptomatic therapy. The results were evaluated by the efficacy index and the protection estimate (T. A. Semenenko, 1991). The total efficacy index and the protection estimate in all the patients of the group were 4.9 and 79.8% respectively. The complicated forms of the disease were recorded in 1.5% of the patients treated with cycloferon and in 10.5 and 11.3% of the patients not treated with cycloferon.
Dreyfus, David H
Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk. Copyright © 2011 Elsevier B.V. All rights reserved.
34--- I lr_ Transworld Research Network 37/661 (2), Fort P.O., Trivandrum-695 023, Kerala, India Recent Development in Gene Therapy , 2007: 77-94...ISBN: 81-7895-262-9 Editor: Jim Xiang Adenovirus-mediated gene therapy against viral biothreat agents Josh Q.H. Wu Chemical Biological Defence... therapy , which introduces therapeutic genes into mammalian cells to achieve therapeutic effective, hds a great potential for use as a defensive
Full Text Available Over the last three decades, interest in the field of gene therapy seems to have fluctuated between hot and cold. Encouraging pre-clinical and clinical data has demonstrated the potential of genetic therapies and yet setbacks in clinical trials have cast doubts in some minds over the clinical future of gene therapy [1-3]. In the last two years, a number of studies have demonstrated therapeutic benefits in clinical trials aimed towards specific monogenetic disorders [4-6], and this has brought renewed optimism to the field. [...
Shih, Wei-Liang; Fang, Chi-Tai; Chen, Pei-Jer
Hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), and Epstein-Barr virus (EBV) contribute to about 10-15 % global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infections have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-cell lymphotropic virus type 1 (HTLV-1) had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA-interference-based therapies for treating HPV-associated cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.
Ellen Van Gulck
Full Text Available Upon interruption of antiretroviral therapy, HIV-infected patients usually show viral load rebound to pre-treatment levels. Four patients, hereafter referred to as secondary controllers (SC, were identified who initiated therapy during chronic infection and, after stopping treatment, could control virus replication at undetectable levels for more than six months. In the present study we set out to unravel possible viral and immune parameters or mechanisms of this phenomenon by comparing secondary controllers with elite controllers and non-controllers, including patients under HAART. As candidate correlates of protection, virus growth kinetics, levels of intracellular viral markers, several aspects of HIV-specific CD4+ and CD8+ T cell function and HIV neutralizing antibodies were investigated. As expected all intracellular viral markers were lower in aviremic as compared to viremic subjects, but in addition both elite and secondary controllers had lower levels of viral unspliced RNA in PBMC as compared to patients on HAART. Ex vivo cultivation of the virus from CD4+ T cells of SC consistently failed in one patient and showed delayed kinetics in the three others. Formal in vitro replication studies of these three viruses showed low to absent growth in two cases and a virus with normal fitness in the third case. T cell responses toward HIV peptides, evaluated in IFN-γ ELISPOT, revealed no significant differences in breadth, magnitude or avidity between SC and all other patient groups. Neither was there a difference in polyfunctionality of CD4+ or CD8+ T cells, as evaluated with intracellular cytokine staining. However, secondary and elite controllers showed higher proliferative responses to Gag and Pol peptides. SC also showed the highest level of autologous neutralizing antibodies. These data suggest that higher T cell proliferative responses and lower replication kinetics might be instrumental in secondary viral control in the absence of
The US Food and Drug Administration (FDA) approved the first oncolytic viral therapy (OVT), Imlygic (talimogene laherparepvec), in October 2015 for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery, although talimogene has not been shown to improve overall survival or have an effect on visceral metastases. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.
Full Text Available GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA boost vaccine (GOVX-B11, was undertaken in HIV infected participants on antiretroviral treatment (ART to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI. Nine men who began antiretroviral therapy (ART within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.clinicaltrials.gov NCT01378156.
Kotterman, Melissa A; Chalberg, Thomas W; Schaffer, David V
In a range of human trials, viral vectors have emerged as safe and effective delivery vehicles for clinical gene therapy, particularly for monogenic recessive disorders, but there has also been early work on some idiopathic diseases. These successes have been enabled by research and development efforts focusing on vectors that combine low genotoxicity and immunogenicity with highly efficient delivery, including vehicles based on adeno-associated virus and lentivirus, which are increasingly enabling clinical success. However, numerous delivery challenges must be overcome to extend this success to many diseases; these challenges include developing techniques to evade preexisting immunity, to ensure more efficient transduction of therapeutically relevant cell types, to target delivery, and to ensure genomic maintenance. Fortunately, vector-engineering efforts are demonstrating promise in the development of next-generation gene therapy vectors that can overcome these barriers. This review highlights key historical trends in clinical gene therapy, the recent clinical successes of viral-based gene therapy, and current research that may enable future clinical application.
Full Text Available Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.
Walker-Sperling, Victoria E; Pohlmeyer, Christopher W; Veenhuis, Rebecca T; May, Megan; Luna, Krystle A; Kirkpatrick, Allison R; Laeyendecker, Oliver; Cox, Andrea L; Carrington, Mary; Bailey, Justin R; Arduino, Roberto C; Blankson, Joel N
HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication. © 2016.
Chereau, Fanny; Madec, Yoann; Sabin, Caroline
OBJECTIVE: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. MET...
Daniel E Kaufmann
Full Text Available Early treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI, has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection.Fourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79% patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%, six (43%, and three (21% of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria.These data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low
Sela, Alon; Goldenberg, Dmitri; Ben-Gal, Irad; Shmueli, Erez
Numerus works that study the spread of information in social networks include a spreading mechanism in which a set of nodes is initially infected (i.e. seeded), followed by a viral process, which spontaneously spread the message through the nodes of the network. These models are used to describe the spread of rumors as well as the spread of new products and services. In reality however, it is quite rare that a product or service spreads through a social networks solely by viral forces. It is ...
Hana A. Pawestri
Full Text Available siRNA (small interfering ribonucleic acid adalah sebuah metode yang dapat digunakan untuk mengatasi infeksi virus yang prinsip kerjanya berdasarkan metode komplementer dsRNA (double stranded RNA pada RNA virus sehingga menyebabkan kegagalan proses transkripsi (silencing. Untuk lebih memahami bagaimana proses kerja dan ulasan penelitian siRNA yang terkini, di dalam tulisan ini ditinjau siRNA sebagai metoda yang dikembangkan untuk mengatasi infeksi dan meneliti efeknya pada replikasi beberapa virus seperti Hepatitis C, Influenza, Polio, dan HIV. Kami menemukan bahwa urutan basa nukleotida dari target siRNA sangat penting. Hal tersebut harus homolog dengan target RNA virus dan tidak menganggu RNA sel inang. Untuk mengurangi kegagalan terapi siRNA oleh adanya mutasi, digunakan beberapa siRNA yang sekaligus menjadi target RNA virus yang berbeda. Namun demikian, terapi siRNA masih menghadapi beberapa kesulitan seperti pengiriman (transfer khusus ke jaringan yang terinfeksi dan perlindungan siRNA dari perusakan oleh nuklease. Berdasarkan beberapa penelitian yang telah dilakukan, siRNA dapat digunakan sebagai alternatif untuk mengobati infeksi yang disebabkan oleh virus. Terapi tersebut direkomendasikan untuk dilakukan uji klinis dengan memperhatikan beberapa aspek seperti desain siRNA dan mekanisme transfer. (Health Science Indones 2010; 1: 58 - 65 Kata kunci: siRNA, infeksi virus, target virus, alternatif terapi Abstract SiRNA is a promising method to deal with viral infections. The principle of siRNA is based on the complementarily of (synthetic dsRNA to an RNA virus which, in consequence, will be silenced. Many studies are currently examining the effects of siRNA on replication of diverse virus types like Hepatitis C, polio and HIV. The choice of the siRNA target sequence is crucial. It has to be very homologous to the target RNA, but it cannot target RNA of the host cell. To reduce the possibility for the virus to escape from the siRNA therapy by
Full Text Available Zeeshan Ahmad, Robert A Kratzke Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA Abstract: Oncolytic virotherapy is the use of replication-competent viruses to treat malignancies. The potential of oncolytic virotherapy as an approach to cancer therapy is based on historical evidence that certain viral infections can cause spontaneous remission of both hematologic and solid tumor malignancies. Oncolytic virotherapy may eliminate cancer cells through either direct oncolysis of infected tumor cells or indirect immune-mediated oncolysis of uninfected tumor cells. Recent advances in oncolytic virotherapy include the development of a wide variety of genetically attenuated RNA viruses with precise cellular tropism and the identification of cell-surface receptors that facilitate viral transfer to the tissue of interest. Current research is also focused on targeting metastatic disease by sustaining the release of progeny viruses from infected tumor cells and understanding indirect tumor cell killing through immune-mediated mechanisms of virotherapy. The purpose of this review is to critically evaluate recent evidence on the clinical development of tissue-specific viruses capable of targeting tumor cells and eliciting secondary immune responses in lung cancers and mesothelioma. Keywords: lung cancer, mesothelioma, VSV, adenovirus, measles
Since 1996, Infection caused by the human immunodeficiency virus(HIV) can be successfully treated with a combination therapy of 3 antiviral drugs from 2 different classes. Life expectancy has increased dramatically by this treatment. Especially in the early years these combination therapies had many
Ramanan, Vyas; Trehan, Kartik; Ong, Mei Lyn; Luna, Joseph M.; Hoffmann, Hans Heinrich; Espiritu, Christine; Sheahan, Timothy P.; Chandrasekar, Hamsika; Schwartz, Robert E.; Christine, Kathleen S.; Rice, Charles M.; van Oudenaarden, Alexander; Bhatia, Sangeeta N.
Hepatitis C virus (HCV) is a positive single-stranded RNA virus of enormous global health importance, with direct-acting antiviral therapies replacing an immunostimulatory interferon-based regimen. The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have
Ramanan, Vyas; Trehan, Kartik; Ong, Mei-Lyn; Luna, Joseph M; Hoffmann, Hans-Heinrich; Espiritu, Christine; Sheahan, Timothy P; Chandrasekar, Hamsika; Schwartz, Robert E; Christine, Kathleen S; Rice, Charles M; van Oudenaarden, Alexander; Bhatia, Sangeeta N
Hepatitis C virus (HCV) is a positive single-stranded RNA virus of enormous global health importance, with direct-acting antiviral therapies replacing an immunostimulatory interferon-based regimen. The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have
Kasala, Dayananda; Yoon, A-Rum; Hong, Jinwoo; Kim, Sung Wan; Yun, Chae-Ok
Viral vectors are promising gene carriers for cancer therapy. However, virus-mediated gene therapies have demonstrated insufficient therapeutic efficacy in clinical trials due to rapid dissemination to nontarget tissues and to the immunogenicity of viral vectors, resulting in poor retention at the disease locus and induction of adverse inflammatory responses in patients. Further, the limited tropism of viral vectors prevents efficient gene delivery to target tissues. In this regard, modification of the viral surface with nanomaterials is a promising strategy to augment vector accumulation at the target tissue, circumvent the host immune response, and avoid nonspecific interactions with the reticuloendothelial system or serum complement. In the present review, we discuss various chemical modification strategies to enhance the therapeutic efficacy of viral vectors delivered either locally or systemically. We conclude by highlighting the salient features of various nanomaterial-coated viral vectors and their prospects and directions for future research.
Rubin, Adam D; Hogikyan, Norman D; Oh, Alex; Feldman, Eva L
The aims of this study were to demonstrate the ability to enhance nerve regeneration by remote delivery of a viral vector to the crushed recurrent laryngeal nerve (RLN), to demonstrate the usefulness of a crushed RLN model to test the efficacy of viral gene therapy, and to discuss future potential applications of this approach. Animal study. Adult Sprague-Dawley rats were assigned to two groups. In the experimental group, an adeno-associated viral (AAV) vector carrying a zinc-finger transcription factor, which stimulates endogenous insulinlike growth factor I production (AAV2-TO-6876vp16), was injected into the crushed RLN. In the control group, an AAV vector carrying the gene for green fluorescent protein was injected into the crushed RLN. Unilateral RLN paralysis was confirmed endoscopically. At 1 week, laryngeal endoscopies were repeated and recorded. Larynges were cryosectioned in 15-μm sections and processed for acetylcholine histochemistry (motor endplates) followed by neurofilament immunoperoxidase (nerve fibers). Percentage nerve-endplate contact (PEC) was determined and compared. Vocal fold motion was evaluated by blinded reviewers using a visual analogue scale (VAS). The difference between PEC on the crushed and uncrushed sides was statistically less in the experimental group (0.54 ± 0.18 vs. 0.30 ± 0.26, P = .0006). The VAS score at 1 week was significantly better in the experimental group (P = .002). AAV2-TO-6876vp16 demonstrated a neurotrophic effect when injected into the crushed RLN. The RLN offers a conduit for viral gene therapy to the brainstem that could be useful for the treatment of RLN injury or bulbar motor neuron disease. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.
... Oncolytic Viral Cancer Therapies AGENCY: National Institutes of Health, Public Health Service, HHS. ACTION... gene is expressed. For example, the foreign DNA can be related to a viral pathogen, tumor- associated... subject, the foreign gene is expressed in vivo to elicit an immune response or express the therapeutic...
Engelen, B.; Engelhardt, T.; Sahlberg, M.; Cypionka, H.
The marine deep biosphere represents the largest biotope on Earth. Throughout the last years, we have obtained interesting insights into its microbial community composition. However, one component that was completely overlooked so far is the viral inventory of deep-subsurface sediments. While viral infections were identified to have a major impact on the benthic microflora of deep-sea surface sediments (Danavaro et al. 2008), no studies were performed on deep-biosphere samples, so far. As grazers probably play only a minor role in anoxic and highly compressed deep sediments, viruses might be the main “predators” for indigenous microorganisms. Furthermore, the release of cell components, called “the viral shunt”, could have a major impact on the deep biosphere in providing labile organic compounds to non-infected microorganisms in these generally nutrient depleted sediments. However, direct counting of viruses in sediments is highly challenging due to the small size of viruses and the high background of small particles. Even molecular surveys using “universal” PCR primers that target phage-specific genes fail due to the vast phage diversity. One solution for this problem is the lysogenic viral life cycle as many bacteriophages integrate their DNA into the host genome. It is estimated that up to 70% of cultivated bacteria contain prophages within their genome. Therefore, culture collections (Batzke et al. 2007) represent an archive of the viral composition within the respective habitat. These prophages can be induced to become free phage particles in stimulation experiments in which the host cells are set under certain stress situations such as a treatment with UV exposure or DNA-damaging antibiotics. The study of the viral component within the deep biosphere offers to answer the following questions: To which extent are deep-biosphere populations controlled by viral infections? What is the inter- and intra-specific diversity and the host-specific viral
Liu, Yang; Wang, Dong-An
There are safety concerns regarding viral vectors in regenerative medicine research because of adverse experiences in conventional gene therapy with systemic delivery of recombinant virus. Transgenic cell therapy emerges as an attractive strategy, in which the genes of interest are delivered in vitro into isolated cells first; instead of transgene vectors, these transgenic cells are then implanted back to the host. This ex vivo strategy enables the examination of cell viability and phenotype before subsequent transplantation and prevents to the most extent the potential delivery-related hazards caused by exposure of viral components to the host. The transgenic implants are often localized, thus traceable for safety monitoring except those cases involving systemic distribution of transgenic cells. The safety of ex vivo process used in viral vector-mediated transgenic cell therapy for regenerative medicine purpose. Safety concerns related to viral vector delivery can be dispelled in the majority of regenerative medicine applications by transgenic cell therapy. The ex vivo process executes in vitro transfection before subsequent transplantation of transgenic cells so that it avoids the exposure of viral components (particularly capsids or envelops) to the host, while this exposure is inevitable in conventional in vivo gene therapy. Besides, the practice of localized cell implantation and in vitro manipulation also reinforce the safety of transgenic cell therapy. Given the significantly reduced delivery-related hazard, viral vector-mediated transgenic cell therapy can be generally considered as a safe approach for most regenerative medicine applications.
Steer, H W
Four patients are described who developed pseudomembranous colitis in association with clindamycin therapy. Rectal biopsies from two patients were studied with the electron microscope and compared with the ultrastructural appearance of the rectal mucosa from seven normal people. Ultrastructural evidence for a viral colitis was obtained. The significance of the clindamycin therapy to the viral colitis and the contribution of the viral colitis to the clinical state are discussed. Images Fig 2 Fig 3 Fig 4 Fig 5 Fig 6 Fig 7 Fig 8 Fig 9 Fig 10 Fig 11 Fig 12 Fig 13 Fig 14 PMID:1193426
Full Text Available Dear colleagues, continuing the rubric of the journal about the treatment of infectious diseases by medicinal plants, we want to present the methods of using medicinal plants as an additional therapy for treatment of viral hepatitis in addition to the main treatment according to the generally clinical standards of antiviral therapy. Viral hepatitis compiles a large group of human infectious diseases characterized by a predominant liver damage. “Currently, viral hepatitis is recognized as a major public health problem requiring urgent action”, said Dr Margaret Chan, WHO Director-General (WHO Global hepatitis report, 2017. Treatment of viral hepatitis is a complex task and involves the use of generally clinical recommendations or standards. There are criteria for determining the need for pharmacotherapy and the most rational scheme for antiviral treatment in every case of viral hepatitis. The purpose of antiviral therapy is to achieve a stable virologic response, to prevent the progression of the disease, the development of cirrhosis and hepatocellular carcinoma. However, at the present stage a stable virologic response in the general population of patients can be achieved in approximately 60 % of cases. In addition, standard antiviral drugs have side effects, are of high cost and are contraindicated in a number of clinical situations, for example, with a decrease in the number of blood elements (thrombocytopenia, leukopenia, anemia, at the stage of decompensated liver cirrhosis. Probably, all this induces to use alternative methods of therapy, which remain popular both among general practitioners and patients with this infection. The question of the treatment of viral hepatitis with medicinal herbs has been studied for a long time. According to some authors, there is no scientific evidence that hepatitis C can be cured by herbs. The only scientifically proven method of fighting the virus is antiviral therapy. However, there are other points
Full Text Available Allogeneic transplantation with CCR5-delta 32 (CCR5-d32 homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN, clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9, transcription activator-like effectors nuclease (TALEN, short hairpin RNA (shRNA, and a ribozyme. While there are multiple gene therapy strategies being tested, in this review we reflect on our current knowledge of inhibition of CCR5 specifically and whether this approach allows for consequent viral escape.
Chereau, Fanny; Madec, Yoann; Sabin, Caroline; Obel, Niels; Ruiz-Mateos, Ezequiel; Chrysos, Georgios; Fidler, Sarah; Lehmann, Clara; Zangerle, Robert; Wittkop, Linda; Reiss, Peter; Hamouda, Osamah; Estrada Perez, Vicente; Leal, Manuel; Mocroft, Amanda; Garcia De Olalla, Patricia; Ammassari, Adriana; D'Arminio Monforte, Antonella; Mussini, Cristina; Segura, Ferran; Castagna, Antonella; Cavassini, Matthias; Grabar, Sophie; Morlat, Philippe; De Wit, Stéphane; Lambotte, Olivier; Meyer, Laurence
HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.
Denis Berdasquera Corcho
Full Text Available A pesar de las mejorías sanitarias que existen en muchos países del mundo, la hepatitis viral A continúa siendo un problema de salud que se presenta en forma de brotes y estos con mayor frecuencia en instituciones cerradas como son los círculos infantiles, los jardines de la infancia, las escuelas semiinternas y de régimen interno, así como en campamentos y unidades militares, entre otras. En este artículo se realiza una revisión documental sobre el tema, y se resumen las principales medidas que el personal de la Atención Primaria de Salud debe tomar en el control de foco de la hepatitis viral A en instituciones cerradas.In spite of the sanitation improvement in many countries, viral hepatitis A remains a health problem that occurs in the form of outbreaks which very frequently affect enclosed institutions such as day-care centers, kindergartens, boarding schools, camps, and military barracks, among others. This article makes a documentary review on the topic and summarizes the main measures that the primary health care personnel should take to control viral hepatitis A foci in enclosed institutions.
Full Text Available Silicon plays an important role in providing tolerance to various abiotic stresses and augmenting plant resistance against diseases. However, there is a paucity of reports about the effect of silicon on bacterial and viral pathogens of plants. In general, the effect of silicon on plant resistance against bacterial diseases is considered to be due to either physical defense or increased biochemical defense. In this study, the interaction between silicon foliar or soil-treatments and reduced bacterial and viral severity was reviewed. The current review explains the agricultural importance of silicon in plants, refers to the control of bacterial pathogens in different crop plants by silicon application, and underlines the different mechanisms of silicon-enhanced resistance. A section about the effect of silicon in decreasing viral disease intensity was highlighted. By combining the data presented in this study, a better comprehension of the complex interaction between silicon foliar- or soil-applications and bacterial and viral plant diseases could be achieved.
Full Text Available Two mammalian introns, the human growth hormone intron and the Simian virus 40 large T antigen intron, were inserted into the coding sequences of diphtheria toxin fragment A (DT-A and barnase (Bar, respectively, to disrupt their open-reading frames (ORFs. Expression of these two toxic proteins were totally abolished, which enabled the production of normal levels of recombinant baculoviral and adeno-associated viral (AAV vectors in insect cells. When these viral vectors were introduced into mammalian cells, the introns were spliced out and the toxic proteins were expressed, which resulted in apoptosis in mammalian cells. This is the first report to show that viral vectors harboring toxin genes can be produced at normal levels by exploiting the intron-splicing mechanism of insect cells. Furthermore, viral vectors carrying the DT-A gene under control of tumor-specific promoters were able to exert tumor-specific cell killing. This novel method to produce viral vectors harboring toxic genes under control of tumor-specific promoter offers a powerful tool for further research, as well as for the development of toxin-based suicide gene therapy drugs.
Victoria E. Walker-Sperling
Full Text Available HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of <100 copies/mL. She did not have any known protective HLA alleles, but significant immune activation of CD8+ T cells and natural killer (NK cells was present, and both cell types inhibited viral replication. Virus cultured from this patient replicated as well in vitro as virus isolated from her partner, a patient with AIDS who was the source of transmission. Virologic breakthrough occurred 9 months after her initial presentation and was associated with an increase in CD4+ T cell activation levels and a significant decrease in NK cell inhibitory capacity. Remarkably, CD8+ T cell inhibitory capacity was preserved and there were no new escape mutations in targeted Gag epitopes. These findings suggest that fully replication-competent virus can be controlled in acute HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication.
Barik, Sailen; Lu, Patrick
Chemically synthesized short interfering RNA (siRNA) has ushered a new era in the application of RNA interference (RNAi) against viral genes. We have paid particular attention to respiratory viruses that wreak heavy morbidity and mortality worldwide. The clinically significant ones include respiratory syncytial virus (RSV), parainfluenza virus (PIV) (two Paramyxoviruses), and influenza virus (an Orthomyxovirus). As the infection by these viruses is clinically restricted to the respiratory tissues, mainly the lungs, the logical route for the application of the siRNA was also the same, i.e., via the nasal route. Following the initial success of single intranasal siRNA against RSV, we now offer two new strategies: (1) second-generation siRNAs, used against the paramyxoviral RNA polymerase large subunit (L), (2) siRNA cocktail with a novel transfection reagent, used against influenza virus. Based on these results, we propose the following consensus for designing intranasal antiviral siRNAs: (a) modified 19-27 nt-long double-stranded siRNAs are functional in the lung, (b) excessive 2'-OMe and 2'-F modifications in either or both strands of these siRNAs reduce efficacy, (c) limited modifications in the sense strand are beneficial, although their precise efficacy may be position-dependent, (d) cocktail of multiple siRNAs can be highly effective against multiple viral strains and subtypes.
Zibert, John Robert; Wallbrecht, Katrin; Schön, Margarete
with epidermal expression of human TGF-ß1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM...... in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.......-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue...
Full Text Available Introduction: Truvada is licenced for HIV-1 prevention in the USA and is available in the private sector. Tenofovir performed as well as Truvada in the PARTNERS PrEP study and is used as HIV pre-exposure prophylaxis (PreP in some settings. The clinical efficacy of Tenofovir for PrEP outside a clinical trial is unknown. Antiretroviral therapy (ART at acute HIV-1 infection (AHI limits the size of the reservoir, optimizing the chance of maintaining viral control off therapy. As such ART at acute HIV infection is proposed to offer a functional cure in a minority of subjects. We present two cases where Tenofovir PrEP failed to prevent HIV acquisition and failed to limit viral reservoir. Materials and Methods: Two individuals receiving tenofovir monotherapy for Hepatitis B monoinfection were diagnosed with AHI as defined by a negative HIV antibody test within three months of a positive HIV test following unsafe sex with casual male partners. In-depth histories were taken. Viral genotypes and Tenofovir drug levels were measured from samples taken as close to HIV seroconversion as possible and subsequent samples were analyzed for proviral Total HIV-1 DNA by qPCR. Results: Patient A had received tenofovir for the preceding six years and always maintained an undetectable Hepatitis B viral load with no concerns about adherence. Two weeks preceding the positive HIV antibody test, he experienced mild symptoms (fever, pharyngitis of HIV seroconversion. HIV status was confirmed by a repeat fourth generation HIV antibody test and by Western Blot and an HIV viral load was undetectable. Tenofovir trough level at HIV diagnosis was within normal limits. The regimen was intensified to Eviplera and a total HIV-1 DNA was 1381 copies/million CD4 T cells. Patient B received four regimens for hepatitis B treatment before starting tenofovir monotherapy in 2011 and subsequently maintained an undetectable hepatitis B viral load. After three years of tenofovir monotherapy he
Arun K. Nalla
Full Text Available Stem cell gene therapy approaches for Human Immunodeficiency Virus (HIV infection have been explored in clinical trials and several anti-HIV genes delivered by retroviral vectors were shown to block HIV replication. However, gammaretroviral and lentiviral based retroviral vectors have limitations for delivery of anti-HIV genes into hematopoietic stem cells (HSC. Foamy virus vectors have several advantages including efficient delivery of transgenes into HSC in large animal models, and a potentially safer integration profile. This review focuses on novel anti-HIV transgenes and the potential of foamy virus vectors for HSC gene therapy of HIV.
Liras, A; Olmedillas, S
High-purity plasma-derived and recombinant factors are currently safe and efficient treatment for haemophilia. The mid-term future of haemophilia treatment will involve the use of modified recombinant factors to achieve advantages such as decreased immunogenicity in inhibitor formation and enhanced efficacy as a result of their longer half-life. In the long-term, gene therapy and cell therapy strategies will have to be considered. Achievements in cell therapy to date have been using embryonic stem cells and hepatic sinusoidal endothelial cells. Current gene therapy strategies for haemophilia are based on gene transfer using adeno-associated viruses and non-viral vectors. Gene therapy for haemophilia is justified because it is a chronic disease and because a very regular factor infusion is required that may involve fatal risks and because it is very expensive. Haemophilia is a very good candidate for use of gene therapy protocols because it is a monogenic disease, and even low expression is able to achieve reversion from a severe to a moderate phenotype. The current trends in haemophilia using adeno-associated viral vectors are safe but also involve immunogenicity problems. The other alternatives are non-viral vectors. There have been in recent years relevant advances in non-viral transfection that raise hope for considering this possibility. Several research groups are opting for this experimental alternative. An expression over 5%, representing a moderate phenotype, for a few months with a high safety, regarding vector, transfected cells, and implantation procedure, would already be a great success. This may represent an intermediate protocol in which the expression levels and times obtained are lower and shorter respectively as compared to viral vectors, but which provide a potential greater patient safety. This may more readily win acceptance among both patients and haematologists because fatal events in the past due to HIV/HCV infection may constrain the
Uta Griesenbach; Makoto Inoue; Mamoru Hasegawa; et al
Uta Griesenbach1, Makoto Inoue2, Mamoru Hasegawa2, Eric WFW Alton11Department of Gene Therapy, Imperial College London, UK; The UK Cystic Fibrosis Gene Therapy Consortium; 2DNAVEC Corporation, Tsukuba, JapanAbstract: Gene transfer to the airway epithelium has been more difficult than originally anticipated, largely because of significant extra- and intracellular barriers in the lung. In general, viral vectors are more adapted to overcoming these barriers than nonviral gene transfer agents and...
Sanchala, Dhaval S; Bhatt, Lokesh K; Prabhavalkar, Kedar S
Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.
Akbulut, Talha; Park, Frank
Many pediatric diseases have reached a therapeutic plateau using currently available surgical and pharmacological approaches. Gene therapy has emerged as an exciting new technology to manipulate cells in the mammalian system, and in some cases, this method has achieved amazing therapeutic benefits. Compared to other organs, such as the brain, liver and lung, methods to genetically modify renal cells have received relatively little attention. The current review will discuss the challenges and ...
Vandenberghe, L H; Auricchio, A
Vectors derived from adeno-associated virus (AAV) are currently the most promising vehicles for therapeutic gene delivery to the retina. Recently, subretinal administration of AAV2 has been demonstrated to be safe and effective in patients with a rare form of inherited childhood blindness, suggesting that AAV-mediated retinal gene therapy may be successfully extended to other blinding conditions. This is further supported by the great versatility of AAV as a vector platform as there are a large number of AAV variants and many of these have unique transduction characteristics useful for targeting different cell types in the retina including glia, epithelium and many types of neurons. Naturally occurring, rationally designed or in vitro evolved AAV vectors are currently being utilized to transduce several different cell types in the retina and to treat a variety of animal models of retinal disease. The continuous and creative development of AAV vectors provides opportunities to overcome existing challenges in retinal gene therapy such as efficient transfer of genes exceeding AAV's cargo capacity, or the targeting of specific cells within the retina or transduction of photoreceptors following routinely used intravitreal injections. Such developments should ultimately advance the treatment of a wide range of blinding retinal conditions.
Fridlender, Zvi G; Sun, Jing; Singhal, Sunil; Kapoor, Veena; Cheng, Guanjun; Suzuki, Eiji; Albelda, Steven M
The most widely used approach to cancer immunotherapy is vaccines. Unfortunately, the need for multiple administrations of antigens often limits the use of one of the most effective vaccine approaches, immunogene therapy using viral vectors, because neutralizing antibodies are rapidly produced. We hypothesized that after viral immunogene therapy “primed” an initial strong antitumor immune response, subsequent “boosts” could be provided by sequential courses of chemotherapy. Three adenoviral (Ad)-based immunogene therapy regimens were administered to animals with large malignant mesothelioma and lung cancer tumors followed by three weekly administrations of a drug regimen commonly used to treat these tumors (Cisplatin/Gemcitabine). Immunogene therapy followed by chemotherapy resulted in markedly increased antitumor efficacy associated with increased numbers of antigen-specific, activated CD8+ T-cells systemically and within the tumors. Possible mechanisms included: (i) decreases in immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T-regulatory cells (T-regs), and B-cells, (ii) stimulation of memory cells by intratumoral antigen release leading to efficient cross-priming, (iii) alteration of the tumor microenvironment with production of “danger signals” and immunostimulatory cytokines, and (iv) augmented trafficking of T-cells into the tumors. This approach is currently being tested in a clinical trial and could be applied to other trials of viral immunogene therapy. PMID:20683443
Levi-Drummer Rachel S
Full Text Available Abstract Background High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. Methods A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15 with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9 with no dose reduction. Results Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. Conclusions These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C.
Full Text Available Infections are still an important cause of mortality and morbidity in pediatric cancer patients. Most of the febrile episodes in immunocompromised patients are classified as a fever of unknown origin (FUO while bacteria are the more frequent causes of documented infections. Viral infections are also feared during chemotherapy but less data are available on their incidence and morbidity. We reviewed the literature on incidence, morbidity, and mortality of viral infections in children undergoing chemotherapy and discussed the evidence concerning the prophylaxis and the therapy.
Full Text Available Uta Griesenbach1, Makoto Inoue2, Mamoru Hasegawa2, Eric WFW Alton11Department of Gene Therapy, Imperial College London, UK; The UK Cystic Fibrosis Gene Therapy Consortium; 2DNAVEC Corporation, Tsukuba, JapanAbstract: Gene transfer to the airway epithelium has been more difficult than originally anticipated, largely because of significant extra- and intracellular barriers in the lung. In general, viral vectors are more adapted to overcoming these barriers than nonviral gene transfer agents and are, therefore, more efficient in transferring genes into recipient cells. Viral vectors derived from adenovirus, adeno-associated virus, and Sendai virus, which all have a natural tropism for the airway epithelium, have been evaluated for cystic fibrosis (CF gene therapy. Although these vectors transduce airway epithelial cells efficiently, gene expression is transient and repeated administration is inefficient. They are, therefore, unlikely to be suitable for CF gene therapy. More recently, lentiviruses (LV have been assessed for lung gene transfer. In contrast to retroviruses, they transduce nondividing cells and randomly integrate into the genome. However, LVs do not have a natural tropism for the lung, and a significant amount of effort has been put into pseudotyping these vectors with proteins suitable for airway gene transfer. Several studies have shown that LV-mediated transduction leads to persistent gene expression (for the lifetime of the animal in the airways and, importantly, repeated administration is feasible. Thus, appropriately pseudotyped LV vectors are promising candidates for CF gene therapy. Here, we will review preclinical and clinical research related to viral CF gene therapy.Keywords: cystic fibrosis, gene therapy, adenovirus, AAV, lentivirus, Sendai virus
Teunissen, Jasmijn; Hochs, Anne H J; Vaessen-Verberne, Anja; Boehmer, Annemie L M; Smeets, Carien C J M; Brackel, Hein; van Gent, René; Wesseling, Judith; Logtens-Stevens, Danielle; de Moor, Ronald; Rosias, Philippe P R; Potgieter, Steph; Faber, Marianne R; Hendriks, Han J E; Janssen-Heijnen, Maryska L G; Loza, Bettina F
Bronchiolitis is a common disorder in young children that often results in hospitalisation. Except for a possible effect of nebulised hypertonic saline (sodium chloride), no evidence-based therapy is available. This study investigated the efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis. In this multicentre, double-blind, randomised, controlled trial, children hospitalised with acute viral bronchiolitis were randomised to receive either nebulised 3%, 6% hypertonic saline or 0.9% normal saline during their entire hospital stay. Salbutamol was added to counteract possible bronchial constriction. The primary endpoint was the length of hospital stay. Secondary outcomes were need for supplemental oxygen and tube feeding. From the 292 children included in the study (median age 3.4 months), 247 completed the study. The median length of hospital stay did not differ between the groups: 69 h (interquartile range 57), 70 h (IQR 69) and 53 h (IQR 52), for 3% (n=84) and 6% (n=83) hypertonic saline and 0.9% (n=80) normal saline, respectively, (p=0.29). The need for supplemental oxygen or tube feeding did not differ significantly. Adverse effects were similar in the three groups. Nebulisation with hypertonic saline (3% or 6% sodium chloride) although safe, did not reduce the length of stay in hospital, duration of supplemental oxygen or tube feeding in children hospitalised with moderate-to-severe viral bronchiolitis. ©ERS 2014.
Mutnal, Manohar B; Hu, Shuxian; Schachtele, Scott J; Lokensgard, James R
Previous studies have demonstrated the existence of a subset of B lymphocytes, regulatory B cells (Bregs), which modulate immune function. In this study, in vivo and in vitro experiments were undertaken to elucidate the role of these Bregs in controlling neuroinflammation following viral brain infection. We used multicolor flow cytometry to phenotype lymphocyte subpopulations infiltrating the brain, along with in vitro cocultures to assess their anti-inflammatory and immunoregulatory roles. This distinctive subset of CD19(+)CD1d(hi)CD5(+) B cells was found to infiltrate the brains of chronically infected animals, reaching highest levels at the latest time point tested (30 d postinfection). B cell-deficient Jh(-/-) mice were found to develop exacerbated neuroimmune responses as measured by enhanced accumulation and/or retention of CD8(+) T cells within the brain, as well as increased levels of microglial activation (MHC class II). Conversely, levels of Foxp3(+) regulatory T cells were found to be significantly lower in Jh(-/-) mice when compared with wild-type (Wt) animals. Further experiments showed that in vitro-generated IL-10-secreting Bregs (B10) were able to inhibit cytokine responses from microglia following stimulation with viral Ags. These in vitro-generated B10 cells were also found to promote proliferation of regulatory T cells in coculture studies. Finally, gain-of-function experiments demonstrated that reconstitution of Wt B cells into Jh(-/-) mice restored neuroimmune responses to levels exhibited by infected Wt mice. Taken together, these results demonstrate that Bregs modulate T lymphocyte as well as microglial cell responses within the infected brain and promote CD4(+)Foxp3(+) T cell proliferation in vitro. Copyright © 2014 by The American Association of Immunologists, Inc.
Influence of induction therapy, immunosuppressive regimen and anti-viral prophylaxis on development of lymphomas after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry.
Crespo-Leiro, Maria G; Alonso-Pulpón, Luis; Arizón, José M; Almenar, Luis; Delgado, Juan F; Palomo, Jesús; Manito, Nicolás; Rábago, Gregorio; Lage, Ernesto; Diaz, Beatriz; Roig, Eulalia; Pascual, Domingo; Blasco, Teresa; de la Fuente, Luis; Campreciós, Marta; Vázquez de Prada, José A; Muñiz, Javier
Lymphoma after heart transplantation (HT) has been associated with induction therapy and herpesvirus infection. It is not known whether anti-viral agents administered immediately after HT can reduce the incidence of lymphoma. This study was a retrospective review of 3,393 patients who underwent HT in Spain between 1984 and December 2003. Variables examined included development of lymphoma and, as possible risk factors, recipient gender and age, induction therapies (anti-thymocyte globulin, OKT3 and anti-interleukin-2 receptor antibodies) and anti-viral prophylaxis (acyclovir or ganciclovir). To study the effect of evolving treatment strategy, three HT eras were considered: 1984 to 1995; 1996 to 2000; and 2001 to 2003. Induction therapy was employed in >60% of HTs, and anti-viral prophylaxis in >50%. There were 62 cases of lymphoma (3.1 per 1,000 person-years, 95% confidence interval: 2.4 to 4.0). Univariate analyses showed no influence of gender, age at transplant, HT era, pre-HT smoking or the immunosuppressive maintenance drugs used in the first 3 months post-HT. The induction agent anti-thymocyte globulin (ATG) was associated with increased risk of lymphoma, and prophylaxis with acyclovir with decreased risk of lymphoma. Multivariate analyses (controlling for age group, gender, pre-HT smoking and immunosuppression in the first 3 months with mycophenolate mofetil and/or tacrolimus) showed that induction increased the risk of lymphoma if anti-viral prophylaxis was not used (regardless of induction agent and anti-viral agent), but did not increase the risk if anti-viral prophylaxis was used. Induction therapies with ATG or OKT3 do or do not increase the risk of lymphoma depending on whether anti-viral prophylaxis with acyclovir or ganciclovir is or is not employed, respectively.
Curtis L Cooper
Full Text Available Currently, hepatitis C virus (HCV antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.
Shimamura, Munehisa; Sato, Naoyuki; Yoshimura, Shinichi; Kaneda, Yasufumi; Morishita, Ryuichi
VEGF and HGF are pleiotropic factors that regulate cell growth, cell motility, and morphogenesis of various types of cells. The receptors of these growth factors are expressed in neurons and endothelial cells, and are identified as neurotrophic, neuroprotective, and angiogenic factors. Indeed, gene therapy using viral vectors encoding the VEGF or HGF gene has been reported to be effective for preventing the expansion of ischemic injury. However, the safety issue of viral vectors is a major problem in clinical application. To overcome this problem, we have developed an HVJ-based non-viral vector, which achieves high-efficiency transfection rates of viral vectors with the safety of liposomes. This review discusses the feasibility of gene therapy using an HVJ-based non-viral vector containing the VEGF or HGF gene for cerebral ischemia.
Juanes, José M; Gallego, Asunción; Tárraga, Joaquín; Chaves, Felipe J; Marín-Garcia, Pablo; Medina, Ignacio; Arnau, Vicente; Dopazo, Joaquín
The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use. Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org . Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.
Weber, Nicholas K; Forman, Lisa M; Trotter, James F
Hepatitis B (HBV) is an uncommon indication for liver transplantation in the US accounting for approximately 5% of cases. Recurrence prophylaxis is typically long-term hepatitis B immune-globulin (HBIg) and an oral anti-HBV agent. Because of high HBIg costs and improving efficacy of new oral agents, there is increasing interest in HBIg discontinuation. To describe results of a protocol at our center including HBV vaccination and HBIg discontinuation. All patients received HBIg therapy and an oral anti-viral agent from the time of transplant. Patients transplanted for HBV with a stable post-operative clinical course underwent HBV vaccination and HBIg discontinuation. After HBIg discontinuation, patients were monitored for HBV recurrence for at least one year. Recurrence was defined as either viral (HBV-DNA 10(4) copies/ml on two consecutive occasions) or hepatitis (viral recurrence with elevated liver transaminases). Of 1182 recipients, 36 (3%) had HBV. Twenty-four were excluded from the protocol, and the remaining 12 patients underwent HBIg withdrawal. Median age at HBIg discontinuation was 56 (range, 36-70) years, median time from transplant to HBIg discontinuation was 62.8 (range, 27.5-128) months, and median time of follow-up after discontinuation was 27.4 (range, 13-69) months. Of the 12 patients vaccinated, no patients maintained HBSAb >or= 10 IU/l at last follow-up. There was no viral or hepatitis recurrence and no deaths or graft loss. HBIg discontinuation with maintenance oral anti-viral monotherapy is safe and effective for HBV liver transplant recipients. Vaccination is not effective in this population.
Emdad, Luni; Das, Swadesh K; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B
In principle, viral gene therapy holds significant potential for the therapy of solid cancers. However, this promise has not been fully realized and systemic administration of viruses has not proven as successful as envisioned in the clinical arena. Our research is focused on developing the next generation of efficacious viruses to specifically treat both primary cancers and a major cause of cancer lethality, metastatic tumors (that have spread from a primary site of origin to other areas in the body and are responsible for an estimated 90% of cancer deaths). We have generated a chimeric tropism-modified type 5 and 3 adenovirus that selectively replicates in cancer cells and simultaneously produces a secreted anti-cancer toxic cytokine, melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24), referred to as a Cancer Terminator Virus (CTV) (Ad.5/3-CTV). In preclinical animal models, injection into a primary tumor causes selective cell death and therapeutic activity is also observed in non-injected distant tumors, i.e., "bystander anti-tumor activity". To enhance the impact and therapeutic utility of the CTV, we have pioneered an elegant approach in which viruses are encapsulated in microbubbles allowing "stealth delivery" to tumor cells that when treated with focused ultrasound causes viral release killing tumor cells through viral replication, and producing and secreting MDA-7/IL-24, which stimulates the immune system to attack distant cancers, inhibits tumor angiogenesis and directly promotes apoptosis in distant cancer cells. This strategy is called UTMD (ultrasound-targeted microbubble-destruction). This novel CTV and UTMD approach hold significant promise for the effective therapy of primary and disseminated tumors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Kranzusch, Philip J; Whelan, Sean P J
Arenaviruses form a noncytolytic infection in their rodent hosts, yet can elicit severe hemorrhagic disease in humans. How arenaviruses regulate gene expression remains unclear, and further understanding may provide insight into the dichotomy of these disparate infection processes. Here we reconstitute arenavirus RNA synthesis initiation and gene expression regulation in vitro using purified components and demonstrate a direct role of the viral Z protein in controlling RNA synthesis. Our data reveal that Z forms a species-specific complex with the viral polymerase (L) and inhibits RNA synthesis initiation by impairing L catalytic activity. This Z-L complex locks the viral polymerase in a promoter-bound, catalytically inactive state and may additionally ensure polymerase packaging during virion maturation. Z modulates host factors involved in cellular translation, proliferation, and antiviral signaling. Our data defines an additional role in governing viral RNA synthesis, revealing Z as the center of a network of host and viral connections that regulates viral gene expression.
Kranzusch, Philip J.; Whelan, Sean P. J.
Arenaviruses form a noncytolytic infection in their rodent hosts, yet can elicit severe hemorrhagic disease in humans. How arenaviruses regulate gene expression remains unclear, and further understanding may provide insight into the dichotomy of these disparate infection processes. Here we reconstitute arenavirus RNA synthesis initiation and gene expression regulation in vitro using purified components and demonstrate a direct role of the viral Z protein in controlling RNA synthesis. Our data reveal that Z forms a species-specific complex with the viral polymerase (L) and inhibits RNA synthesis initiation by impairing L catalytic activity. This Z–L complex locks the viral polymerase in a promoter-bound, catalytically inactive state and may additionally ensure polymerase packaging during virion maturation. Z modulates host factors involved in cellular translation, proliferation, and antiviral signaling. Our data defines an additional role in governing viral RNA synthesis, revealing Z as the center of a network of host and viral connections that regulates viral gene expression. PMID:22106304
Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.......Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load....
This document is a consensus statement, produced at the request of the American College of Veterinary Internal Medicine that reflects the opinion of an expert panel regarding the prevalence and host range, clinical manifestations, and the potential for ultimate eradication of bovine viral diarrhea v...
Colella, Pasqualina; Auricchio, Alberto
Inherited retinopathies (IRs) are common and untreatable blinding conditions inherited mostly as monogenic due to mutations in genes expressed in retinal photoreceptors (PRs) and in retinal pigment epithelium (RPE). Over the last two decades, the retina has emerged as one of the most favorable target tissues for gene therapy given its small size and its enclosed and immune-privileged environment. Different types of viral vectors have been developed, especially those based on the adeno-associated virus (AAV), which efficiently deliver therapeutic genes to PRs or RPE upon subretinal injections. Dozens of successful proofs of concept of the efficacy of gene therapy for recessive and dominant IRs have been generated in small and large models that have paved the way to the first clinical trials using AAV in patients with Leber congenital amaurosis, a severe form of childhood blindness. The results from these initial trials suggest that retinal gene therapy with AAV is safe in humans, that vision can be improved in patients that have suffered from severe impairment of visual function, in some cases for decades, and that readministration of AAV to the subretinal space is feasible, effective, and safe. However, none of the trials could match the levels of efficacy of gene therapy observed in a dog model of the disease, suggesting that there is room for improvement. In conclusion, these results bode well for further testing of AAV-mediated retinal gene therapy in patients with other monogenic and complex forms of blindness.
Maintenance of T1 response as induced during PEG-IFNalpha plus ribavirin therapy controls viral replication in genotype-1 patients with chronic hepatitis C La respuesta inmune T1 inducida durante el tratamiento con PEG-IFNα mαs ribavirina controla la replicaciσn viral en pacientes con hepatitis crónica C
(1-1,2 g/día durante 48 semanas. Los 28 pacientes (edad media 45 ± 8 años finalizaron el tratamiento y seguimiento: 12 (43% presentaron respuesta viral sostenida (RVS, 13 recidivaron (47% y sólo 3 fueron no respondedores (10%. Se estudiaron 16 controles sanos (edad media de 39 ± 17 años. Se analizó mediante citometría de flujo la producción intracitoplásmica de IL-4, IFNγ y TNFα por los linfocitos T CD8+ en reposo y tras ser estimulados con un ιster de forbol. Anαlisis estadístico: t de Student, test de χ² y ANOVA; se agrupan los pacientes recidivantes y no respondedores para obtener mayor potencia estadística. Resultados: no se encontraron diferencias significativas entre los niveles de citocinas de controles sanos y pacientes con HCC. Al tercer mes de tratamiento, los niveles de IL-4 inducidos tendían a ser menores en los pacientes que obtuvieron una RVS que en el resto de pacientes (0,97 vs. 2,58; p = 0,1; tampoco se encontró significación estadística en relación a los niveles de IIFNγ y de TTNFα. Al final del tratamiento, la producciσn de IIFNγ estimulado fue significativamente mayor en los pacientes que obtuvieron una RVS (20 vs. 8; p < 0,05. Por el contrario, la producción de IL-4 fue mayor en los pacientes no respondedores, aunque estos datos no alcanzaron significación estadística (p < 0,1. No se encontraron diferencias en relación con los niveles de TTNFα (14 vs. 7; p < 0,2. Conclusiones: el mantenimiento de la respuesta inmune tipo T1 durante el tratamiento combinado, medida en función de la síntesis de IIFNγ por los linfocitos T CD8, se asocia con RVS y sugiere el control de la replicaciσn y el aclaramiento posterior de los pacientes infectados con el genotipo 1 del VHC.
Fernandes, H S; Silva Teixeira, C S; Fernandes, P A; Ramos, M J; Cerqueira, N M F S A
Amino acid depletion in the blood serum is currently being exploited and explored for therapies in tumors or viral infections that are auxotrophic for a certain amino acid or have a metabolic defect and cannot produce it. The success of these treatments is because normal cells remain unaltered since they are less demanding and/or can synthesize these compounds in sufficient amounts for their needs by other mechanisms. Areas covered: This review is focused on amino acid depriving enzymes and their formulations that have been successfully used in the treatment of several types of cancer and viral infections. Particular attention will be given to the enzymes L-asparaginase, L-arginase, L-arginine deiminase, and L-methionine-γ-lyase. Expert opinion: The immunogenicity and other toxic effects are perhaps the major limitations of these therapies, but they have been successfully decreased either through the expression of these enzymes from other organisms, recombination processes, pegylation of the selected enzymes or by specific mutations in the proteins. In 2006, FDA has already approved the use of L-asparaginase in the treatment of acute lymphoblastic leukemia. Other enzymes and in particular L-arginase, L-arginine deiminase, and L-methioninase have been showing promising results in vitro and in vivo studies.
Full Text Available Type I interferons (IFNs are known to mediate viral control, and also promote survival and expansion of virus-specific CD8+ T cells. However, it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. One of the best-characterized anti-viral signaling mechanisms of Type I IFNs is mediated by the IFN-inducible dsRNA activated protein kinase, PKR. Here, we have investigated the role of PKR and Type I IFNs in regulating viral clearance and CD8+ T cell response during primary and secondary viral infections. Our studies demonstrate differential requirement for PKR, in viral control versus elicitation of CD8+ T cell responses during primary infection of mice with lymphocytic choriomeningitis virus (LCMV. PKR-deficient mice mounted potent CD8+ T cell responses, but failed to effectively control LCMV. The compromised LCMV control in the absence of PKR was multifactorial, and linked to less effective CD8+ T cell-mediated viral suppression, enhanced viral replication in cells, and lower steady state expression levels of IFN-responsive genes. Moreover, we show that despite normal expansion of memory CD8+ T cells and differentiation into effectors during a secondary response, effective clearance of LCMV but not vaccinia virus required PKR activity in infected cells. In the absence of Type I IFN signaling, secondary effector CD8+ T cells were ineffective in controlling both LCMV and vaccinia virus replication in vivo. These findings provide insight into cellular pathways of Type I IFN actions, and highlight the under-appreciated importance of innate immune mechanisms of viral control during secondary infections, despite the accelerated responses of memory CD8+ T cells. Additionally, the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity, which have implications in the rational design of vaccines.
Terpstra, C; Kroese, A H
This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.
Silicon plays an important role in providing tolerance to various abiotic stresses and augmenting plant resistance against diseases. However, there is a paucity of reports about the effect of silicon on bacterial and viral pathogens of plants. In general, the effect of silicon on plant resistance against bacterial diseases is considered to be due to either physical defense or increased biochemical defense. In this study, the interaction between silicon foliar or soil-treatments and reduced ba...
Loisel, D A; Du, G; Ahluwalia, T S
BACKGROUND: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. OBJECTIVE: We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses...... and the risk of virus-induced exacerbations during the peak fall season. METHODS: The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication...... differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma....
Cheng, Jian; Tang, Xin; Zhao, Jie; Shi, Ting; Zhao, Peng; Lin, Chao
Nano-polyplexes from bioreducible cationic polymers have a massive promise for cancer gene therapy. However, the feasibility of cationic polyurethanes for non-viral gene therapy is so far not well studied. In this work, a linear cationic polyurethane containing disulfide bonds, urethane linkages and protonable tertiary amino groups was successfully generated by stepwise polycondensation reaction between 2,2'-dithiodiethanol bis(p-nitrophenyl carbonate) and 1,4-bis(3-aminopropyl)piperazine (BAP). We confirmed that the cationic polyurethane (denoted as PUBAP) displayed superior gene delivery properties to its cationic polyamide analogue, thus causing higher in vitro transfection efficiency in MCF-7 and SKOV-3 cells. Besides, further folate-PEGylation and hydrophobic deoxycholic acid (DCA) conjugation to amino-containing PUBAP can be conducted to afford multifunctional polyurethane gene delivery system. After optimization, folate-decorated nano-polyplexes from the PUBAP conjugated with 8 folate-PEG chains and 12 DCA residues exhibited superb colloidal stability under physiological conditions, and performed rapid uptake via folate receptor-mediated endocytosis, efficient intracellular gene release and nucleus translocation into SKOV-3 cells in vitro and in vivo. Importantly, PUBAP based polyplexes possess low cytotoxicity as a result of PUBAP biodegradability. Therefore, marked growth inhibition of SKOV-3 tumor xenografted in Balb/c nude mice was achieved with negligible side effects on the mouse health after intravenous administration of PUBAP based polyplexes with a therapeutic plasmid encoding for TNF-related apoptosis-inducing ligand. This work provides a new insight into biomedical application of bio-responsive polyurethanes for cancer therapy. In this study, we have confirmed that disulfide-based cationic polyurethane presents a new non-viral vector for gene transfer and cancer gene therapy. The significance of this work includes: (1) design and synthesis of a
Full Text Available Kaposi’s sarcoma-associated herpesvirus (KSHV is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing.
Sam, Tanyka Suzanne; Hutton, Heidi E; Lau, Bryan; McCaul, Mary E; Keruly, Jeanne; Moore, Richard; Chander, Geetanjali
Panic symptoms are prevalent among PLWHAs, yet few studies have examined their relationship with HIV outcomes. Using data from an observational cohort study in Baltimore, MD, we examined the association between panic symptoms and antiretroviral therapy (ART) use, medication adherence, and viral suppression. Data were analyzed using generalized estimating equations and adjusted for age, sex, race/ethnicity, cocaine and/or heroin use, clinic enrollment time, alcohol use, and depressive symptoms. Between June 2010 and September 2012, 1195 individuals participated in 2080 audio computer assisted interviews; 9.9 % (n = 118) of individuals endorsed current panic symptoms. In multivariate analysis, panic symptoms were associated with decreased ART use (IRR 0.94; p = 0.05). Panic symptoms were neither associated with medication adherence nor viral suppression. These findings were independent of depressive symptoms and substance use. Panic symptoms are under-recognized in primary care settings and present an important barrier to ART use. Further studies investigating the reasons for this association are needed.
Yan, Chen; Teng, Zhi Ping; Chen, Yun Xin; Shen, Dan Hua; Li, Jin Tao; Zeng, Yi
To explore the viral etiology of human breast cancer to determine whether there are novel molecular targets for gene therapy of breast cancer and provide evidence for the research of gene therapy and vaccine development for breast cancer. PCR was used to screen HPV16 and HPV18 oncogenes E6 and E7 in the SKBR3 cell line and in 76 paraffin embedded breast cancer tissue samples. RNA interference was used to knock down the expression of HPV18 E6 and E7 in SKBR3 cells, then the changes in the expression of cell-cycle related proteins, cell viability, colony formation, metastasis, and cell cycle progression were determined. HPV18 oncogenes E6 and E7 were amplified and sequenced from the SKBR3 cells. Of the patient samples, 6.58% and 23.68% were tested to be positive for HPV18 E6 and HPV18 E7. In the cell culture models, the knockdown of HPV18 E6 and E7 inhibited the proliferation, metastasis, and cell cycle progression of SKBR3 cell. The knockdown also clearly affected the expression levels of cell cycle related proteins. HPV was a contributor to virus caused human breast cancer, suggesting that the oncogenes in HPV were potential targets for gene therapy of breast cancer. Copyright © 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.
Norian, Lyse A. [Department of Urology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); James, Britnie R. [Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); Griffith, Thomas S., E-mail: firstname.lastname@example.org [Department of Urology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States)
Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical and early clinical trials, due to its preferential ability to induce apoptotic cell death in cancer cells and its minimal toxicity. One limitation of TRAIL use is the fact that many tumor types display an inherent resistance to TRAIL-induced apoptosis. To circumvent this problem, researchers have explored a number of strategies to optimize TRAIL delivery and to improve its efficacy via co-administration with other anti-cancer agents. In this review, we will focus on TRAIL-based gene therapy approaches for the treatment of malignancies. We will discuss the main viral vectors that are being used for TRAIL gene therapy and the strategies that are currently being attempted to improve the efficacy of TRAIL as an anti-cancer therapeutic.
Lyse A. Norian
Full Text Available Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL has shown particular promise in pre-clinical and early clinical trials, due to its preferential ability to induce apoptotic cell death in cancer cells and its minimal toxicity. One limitation of TRAIL use is the fact that many tumor types display an inherent resistance to TRAIL-induced apoptosis. To circumvent this problem, researchers have explored a number of strategies to optimize TRAIL delivery and to improve its efficacy via co-administration with other anti-cancer agents. In this review, we will focus on TRAIL-based gene therapy approaches for the treatment of malignancies. We will discuss the main viral vectors that are being used for TRAIL gene therapy and the strategies that are currently being attempted to improve the efficacy of TRAIL as an anti-cancer therapeutic.
Akil, Omar; Seal, Rebecca P; Burke, Kevin; Wang, Chuansong; Alemi, Aurash; During, Matthew; Edwards, Robert H; Lustig, Lawrence R
Mice lacking the vesicular glutamate transporter-3 (VGLUT3) are congenitally deaf due to loss of glutamate release at the inner hair cell afferent synapse. Cochlear delivery of VGLUT3 using adeno-associated virus type 1 (AAV1) leads to transgene expression in only inner hair cells (IHCs), despite broader viral uptake. Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response. Lastly, we demonstrate partial reversal of the morphologic changes seen within the afferent IHC ribbon synapse. These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness. Copyright © 2012 Elsevier Inc. All rights reserved.
Beyer, Marc; Abdullah, Zeinab; Chemnitz, Jens M; Maisel, Daniela; Sander, Jil; Lehmann, Clara; Thabet, Yasser; Shinde, Prashant V; Schmidleithner, Lisa; Köhne, Maren; Trebicka, Jonel; Schierwagen, Robert; Hofmann, Andrea; Popov, Alexey; Lang, Karl S; Oxenius, Annette; Buch, Thorsten; Kurts, Christian; Heikenwalder, Mathias; Fätkenheuer, Gerd; Lang, Philipp A; Hartmann, Pia; Knolle, Percy A; Schultze, Joachim L
Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.
Reekie, J; Mocroft, A; Ledergerber, B
OBJECTIVES: HIV-infected persons experience different patterns of viral suppression after initiating combination antiretroviral therapy (cART). The relationship between such differences and risk of virological failure after starting a new antiretroviral could help with patient monitoring strategies...... to increasing the provision of adherence counselling....
Davies, Mary-Ann; Boulle, Andrew; Technau, Karl; Eley, Brian; Moultrie, Harry; Rabie, Helena; Garone, Daniela; Giddy, Janet; Wood, Robin; Egger, Matthias; Keiser, Olivia
To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. Analysis of data from children (5000 copies/ml on two consecutive occasions treatment in virologically suppressed children. © 2012 Blackwell Publishing Ltd.
V. N. Timchenko
Full Text Available The study included 338 HIV-infected children (B-23 and 350 children with perinatal contact HIV infection (R-75, consisting on the dispensary in the department of maternal and child the St. Petersburg City AIDS Center. In 32 persons (9.5% diagnosed with secondary infections. In the structure of viral opportunistic infections (herpesvirus, SARS amounted to 39.8%, bacterial (bronchitis, tonsillitis, pyoderma, tuberculosis — 34.8%, fungal and parasitic (candidiasis of the oral mucosa, PCP — 25.4 %. Combined therapy (causal, pathogenetic, symptomatic SARS in children with B-23 and R-75, allows you to get in early (6th d. Treatment regress the main symptoms of acute respiratory diseases. Modern therapy of congenital cytomegalovirus infection (VTSMI in children with B-23 and R-75 of the first year of life with antitsitomegalovirusnogo immunoglobulin and preparation of human recombinant interferon alfa-2b in the form of rectal suppositories — VIFERON, causes persistent normalization of clinical and laboratory parameters.
Fidler, Sarah; Olson, Ashley D; Bucher, Heiner C; Fox, Julie; Thornhill, John; Morrison, Charles; Muga, Roberto; Phillips, Andrew; Frater, John; Porter, Kholoud
Few individuals commencing antiretroviral therapy (ART) in primary HIV infection (PHI) maintain undetectable viremia after treatment cessation. Associated factors remain unclear given the importance of the phenomenon to cure research. Using CASCADE data of seroconverters starting ART in PHI (≤6 months from seroconversion), we estimated proportions experiencing viral blips (>400 copies followed by HIV-RNA/mL without alteration of regimen) while on ART. We used Cox models to examine the association between time from ART stop to loss of control (2 consecutive measurements >1000 copies per milliliter) and magnitude and frequency of blips while on ART, time from seroconversion to ART, time on ART, adjusting for mean number of HIV-RNA measurements/year while on ART, and other confounders. Seven hundred seventy-eight seroconverters started ART in PHI with ≥3 HIV-RNA measurements. Median interquartile range (IQR) ART duration was 16.2 (8.0-35.9) months, within which we observed 13% with ≥1 blip. Of 228 who stopped ART, 119 rebounded; time to loss of control was associated with longer interval between seroconversion and ART initiation [hazard ratio (HR) = 1.16 per month; 1.04, 1.28], and blips while on ART (HR = 1.71 per blip; 95% confidence interval = 0.94 to 3.10). Longer time on ART (HR = 0.84 per additional month; 0.76, 0.92) was associated with lower risk of losing control. Of 228 stopping ART, 22 (10%) maintained post treatment control (PTC), ie, HIV-RNA HIV viral blips on therapy are associated with subsequent viral rebound on stopping ART among individuals treated in PHI. Longer duration on ART is associated with a greater chance of PTC.
Full Text Available A major challenge in neurological gene therapy is safe delivery of transgenes to sufficient cell numbers from the circulation or periphery. This is particularly difficult for diseases involving spinal cord motor neurons such as amyotrophic lateral sclerosis (ALS. We have examined the feasibility of non-viral gene delivery to spinal motor neurons from intraperitoneal injections of plasmids carried by ‘immunogene’ nanoparticles targeted for axonal retrograde transport using antibodies. PEGylated polyethylenimine (PEI-PEG12 as DNA carrier was conjugated to an antibody (MLR2 to the neurotrophin receptor p75 (p75NTR. We used a plasmid (pVIVO2 designed for in vivo gene delivery that produces minimal immune responses, has improved nuclear entry into post mitotic cells and also expresses green fluorescent protein (GFP. MLR2-PEI-PEG12 carried pVIVO2 and was specific for mouse motor neurons in mixed cultures containing astrocytes. While only 8% of motor neurons expressed GFP 72 h post transfection in vitro, when the immunogene was given intraperitonealy to neonatal C57BL/6J mice GFP specific motor neuron expression was observed in 25.4% of lumbar, 18.3% of thoracic and 17.0 % of cervical motor neurons, 72 h post transfection. PEI-PEG12 carrying pVIVO2 by itself did not transfect motor neurons in vivo, demonstrating the need for specificity via the p75NTR antibody MLR2. This is the first time that specific transfection of spinal motor neurons has been achieved from peripheral delivery of plasmid DNA as part of a non-viral gene delivery agent. These results stress the specificity and feasibility of immunogene delivery targeted for p75NTR expressing motor neurons, but suggests that further improvements are required to increase the transfection efficiency of motor neurons in vivo.
Huang, Hai; Zhou, Wei; Zhu, Haiyan; Zhou, Pei; Shi, Xunlong
Although current antiviral treatments (nucleoside analogs, NAs) for chronic hepatitis B virus (HBV) infection are effective in suppressing HBV-DNA replication, their clinical outcomes can be compromised by the increasing drug resistance and the inefficiency in promoting HBsAg/HBeAg seroconversion. In this study, we will explore possible effects and mechanism of a natural product baicalin (BA) with the anti-HBV efficacy of entecavir (ETV), a first-line anti-HBV drug, in HBV-DNA, HBsAg/HBeAg seroconversion and drug-resistance. The co-effects of BA and ETV were conducted in wild-type/NA-resistance mutant HBV cell lines and DHBV-infected duckling models. HBV-DNA/RNAs, HBsAg/HBeAg, host factors (hepatocyte nuclear factors) were explored for possible anti-HBV mechanism. BA could significantly enhance and reduced HBsAg and HBeAg in hepG2.2.15, a wild-type HBV cell line. Co-treatment of BA and ETV had a more dramatic effect in NA-resistant HBV(rtM204V/rtLl80M) transfected hepG2 cells. Our study further revealed that BA mainly inhibited the production of HBV RNAs (3.5, 2.4, 2.1kb), the templates for viral proteins and HBV-DNA synthesis. BA blocked HBV RNAs transcription possibly by down-regulating transcription and expression of HBV replication dependent hepatocyte nuclear factors (HNF1α and HNF4α). Thus, BA may benefit the anti-HBV therapy via inhibiting HBV viral RNAs. Copyright © 2017 Elsevier Inc. All rights reserved.
Sandaa, R.-A.; Gómez-Consarnau, L.; Pinhassi, J.
We demonstrate here results showing that bottom-up and top-down control mechanisms can operate simultaneously and in concert in marine microbial food webs, controlling prokaryote diversity by a combination of viral lysis and substrate limitation. Models in microbial ecology predict that a shift...
Dreer, Marcel; van de Poel, Saskia; Stubenrauch, Frank
Human papillomaviruses have adjusted their replication levels to the differentiation state of the infected keratinocyte. PV genomes replicate in undifferentiated cells at low levels and to high levels in differentiated cells. Genome replication requires the viral E1 helicase and the viral E2 transcription/replication activator. The limited replication in undifferentiated cells is predominantly due to the expression of the highly conserved E8^E2 viral repressor protein, which is a fusion between E8 and the C-terminal half of the E2 protein. E8^E2 is a sequence-specific DNA binding protein that inhibits viral gene expression and viral genome replication. The E8 domain is required for repression activities, which are mainly due to the interaction with cellular NCoR/SMRT corepressor complexes. In the case of HPV16, the most carcinogenic HPV type, E8^E2 not only limits genome replication in undifferentiated cells but also productive replication in differentiated epithelium. E8^E2 is expressed from a separate promoter that is controlled by unknown cellular factors and the viral transcription and replication regulators E1, E2 and E8^E2. In summary, E8^E2 is an important negative regulator whose levels may be critical for the outcome of HPV infections. Copyright © 2016 Elsevier B.V. All rights reserved.
Baumann, Michael A.; Beloussov, Alexandre V.; Bakir, Julide; Armon, Deganit; Olsen, Howard B.; Salem, Dana
A tiered communications architecture for managing network traffic in a distributed system. Communication between client or control computers and a plurality of hardware devices is administered by agent and monitor devices whose activities are coordinated to reduce the number of open channels or sockets. The communications architecture also improves the transparency and scalability of the distributed system by reducing network mapping dependence. The architecture is desirably implemented in a proton beam therapy system to provide flexible security policies which improve patent safety and facilitate system maintenance and development.
Full Text Available The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs, which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host–pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.
Trevisan, Marta; Sinigaglia, Alessandro; Desole, Giovanna; Berto, Alessandro; Pacenti, Monia; Palù, Giorgio; Barzon, Luisa
The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs), which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host-pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.
Martins, Thomas B
.... During the development of a seven-analyte serologic viral respiratory antibody profile, internal controls for detecting sample addition and interfering rheumatoid factor (RF) were investigated...
Matthew O. Old
Full Text Available Objective: Cancer affects the head and neck region frequently and leads to significant morbidity and mortality. Oncolytic viral therapy has the potential to make a big impact in cancers that affect the head and neck. We intend to review the current state of oncolytic viruses in the treatment of cancers that affect the head and neck region. Method: Data sources are from National clinical trials database, literature, and current research. Results: There are many past and active trials for oncolytic viruses that show promise for treating cancers of the head and neck. The first oncolytic virus was approved by the FDA October 2015 (T-VEC, Amgen for the treatment of melanoma. Active translational research continues for this and many other oncolytic viruses. Conclusion: The evolving field of oncolytic viruses is impacting the treatment of head and neck cancer and further trials and agents are moving forward in the coming years. Keywords: Head and neck squamous cell carcinoma, Oncolytic viruses, Clinical trials, Novel therapeutics
Li, Juan; Sun, Wunchang; Wang, Bing; Xiao, Xiao; Liu, Xiang-Qin
Inteins catalyze protein splicing in a fashion similar to how self-splicing introns catalyze RNA splicing. Splitinteins catalyze precise ligation of two separate polypeptides through trans-splicing in a highly specific manner. Here we report a method of using protein trans-splicing to circumvent the packaging size limit of gene therapy vectors. To demonstrate this method, we chose a large dystrophin gene and an adeno-associated viral (AAV) vector, which has a small packaging size. A highly functional 6.3-kb Becker-form dystrophin cDNA was broken into two pieces and modified by adding appropriate split-intein coding sequences, resulting in splitgenes sufficiently small for packaging in AAV vectors. The two split-genes, after codelivery into target cells, produced two polypeptides that spontaneously trans-spliced to form the expected Becker-form dystrophin protein in cell culture in vitro. Delivering the split-genes by AAV1 vectors into the muscle of a mouse model of Duchenne muscular dystrophy rendered therapeutic gene expression and benefits.
Full Text Available Padma Sampath, Steve H ThorneDepartment of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USAAbstract: The field of oncolytic virology has made great strides in recent years. However, one key finding has been that the use of viral agents that replicate selectively in tumors is usually insufficient to achieve anything beyond small and transient responses. Instead, like most cancer therapies, oncolytic viruses are most effective in combination with other therapies, which is where they have proven therapeutic effects in clinical and preclinical studies. In cases of some of the smaller RNA viruses, effects can only be achieved through combination regimens with chemotherapy, radiotherapy, or targeted conventional therapies. However, larger DNA viruses are able to express one or more transgenes; thus, therapeutic mechanisms can be built into the viral vector itself. The incorporated approaches into arming oncolytic viruses through transgene expression will be the main focus of this review, including use of immune activators, prodrug converting enzymes, anti-angiogenic factors, and targeting of the stroma. This will focus on poxviruses as model systems with large cloning capacities, which have routinely been used as transgene expression vectors in different settings, including vaccine and oncolytic viral therapy.Keywords: vaccinia, poxvirus, immunotherapy, angiogenesis, prodrug
Reifenberg, J M; Navarro, P; Coste, J
During the National Multicentric Study concerning the introduction of NAT for HCV and HIV-1 viruses in blood donation screening which was supervised by the Medical and Scientific departments of the French Blood Establishment (Etablissement français du sang--EFS), Transcription-Mediated transcription Amplification (TMA) technology (Chiron/Gen Probe) was experimented in the Molecular Biology Laboratory of Montpellier, EFS Pyrénées-Méditerranée. After a preliminary phase of qualification of the material and training of the technicians, routine screening of homologous blood and apheresis donations using this technology was applied for two months. In order to evaluate the different NAT systems, exhaustive daily operations and data were registered. Among these, the luminescence results expressed as RLU of the positive and negative calibrators and the associated internal controls were analysed using Control Charts, Statistical Process Control methods, which allow us to display rapidly process drift and to anticipate the appearance of incidents. This study demonstrated the interest of these quality control methods, mainly used for industrial purposes, to follow and to increase the quality of any transfusion process. it also showed the difficulties of the post-investigations of uncontrolled sources of variations of a process which was experimental. Such tools are in total accordance with the new version of the ISO 9000 norms which are particularly focused on the use of adapted indicators for processes control, and could be extended to other transfusion activities, such as blood collection and component preparation.
Beer, Linda; Bradley, Heather; Mattson, Christine L; Johnson, Christopher H; Hoots, Brooke; Shouse, Roy L
To examine trends in racial/ethnic disparities in antiretroviral therapy (ART) prescription and viral suppression among HIV-infected persons in care, overall and among men who have sex with men (MSM), from 2009 to 2013. The Medical Monitoring Project (MMP) is a complex sample survey of HIV-infected adults receiving medical care in the United States. We used weighted interview and medical record data collected June 2009-May 2014 to estimate the prevalence of ART prescription and viral suppression among racial/ethnic groups overall and among MSM. We found significant increases in ART prescription and viral suppression among all racial/ethnic groups from 2009 to 2013, both overall and among MSM. By 2013, overall and among MSM, the Hispanic-white disparity in ART prescription was nonexistent, and the black-white disparity was not significant after accounting for differences between blacks and whites in age and length of HIV diagnosis. Despite reductions in racial/ethnic disparities in viral suppression over the time period, significant disparities remained among the total population, even after adjusting for differences in racial/ethnic group characteristics. Encouragingly, however, there was no significant Hispanic-white disparity in viral suppression among MSM by 2013. Despite significant improvements in ART prescription and viral suppression in recent years, racial and ethnic disparities persist, particularly for black persons. If the United States is to achieve the National HIV/AIDS Strategy goal of reducing HIV-related health disparities, continued efforts to accelerate the rate of improvement in ART prescription and viral suppression among Hispanic and black persons may need to be prioritized.
Intensive insulin therapy: Tight blood sugar control Intensive insulin therapy can help prevent long-term diabetes complications. Consider the benefits — and understand the commitment. By Mayo Clinic ...
Gebremedhin, Senait; Singh, Aruna; Koons, Stephen; Bernt, William; Konopka, Krystyna; Duzgunes, Nejat
Suicide gene therapy of oral squamous cell carcinoma (OSCC) may be a viable approach to the treatment of this cancer. However, human OSCC cells are relatively resistant to efficient transfection by non-viral vectors. To identify an optimal vector for gene delivery, we compared the transfection activities and efficiencies of Glycofect, Metafectene, Metafectene Pro, Metafectene Easy and FuGENE HD, using the OSCC cell line, HSC-3, and the cervical carcinoma cell line, HeLa. The size distribution and ζ-potential of the complexes of these vectors with plasmid DNA were assessed by nanoparticle tracking analysis and electrophoretic mobility measurements, respectively. Metafectene Easy and FuGENE HD mediated the highest transfection activity (measured as luciferase expression) and efficiency (measured as the percentage of cells transfected with ß-galactosidase). These vectors were used to deliver a plasmid encoding herpes simplex virus thymidine kinase, followed by ganciclovir treatment. By day 9, HeLa cell viability was 22±3% of controls with FuGENE HD and 26±3% with Metafectene Easy. The viability of HSC-3 cells was 42±25% with FuGENE HD, and 58±28% with Metafectene Easy. The reduction in viability was statistically significant in both cases (p⩽0.005; average of 3 independent experiments), although there was considerable variability between experiments with the HSC-3 cells. Copyright © 2014 Elsevier B.V. All rights reserved.
Full Text Available A study of use of ibuprofen in cases of viral upper respiratory tract infections (Vuri in children of early childhood has proved its' safety and efficacy. This medical agent has not only terminate fever but also diminished some other symptoms of Vuri.Key words: ibuprofen, viral upper respiratory tract infections, children.
Ndhlovu, Zaza M.; Stampouloglou, Eleni; Cesa, Kevin; Mavrothalassitis, Orestes; Alvino, Donna Marie; Li, Jonathan Z.; Wilton, Shannon; Karel, Daniel; Piechocka-Trocha, Alicja; Chen, Huabiao; Pereyra, Florencia
ABSTRACT Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8+ T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P = 0.01) as well as treated progressors (P = 0.0003). Nef- and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P = 0.9 for Nef as determined by a Kruskal-Wallis test; P = 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r = −0.6; P = 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8+ T cell feature that would be desirable in a vaccine-induced T cell response. IMPORTANCE Many studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8+ T lymphocytes, is at least
Schieffer, Miriam; Jessen, Heiko K.; Oster, Alexander F.; Pissani, Franco; Soghoian, Damien Z.; Lu, Richard; Jessen, Arne B.; Zedlack, Carmen; Schultz, Bruce T.; Davis, Isaiah; Ranasinghe, Srinika; Rosenberg, Eric S.; Alter, Galit; Schumann, Ralf R.
ABSTRACT Effector CD4 T cell responses have been shown to be critically involved in the containment and clearance of viral pathogens. However, their involvement in the pathogenesis of HIV infection is less clear, given their additional role as preferred viral targets. We previously demonstrated that the presence of HIV-specific CD4 T cell responses is somewhat associated with HIV control and that specific CD4 T cell functions, such as direct cytolytic activity, can contribute to control of HIV viremia. However, little is known about how the induction of HIV-specific CD4 T cell responses during acute HIV infection influences disease progression and whether responses induced during the early phase of infection are preferentially depleted. We therefore longitudinally assessed, in a cohort of 55 acutely HIV-infected individuals, HIV-specific CD4 T cell responses from acute to chronic infection. Interestingly, we found that the breadth, magnitude, and protein dominance of HIV-specific CD4 T cell responses remained remarkably stable over time. Moreover, we found that the epitopes targeted at a high frequency in acute HIV infection were recognized at the same frequency by HIV-specific CD4 T cells in chronic HIV infection. Interestingly the induction of Gag-specific CD4 T cell responses in acute HIV infection was significantly inversely correlated with viral set point in chronic HIV infection (R = −0.5; P = 0.03), while the cumulative contribution of Env-specific CD4 T cell responses showed the reverse effect. Moreover, individuals with HIV-specific CD4 T cell responses dominantly targeting Gag over Env in acute HIV infection remained off antiretroviral therapy significantly longer (P = 0.03; log rank). Thus, our data suggest that the induction of HIV-specific CD4 T cell responses during acute HIV infection is beneficial overall and does not fuel disease progression. IMPORTANCE CD4 T cells are critical for the clearance and control of viral infections. However, HIV
Todd M Pollack
Full Text Available High HIV viral load (VL >100,000 cp/ml is associated with increased HIV transmission risk, faster progression to AIDS, and reduced response to some antiretroviral regimens. To better understand factors associated with high VL, we examined characteristics of patients presenting for treatment in Hanoi, Vietnam. We examined baseline data from the Viral Load Monitoring in Vietnam Study, a randomized controlled trial of routine VL monitoring in a population starting antiretroviral therapy (ART at a clinic in Hanoi. Patients with prior treatment failure or ART resistance were excluded. Characteristics examined included demographics, clinical and laboratory data, and substance use. Logistic regression was used to calculate crude and adjusted odds ratios (aOR and 95% confidence intervals (95% CI. Out of 636 patients, 62.7% were male, 72.9% were ≥30 years old, and 28.3% had a history of drug injection. Median CD4 was 132 cells/mm3, and 34.9% were clinical stage IV. Active cigarette smoking was reported by 36.3% with 14.0% smoking >10 cigarettes per day. Alcohol consumption was reported by 20.1% with 6.1% having ≥5 drinks per event. Overall 53.0% had a VL >100,000 cp/ml. Male gender, low body weight, low CD4 count, prior TB, and cigarette smoking were associated with high VL. Those who smoked 1-10 cigarettes per day were more likely to have high VL (aOR = 1.99, 95% CI = 1.15-3.45, while the smaller number of patients who smoked >10 cigarettes per day had a non-significant trend toward higher VL (aOR = 1.41, 95% CI = 0.75-2.66. Alcohol consumption was not significantly associated with high VL. Tobacco use is increasingly recognized as a contributor to premature morbidity and mortality among HIV-infected patients. In our study, cigarette smoking in the last 30 days was associated with a 1.5 to 2-fold higher odds of having an HIV VL >100,000 cp/ml among patients presenting for ART. These findings provide further evidence of the negative effects of
Pollack, Todd M; Duong, Hao T; Pham, Thuy T; Do, Cuong D; Colby, Donn
High HIV viral load (VL >100,000 cp/ml) is associated with increased HIV transmission risk, faster progression to AIDS, and reduced response to some antiretroviral regimens. To better understand factors associated with high VL, we examined characteristics of patients presenting for treatment in Hanoi, Vietnam. We examined baseline data from the Viral Load Monitoring in Vietnam Study, a randomized controlled trial of routine VL monitoring in a population starting antiretroviral therapy (ART) at a clinic in Hanoi. Patients with prior treatment failure or ART resistance were excluded. Characteristics examined included demographics, clinical and laboratory data, and substance use. Logistic regression was used to calculate crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Out of 636 patients, 62.7% were male, 72.9% were ≥30 years old, and 28.3% had a history of drug injection. Median CD4 was 132 cells/mm3, and 34.9% were clinical stage IV. Active cigarette smoking was reported by 36.3% with 14.0% smoking >10 cigarettes per day. Alcohol consumption was reported by 20.1% with 6.1% having ≥5 drinks per event. Overall 53.0% had a VL >100,000 cp/ml. Male gender, low body weight, low CD4 count, prior TB, and cigarette smoking were associated with high VL. Those who smoked 1-10 cigarettes per day were more likely to have high VL (aOR = 1.99, 95% CI = 1.15-3.45), while the smaller number of patients who smoked >10 cigarettes per day had a non-significant trend toward higher VL (aOR = 1.41, 95% CI = 0.75-2.66). Alcohol consumption was not significantly associated with high VL. Tobacco use is increasingly recognized as a contributor to premature morbidity and mortality among HIV-infected patients. In our study, cigarette smoking in the last 30 days was associated with a 1.5 to 2-fold higher odds of having an HIV VL >100,000 cp/ml among patients presenting for ART. These findings provide further evidence of the negative effects of tobacco use among
Noura Abd Ellah
Full Text Available Low birth weight is associated with both short term problems and the fetal programming of adult onset diseases, including an increased risk of obesity, diabetes and cardiovascular disease. Placental insufficiency leading to intrauterine growth restriction (IUGR contributes to the prevalence of diseases with developmental origins. Currently there are no therapies for IUGR or placental insufficiency. To address this and move towards development of an in utero therapy, we employ a nanostructure delivery system complexed with the IGF-1 gene to treat the placenta. IGF-1 is a growth factor critical to achieving appropriate placental and fetal growth. Delivery of genes to a model of human trophoblast and mouse placenta was achieved using a diblock copolymer (pHPMA-b-pDMAEMA complexed to hIGF-1 plasmid DNA under the control of trophoblast-specific promoters (Cyp19a or PLAC1. Transfection efficiency of pEGFP-C1-containing nanocarriers in BeWo cells and non-trophoblast cells was visually assessed via fluorescence microscopy. In vivo transfection and functionality was assessed by direct placental-injection into a mouse model of IUGR. Complexes formed using pHPMA-b-pDMAEMA and CYP19a-923 or PLAC1-modified plasmids induce trophoblast-selective transgene expression in vitro, and placental injection of PLAC1-hIGF-1 produces measurable RNA expression and alleviates IUGR in our mouse model, consequently representing innovative building blocks towards human placental gene therapies.
Eileen L. Yoon
Full Text Available Hepatitis A virus is one of the most frequent causes of foodborne infection, which is closely associated with sanitary conditions and hygienic practices. The clinical spectrum of acute hepatitis A is wide, ranging from mild case without any noticeable symptoms to severe case with acute liver failure leading to mortality. The severity and outcome are highly correlated with age at infection. In developing countries, most people are infected in early childhood without significant symptom. Ironically, in area where sanitary condition has improved rapidly, adults who do not have immunity for viral hepatitis A (VH-A in early childhood is accumulating. Adults without immunity are exposed to risks of symptomatic disease and large outbreaks in society. In Korea, where hygiene has improved rapidly, acute hepatitis A is a significant health burden that needs to be managed with nationwide health policy. The incidence of symptomatic VH-A has increased since 2000 and peaked in 2009. Korea has designated hepatitis A as a group 1 nationally notifiable infectious disease in 2001. Since 2001, mandatory surveillance system has been established to detect every single case of acute hepatitis A. Universal, nationwide vaccination program for newborns was introduced in 2015. In this review, we will present the current epidemiologic status of viral hepatitis A, and evaluate the effectiveness of the current nationwide strategies for the control of viral hepatitis A in Korea. Furthermore, we presented some action proposals that can help eliminate viral hepatitis A, which is a significant health burden in Korea.
Chiorini Jay A
Full Text Available Abstract Background Pancreatic ductal adenocarcinoma (PDAC remains a leading cause of cancer mortality for which novel gene therapy approaches relying on tumor-tropic adenoviruses are being tested. Methods We obtained the global transcriptional profiling of primary PDAC using RNA from eight xenografted primary PDAC, three primary PDAC bulk tissues, three chronic pancreatitis and three normal pancreatic tissues. The Affymetrix GeneChip HG-U133A was used. The results of the expression profiles were validated applying immunohistochemical and western blot analysis on a set of 34 primary PDAC and 10 established PDAC cell lines. Permissivity to viral vectors used for gene therapy, Adenovirus 5 and Adeno-Associated Viruses 5 and 6, was assessed on PDAC cell lines. Results The analysis of the expression profiles allowed the identification of two clearly distinguishable phenotypes according to the expression of interferon-stimulated genes. The two phenotypes could be readily recognized by immunohistochemical detection of the Myxovirus-resistance A protein, whose expression reflects the activation of interferon dependent pathways. The two molecular phenotypes discovered in primary carcinomas were also observed among established pancreatic adenocarcinoma cell lines, suggesting that these phenotypes are an intrinsic characteristic of cancer cells independent of their interaction with the host's microenvironment. The two pancreatic cancer phenotypes are characterized by different permissivity to viral vectors used for gene therapy, as cell lines expressing interferon stimulated genes resisted to Adenovirus 5 mediated lysis in vitro. Similar results were observed when cells were transduced with Adeno-Associated Viruses 5 and 6. Conclusion Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We
Assaad, F A; Schild, G C
Through the advancement of biological and medical sciences and the application of modern technology, the disease burden imposed by viral, chlamydial and rickettsial disease has steadily decreased. Smallpox has been eradicated, poliomyelitis is under control in many countries, and measles, mumps and rubella viruses may eventually be eliminated in many developed countries. New and improved vaccines have also recently become available for rabies and hepatitis. These are major advancements. Not to be overshadowed however, are the developments which may lead to the prevention or control of other infectious diseases. For many agents, recently acquired knowledge relating to virology, replication, structural and genetic characteristics, and host responses to infection pave the way for disease intervention in numerous ways. For other agents, recent advances in molecular biology make possible new classes of effective vaccines. It is crucial that these advances be incorporated as soon as possible into effective public health programmes for developing as well as developed nations. Much work yet remains, particularly in the prevention and control of respiratory diseases, diarrhoeal diseases, vector-borne diseases and hepatitis. The WHO Viral Diseases Programme has a major role in supporting laboratory and field research on new technologies and intervention strategies, in disseminating technological advances through teaching and training, and in translating the newer knowledge into action programmes for the prevention and control of viral, chlamydial and rickettsial diseases.
Chyuan, I-Tsu; Tsai, Hwei-Fang; Tzeng, Horng-Tay; Sung, Chi-Chang; Wu, Chien-Sheng; Chen, Pei-Jer; Hsu, Ping-Ning
Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-α blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-α blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-α blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose- and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-α blockage therapy occurred at early time points after HBV infection. In addition, TNF-α blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1(high)CD127(low) exhausted T cells. Furthermore, TNF-α blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-α blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-α blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-α-blocking agents.
Blanchard, Miran [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Shim, Kevin G. [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States); Grams, Michael P. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Rajani, Karishma; Diaz, Rosa M. [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Furutani, Keith M. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Thompson, Jill [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Olivier, Kenneth R.; Park, Sean S. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Markovic, Svetomir N. [Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States); Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Pandha, Hardev [The Postgraduate Medical School, University of Surrey, Guildford (United Kingdom); Melcher, Alan [Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds (United Kingdom); Harrington, Kevin [Targeted Therapy Laboratory, The Institute of Cancer Research, London (United Kingdom); Zaidi, Shane [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Targeted Therapy Laboratory, The Institute of Cancer Research, London (United Kingdom); Vile, Richard, E-mail: email@example.com [Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States); Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States); Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds (United Kingdom)
Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary
Greig, Jenny A; Wang, Qiang; Reicherter, Amanda L; Chen, Shu-Jen; Hanlon, Alexandra L; Tipper, Christopher H; Clark, K Reed; Wadsworth, Samuel; Wang, Lili; Wilson, James M
Adeno-associated viral (AAV) vectors are promising vehicles for hemophilia gene therapy, with favorable clinical trial data seen in the treatment of hemophilia B. In an effort to optimize the expression of human coagulation factor VIII (hFVIII) for the treatment of hemophilia A, an extensive study was performed with numerous combinations of liver-specific promoter and enhancer elements with a codon-optimized hFVIII transgene. After generating 42 variants of three reduced-size promoters and three small enhancers, transgene cassettes were packaged within a single AAV capsid, AAVrh10, to eliminate performance differences due to the capsid type. Each hFVIII vector was administered to FVIII knockout (KO) mice at a dose of 10(10) genome copies (GC) per mouse. Criteria for distinguishing the performance of the different enhancer/promoter combinations were established prior to the initiation of the studies. These criteria included prominently the level of hFVIII activity (0.12-2.12 IU/mL) and the pattern of development of anti-hFVIII antibodies. In order to evaluate the impact of capsid on hFVIII expression and antibody formation, one of the enhancer and promoter combinations that exhibited high hFVIII immunogenicity was evaluated using AAV8, AAV9, AAVrh10, AAVhu37, and AAVrh64R1 capsids. The capsids subdivided into two groups: those that generated anti-hFVIII antibodies in ≤20% of mice (AAV8 and AAV9), and those that generated anti-hFVIII antibodies in >20% of mice (AAVrh10, AAVhu37, and AAVrh64R1). The results of this study, which entailed extensive vector optimization and in vivo testing, demonstrate the significant impact that transcriptional control elements and capsid can have on vector performance.
D'Arcy, Nikki; Cloutman-Green, Elaine; Klein, Nigel; Spratt, David A
Nosocomial outbreaks of viral etiology are costly and can have a major impact on patient care. Many viruses are known to persist in the inanimate environment and may pose a risk to patients and health care workers. We investigate the frequency of environmental contamination with common health care-associated viruses and explore the use of torque-teno virus as a marker of environmental contamination. Environmental screening for a variety of clinically relevant viruses was carried out over 3 months in a UK pediatric hospital using air sampling and surface swabbing. Swabs were tested for the presence of virus nucleic acid by quantitative polymerase chain reactions. Viral nucleic acid was found on surfaces and in the air throughout the screening period, with adenovirus DNA being the most frequent. Door handles were frequently contaminated. Torque-teno virus was also found at numerous sites. Evidence of environmental contamination with viral pathogens is present in health care environments and may be indicative of an infectious virus being present. Screening for viruses should be included in infection control strategies. Torque-teno virus may provide a better marker of contamination and reduce time and cost of screening for individual viruses. Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.
Eski, Ikbal; Kirnap, Ahmet; Kirnap, Mehmet
A controller design for mechatronic system which capable of doing passive therapeutic exercises of patients whohave upper extremity limitation is presented in this paper. Expectation fromcontroller is it should produce torque values can exactly repeat degree valuesdepended on time which were taken from first therapy exercises of patients. Thedesigned controller tested with real angle values which was taken from during elbow therapy. Simulationresults showed that the proposed control system ...
Strehlau, R; Kuhn, L; Abrams, E J; Coovadia, A
HIV infection in infancy may influence the developing brain, leading to adverse neurodevelopmental consequences. We aim to describe neurodevelopmental characteristics of a cohort of HIV-infected infants and young children prior to antiretroviral therapy (ART) initiation and after achieving viral suppression. As part of the Neverest 2 trial, 195 HIV-infected children under 2 years of age were assessed using the Ages and Stages Questionnaire (ASQ) prior to ART initiation and at subsequent age-appropriate time points after ART had been started. The ASQ is a simple screening questionnaire used to identify children at risk of neurodevelopmental delays. Questionnaires completed by the parent/caregiver assess neurodevelopmental functioning in five domains: communication, gross motor, fine motor, problem solving and personal-social. Median age pre-ART was 8.8 months (range 2.2-24.9) and 53.9% were male. Mean time to viral suppression was 9.4 months (range 5.9-14.5). Compared with pre-ART better outcomes were reported at time of viral suppression with a lower proportion of children failing the gross motor (31.5% vs. 13%, p = 0.0002), fine motor (21.3% vs. 10.2%, p = 0.017), problem solving (26.9% vs. 9.3%, p = 0.0003) and personal-social (19.6% vs. 7.4%, p = 0.019) domains. However, there was no change in the communication domain (14.8% vs. 12.0%, p = 0.6072). Although achieving viral suppression on ART resulted in significant improvements in markers of neurodevelopmental function of young HIV-infected children, potential neurodevelopmental delays still persisted in a large proportion. Further interventions are needed to limit potential disabilities and maximize developmental outcomes. © 2016 John Wiley & Sons Ltd.
Tracy R Glass
Full Text Available BACKGROUND: Good adherence to antiretroviral therapy (ART is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels. METHODS: Eligible individuals were Caucasians treated with efavirenz (EFV and/or boosted lopinavir (LPV/r with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6 and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2. Viral suppression was defined as having HIV-1 RNA 1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR 0.11, 95% confidence interval (CI: 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94. In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56. CONCLUSIONS: The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.
Glass, Tracy R; Rotger, Margalida; Telenti, Amalio; Decosterd, Laurent; Csajka, Chantal; Bucher, Heiner C; Günthard, Huldrych F; Rickenbach, Martin; Nicca, Dunja; Hirschel, Bernard; Bernasconi, Enos; Wandeler, Gilles; Battegay, Manuel; Marzolini, Catia
Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels. Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA 1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56). The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.
Radebe, Mopo; Gounder, Kamini; Mokgoro, Mammekwa; Ndhlovu, Zaza M.; Mncube, Zenele; Mkhize, Lungile; van der Stok, Mary; Jaggernath, Manjeetha; Walker, Bruce D.; Ndung’u, Thumbi
Objective We characterized protein-specific CD8+ T-cell immunodominance patterns during the first year of HIV-1 infection, and their impact on viral evolution and immune control. Methods We analyzed CD8+ T-cell responses to the full HIV-1 proteome during the first year of infection in eighteen antiretroviral-naïve individuals with acute HIV-1 subtype C infection, all identified prior to seroconversion. Ex vivo and cultured IFN-γ ELISPOT assays were performed and viruses from plasma were sequenced within defined CTL Gag epitopes. Results Nef-specific CD8+ T-cell responses were dominant during the first 4 weeks post infection and made up 40% of total responses at this time, yet by 1 year responses against this region had declined and Gag responses made up to 47% of all T-cell responses measured. An inverse correlation between the breadth of Gag-specific responses and viral load set point was evident at 26 weeks post infection (p=0.0081; r= −0.60) and beyond. An inverse correlation between the number of persistent responses targeting Gag and viral set point was also identified (p=0.01; r=−0.58). Gag-specific responses detectable by the cultured ELISPOT assay correlated negatively with viral load set point (p=0.0013; r=−0.91). Sequence evolution in targeted and non-targeted Gag epitopes in this cohort was infrequent. Conclusions These data underscore the importance of HIV-specific CD8+ T-cell responses, particularly to the Gag protein, in the maintenance of low viral load levels during primary infection and show that these responses are initially poorly elicited by natural infection. These data have implications for vaccine design strategies. PMID:25387316
Blumenthal, R; Loyter, A
Reconstituted viral envelopes (RVEs) are formed by solubilizing intact virus in detergent and reassembling the envelope on removal of detergent. RVEs can be formed in the presence of agents that become encapsulated and can then be utilized in vitro and in vivo for drug delivery, cell destruction, transfer of membrane components, and as vectors for genetic engineering. The problems with biotechnological applications of RVEs and possible strategies for overcoming them are discussed in this article.
V. N. Timchenko; E. B. Yastrebova; O. V. Bulina
The study included 338 HIV-infected children (B-23) and 350 children with perinatal contact HIV infection (R-75), consisting on the dispensary in the department of maternal and child the St. Petersburg City AIDS Center. In 32 persons (9.5%) diagnosed with secondary infections. In the structure of viral opportunistic infections (herpesvirus, SARS) amounted to 39.8%, bacterial (bronchitis, tonsillitis, pyoderma, tuberculosis) — 34.8%, fungal and parasitic (candidiasis of the oral mucosa, PCP) —...
Robert L Cowie
Full Text Available BACKGROUND: Randomized clinical trials demonstrate efficacy and show that inhaled corticosteroid therapy can control asthma, but details concerning their effectiveness in achieving this goal in the community are lacking.
Wang, M; Glass, Z A; Xu, Q
Manipulating the genetic makeup of mammalian cells using programmable nuclease-based genome-editing technology has recently evolved into a powerful avenue that holds great potential for treating genetic disorders. There are four types of genome-editing nucleases, including meganucleases, zinc finger nucleases, transcription activator-like effector nucleases and clustered, regularly interspaced, short palindromic repeat-associated nucleases such as Cas9. These nucleases have been harnessed to introduce precise and specific changes of the genome sequence at virtually any genome locus of interest. The therapeutic relevance of these genome-editing technologies, however, is challenged by the safe and efficient delivery of nuclease into targeted cells. Herein, we summarize recent advances that have been made on non-viral delivery of genome-editing nucleases. In particular, we focus on non-viral delivery of Cas9/sgRNA ribonucleoproteins for genome editing. In addition, the future direction for developing non-viral delivery of programmable nucleases for genome editing is discussed.
Paiva, Leticia R.; Silva, Hallan S.; Ferreira, Silvio C.; Martins, Marcelo L.
Oncolytic virotherapy—the use of viruses that specifically kill tumor cells—is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In this paper, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD8+ T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.
Nowakowska, Justyna; Stuehler, Claudia; Egli, Adrian; Battegay, Manuel; Rauser, Georg; Bantug, Glenn Robert; Brander, Christian; Hess, Christoph; Khanna, Nina
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) belong to the most dreaded complications of immunosuppression. The efficacy of EBV-specific T-cell transfer for PTLD has been previously shown, yet the optimal choice of EBV-derived antigens inducing polyclonal CD4(+) and CD8(+) T cells that cover a wide range of human leukocyte antigen types and efficiently control PTLD remains unclear. A pool of 125 T-cell epitopes from seven latent and nine lytic EBV-derived proteins (EBVmix) and peptide pools of EBNA1, EBNA3c, LMP2a and BZLF1 were used to determine T-cell frequencies and to isolate T cells through the use of the interferon (IFN)-γ cytokine capture system. We further evaluated the phenotype and functionality of the generated T-cell lines in vitro. EBVmix induced significantly higher T-cell frequencies and allowed selecting more CD4(+)IFN-γ(+) and CD8(+)IFN-γ(+) cells than single peptide pools. T cells of all specificities expanded similarly in vitro, recognized cognate antigen, and, to a lower extent, EBV-infected cells, exerted moderate cytotoxicity and showed reduced alloreactivity. However, EBVmix-specific cells most efficiently controlled EBV-infected lymphoblastoid cell lines (LCLs). This control was mainly mediated by EBV-specific CD8(+) cells with an oligoclonal epitope signature covering both latent and lytic viral proteins. Notably, EBV-specific CD4(+) cells unable to control LCLs produced significantly less perforin and granzyme B, probably because of limited LCL epitope presentation. EBVmix induces a broader T-cell response, probably because of its coverage of latent and lytic EBV-derived proteins that may be important to control EBV-transformed B cells and might offer an improvement of T-cell therapies. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
Praetorius, M; Pfannenstiel, S; Klingmann, C; Baumann, I; Plinkert, P K; Staecker, H
Diseases of the inner ear such as presbycusis, tinnitus, sudden hearing loss, and vertigo affect many patients, but so far there are no specific therapy options. Gene therapy might become a potential modality of treatment. Viral vectors are standard in animal models to date. Future considerations, however, call for a further evaluation of non-viral transfection methods. The non-viral transfection agents Metafectene, Superfect, Effectene, and Mirus TransIT were incubated with a plasmid coding for GFP. In vivo, the plasmid-agent mix was injected via the membrane of the round window, and 48 h later the inner ear was perfused, harvested, decalcified, and histologically evaluated for GFP expression. Cationic lipids (Metafectene) and dendrimers (Superfect) were able to transfect cells in the area of the organ of Corti and lead to GFP expression. The polyamine (Mirus TransIT) did show expression of GFP in the area of Rosenthal's canal and in the area of the inner hair cell. The combination of a non-liposomal lipid with a DNA condensing component (Effectene) did not show transfection of the organ of Corti. In the area of the spiral ganglia cells, GFP expression was seen with all the transfection agents. Non-viral transfection agents are able to introduce a reporter gene in cells of the inner ear in vitro and in vivo. There are, however, differences in the efficiency of the transfection. They might be an alternative in gene therapy of the inner ear. Further investigations to elucidate their potential are needed.
Mendelsohn, Joshua B; Spiegel, Paul; Grant, Alison; Doraiswamy, Sathyanarayanan; Schilperoord, Marian; Larke, Natasha; Burton, John Wagacha; Okonji, Jully A; Zeh, Clement; Muhindo, Bosco; Mohammed, Ibrahim M; Mukui, Irene N; Patterson, Njogu; Sondorp, Egbert; Ross, David A
Refugees and host nationals who accessed antiretroviral therapy (ART) in a remote refugee camp in Kakuma, Kenya (2011-2013) were compared on outcome measures that included viral suppression and adherence to ART. This study used a repeated cross-sectional design (Round One and Round Two). All adults (≥18 years) receiving care from the refugee camp clinic and taking antiretroviral therapy (ART) for ≥30 days were invited to participate. Adherence was measured by self-report and monthly pharmacy refills. Whole blood was measured on dried blood spots. HIV-1 RNA was quantified and treatment failures were submitted for drug resistance testing. A remedial intervention was implemented in response to baseline testing. The primary outcome was viral load refugees and 84% (86/102) of Kenyan host nationals participated in the Round One survey; 60% (44/73) and 58% (50/86) of Round One participants were recruited for Round Two follow-up viral load testing. In Round One, refugees were older than host nationals (median age 36 years, interquartile range, IQR 31, 41 vs 32 years, IQR 27, 38); the groups had similar time on ART (median 147 weeks, IQR 38, 64 vs 139 weeks, IQR 39, 225). There was weak evidence for a difference between proportions of refugees and host nationals who were virologically suppressed (Refugee status was not associated with viral suppression in multivariable analysis (adjusted odds ratio: 1.69, 95% CI 0.79, 3.57; p = 0.17). Among those not suppressed at either timepoint, 69% (9/13) exhibited resistance mutations. Virologic outcomes among refugees and host nationals were similar but unacceptably low. Slight improvements were observed after a remedial intervention. Virologic monitoring was important for identifying an underperforming ART program in a remote facility that serves refugees alongside host nationals. This work highlights the importance of careful laboratory monitoring of vulnerable populations accessing ART in remote settings.
Carter, Owen B J; Donovan, Robert; Jalleh, Geoffrey
The authors' objective was to conduct a trial of viral e-mail marketing as a distribution method for tobacco control advertisements. University students (n = 200) in the state of Western Australia were randomly allocated to receive 1 of 2 e-mails with hyperlinks to tobacco control advertisements ("Toilet" and "Rubbish") emphasizing the disgusting nature of smoking. Recipients followed a hyperlink to a Web page playing Toilet or Rubbish on endless loop. Viewers were encouraged to forward the e-mail to their friends and invited to complete an online survey about the advertisement. Unique downloads for each advertisement were identified by internet provider (IP) location and tallied by date and geographical location to assess subsequent dissemination beyond the initial 200 students. There were 826 unique viewings of the advertisements averaging 26.9 viewings per day for the first fortnight, followed by a lower average of 4.1 hits per day for the next 3.5 months. IP addresses identified hits from 3 other Australian states and 7 other countries. Online surveys were completed by 103 respondents (12.5% of total hits) but included few smokers (n = 9). Significantly more respondents rated Toilet as "funny" compared with Rubbish (40% vs. 11%; p viral e-mails being forwarded onwards but only exceptionally compelling tobacco control materials are ever likely to become self-perpetuating.
Full Text Available Influenza A viruses are major pathogens in humans and in animals, whose genome consists of eight single-stranded RNA segments of negative polarity. Viral mRNAs are synthesized by the viral RNA-dependent RNA polymerase in the nucleus of infected cells, in close association with the cellular transcriptional machinery. Two proteins essential for viral multiplication, the exportin NS2/NEP and the ion channel protein M2, are produced by splicing of the NS1 and M1 mRNAs, respectively. Here we identify two human spliceosomal factors, RED and SMU1, that control the expression of NS2/NEP and are required for efficient viral multiplication. We provide several lines of evidence that in infected cells, the hetero-trimeric viral polymerase recruits a complex formed by RED and SMU1 through interaction with its PB2 and PB1 subunits. We demonstrate that the splicing of the NS1 viral mRNA is specifically affected in cells depleted of RED or SMU1, leading to a decreased production of the spliced mRNA species NS2, and to a reduced NS2/NS1 protein ratio. In agreement with the exportin function of NS2, these defects impair the transport of newly synthesized viral ribonucleoproteins from the nucleus to the cytoplasm, and strongly reduce the production of infectious influenza virions. Overall, our results unravel a new mechanism of viral subversion of the cellular splicing machinery, by establishing that the human splicing factors RED and SMU1 act jointly as key regulators of influenza virus gene expression. In addition, our data point to a central role of the viral RNA polymerase in coupling transcription and alternative splicing of the viral mRNAs.
Ferraioli, Giovanna; Tinelli, Carmine; Lissandrin, Raffaella; Zicchetti, Mabel; Dal Bello, Barbara; Filice, Gaetano; Filice, Carlo
To assess the performance of controlled attenuation parameter (CAP) in patients with chronic viral hepatitis. CAP is a new technique that measures the attenuation in the liver of an ultrasound beam, which is directly related to lipid accumulation. Consecutive patients undergoing liver biopsy for chronic viral hepatitis were studied using the M probe of FibroScan device (Echosens, Paris, France). The device estimates liver steatosis in decibel per meter (dB/m). An expert operator performed all measurements. Steatosis was graded according to Kleiner's classification. Pearson or Spearman rank coefficient was used to test correlation between two study variables. Linear regression was used for multivariate model to assess the association between CAP and other variables. Receiver operating characteristic curve analysis was performed to calculate area under the curve (AUROC) for S0 vs S1-S3 and S0-S1 vs S2-S3. 115 subjects (85 males and 30 females) were prospectively studied. The mean values of CAP were 227.1 ± 43.1 for S0; 254.6 ± 38.9 for S1; 297.8 ± 49.4 dB/m for S2-S3. In univariate analysis CAP showed a significant correlation with age, body mass index (BMI), degree of steatosis, and cholesterol. Multivariate regression analysis confirmed the correlation with the degree of steatosis [coefficient, 1.2 (0.60-1.83); P Controlled attenuation parameter could be a useful tool in the clinical management of patients with chronic viral hepatitis for detecting liver steatosis.
Withers, Barbara; Blyth, Emily; Clancy, Leighton E; Yong, Agnes; Fraser, Chris; Burgess, Jane; Simms, Renee; Brown, Rebecca; Kliman, David; Dubosq, Ming-Celine; Bishop, David; Sutrave, Gaurav; Ma, Chun Kei Kris; Shaw, Peter J; Micklethwaite, Kenneth P; Gottlieb, David J
Donor-derived adoptive T-cell therapy is a safe and effective treatment of viral infection posttransplant, but it is limited by donor serostatus and availability and by its personalized nature. Off-the-shelf, third-party virus-specific T cells (VSTs) appear promising, but the long-term safety and durability of responses have yet to be established. We conducted a prospective study of 30 allogeneic hemopoietic stem cell transplant (HSCT) patients with persistent or recurrent cytomegalovirus (CMV) (n = 28), Epstein-Barr virus (n = 1), or adenovirus (n = 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo-expanded VSTs (total = 50 infusions) at a median of 75 days post-HSCT (range, 37 to 349 days). Safety, viral dynamics, and immune recovery were monitored for 12 months. Infusions were safe and well tolerated. Acute graft versus host disease occurred in 2 patients, despite a median HLA match between VSTs and the recipient of 2 of 6 antigens. At 12 months, the cumulative incidence of overall response was 93%. Virological control was durable in the majority of patients; the reintroduction of antiviral therapy after the final infusion occurred in 5 patients. CMV-specific T-cell immunity rose significantly and coincided with a rise in CD8+ terminal effector cells. PD-1 expression was elevated on CD8+ lymphocytes before the administration of third-party T cells and remained elevated at the time of viral control. Third-party VSTs show prolonged benefit, with virological control achieved in association with the recovery of CD8+ effector T cells possibly facilitated by VST infusion. This trial was registered at www.clinicaltrials.gov as #NCT02779439 and www.anzctr.org.au as #ACTRN12613000603718.
Steinbrenner, Holger; Al-Quraishy, Saleh; Dkhil, Mohamed A; Wunderlich, Frank; Sies, Helmut
Viral and bacterial infections are often associated with deficiencies in macronutrients and micronutrients, including the essential trace element selenium. In selenium deficiency, benign strains of Coxsackie and influenza viruses can mutate to highly pathogenic strains. Dietary supplementation to provide adequate or supranutritional selenium supply has been proposed to confer health benefits for patients suffering from some viral diseases, most notably with respect to HIV and influenza A virus (IAV) infections. In addition, selenium-containing multimicronutrient supplements improved several clinical and lifestyle variables in patients coinfected with HIV and Mycobacterium tuberculosis. Selenium status may affect the function of cells of both adaptive and innate immunity. Supranutritional selenium promotes proliferation and favors differentiation of naive CD4-positive T lymphocytes toward T helper 1 cells, thus supporting the acute cellular immune response, whereas excessive activation of the immune system and ensuing host tissue damage are counteracted through directing macrophages toward the M2 phenotype. This review provides an up-to-date overview on selenium in infectious diseases caused by viruses (e.g., HIV, IAV, hepatitis C virus, poliovirus, West Nile virus) and bacteria (e.g., M. tuberculosis, Helicobacter pylori). Data from epidemiologic studies and intervention trials, with selenium alone or in combination with other micronutrients, and animal experiments are discussed against the background of dietary selenium requirements to alter immune functions. PMID:25593145
Rasmussen, Line D; Pedersen, Court; Madsen, Helle D
A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis and was ......A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis...
Sun, Da; Sahu, Bhubanananda; Gao, Songqi; Schur, Rebecca M; Vaidya, Amita M; Maeda, Akiko; Palczewski, Krzysztof; Lu, Zheng-Rong
Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber's congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC). All-trans-retinylamine, which binds to interphotoreceptor retinoid-binding protein (IRBP), was incorporated into the nanoparticles via a polyethylene glycol (PEG) spacer for targeted delivery of pDNA into the retinal pigmented epithelium. The targeted ECO/pDNA nanoparticles provided high GFP expression in the RPE of 1-month-old Rpe65(-/-) mice after subretinal injection. Such mice also exhibited a significant increase in electroretinographic activity, and this therapeutic effect continued for at least 120 days. A safety study in wild-type BALB/c mice indicated no irreversible retinal damage following subretinal injection of these targeted nanoparticles. All-trans-retinylamine-modified ECO/pDNA nanoparticles provide a promising non-viral platform for safe and effective treatment of RPE-specific monogenic eye diseases such as LCA2. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Yamauchi, Masaya; Honda, Norihiro; Hazama, Hisanao; Tachikawa, Shoji; Nakamura, Hiroyuki; Kaneda, Yasufumi; Awazu, Kunio
Background and Aims: There is an urgent need to develop an efficient strategy for the treatment of drug-resistant prostate cancer. Photodynamic therapy (PDT), in which low incident levels of laser energy are used to activate a photosensitizer taken up by tumor cells, is expected as a novel therapy for the treatment of prostate cancer because of the minimal invasive nature of PDT. The present study was designed to assess the efficacy of a novel vector approach combined with a conventional porphyrin-based photosensitizer. Materials and Methods: Our group focused on a non-viral vector (hemagglutinating virus of Japan envelope; HVJ-E) combined with protoporphyrin IX (PpIX) lipid, termed the porphyrus envelope (PE). It has been previously confirmed that HVJ-E has drug-delivering properties and can induce cancer-specific cell death. The PE (HVJ-E contained in PpIX lipid) was developed as a novel photosensitizer. In this study, the antitumor and PDT efficacy of the PE against hormone-antagonistic human prostate cancer cells (PC-3) were evaluated. Results and Conclusions: Our results demonstrated that, under specific circumstances, PDT using the PE was very effective against PC-3 cells. A novel therapy for drug-resistant prostate cancer based on this vector approach is eagerly anticipated. PMID:27141155
Full Text Available This paper is devoted to exploring the combined impact of a generic nonlinear infection rate and infected removable storage media on viral spread. For that purpose, a novel dynamical model with an external compartment is proposed, and the explanations of the main model assumptions (especially the generic nonlinear infection rate are also examined. The existence and global stability of the unique equilibrium of the model are fully investigated, from which it can be seen that computer virus would persist. On this basis, a next-best approach to controlling the level of infected computers is suggested, and the theoretical analysis of optimal control of the model is also performed. Additionally, some numerical examples are given to illustrate the main results.
Heffernan, C; Misturelli, F; Nielsen, L; Gunn, G J; Yu, J
At present, national-level policies concerning the eradication and control of bovine viral diarrhoea (BVD) differ widely across Europe. Some Scandinavian countries have enacted strong regulatory frameworks to eradicate the disease, whereas other countries have few formal policies. To examine these differences, the attitudes of stakeholders and policy makers in 17 European countries were investigated. A web-based questionnaire was sent to policy makers, government and private sector veterinarians, and representatives of farmers' organisations. In total, 131 individuals responded to the questionnaire and their responses were analysed by applying a method used in sociolinguistics: frame analysis. The results showed that the different attitudes of countries that applied compulsory or voluntary frameworks were associated with different views about the attribution or blame for BVD and the roles ascribed to farmers and other stakeholders in its eradication and control.
Akçay, Emine; Çarhan, Ahmet; Hondur, Gözde; Tufan, Zeliha Koçak; Duru, Necati; Kılıç, Selçuk; Ensari, Ezgi Naz; Uğurlu, Nagihan; Çağıl, Nurullah
Viral conjunctivitis are the most frequent infections in ophthalmology clinics. The diagnosis is usually relying on clinical findings and medical history. However, topical antibiotics are often used unnecessarily addition to symptomatic treatment because of unsure agents. We aimed to detect the Adenovirus, Coxsackievirus and Enterovirus from conjunctiva and pharyngeal samples of patients. The conjunctiva and pharyngeal samples of the patients with conjunctivitis were taken by Virocult transport media and kept at -80̊C up to study day. Adenovirus spp, Enterovirus 70 and Enterovirus 71, Coxsackie A24 and Coxsackie A16 were detected by real-time PCR. Samples from healthy health care workers of ophthalmology clinic were used for control group. A total of 176 samples (conjunctival and pharyngeal samples of 62 patient and 26 healthy subjects) were included. The mean age of 34 (55.7%) male and 27 (44.3%) female patients was 34±17. Twenty five (40.3%) of the patients were receiving antibiotic drops at first visit. The main etiologic agent in conjunctival samples was found to be Adenovirus (46/62, 74.2%) followed by Enterovirus 70 (4/62, 6.4%) and Enterovirus 71 (4/62, 6.4%). Coxsackievirus 16 and 24 were also found in 2 patients (1/62 each, 1.6%). Pharyngeal samples were also positive for Adenovirus (20/62, 32.3%), Enterovirus 70 and 71 (7/62, 11.3% and 5/62, 8.1% respectively), Coxsackievirus 16 and 24 (2/62, 3.2% and 1/61, 1.6%). It is very difficult in viral conjunctivitis to make clinical differentiation caused by different agents because of common clinical signs and symptoms. In routine clinical work, the viral conjunctivitis usually related with Adenovirus. But almost one fourth of the patients' conjunctivitis were not related to Adenovirus, which shows the importance of the laboratory diagnostics. True diagnosis plays an important role on prevention of contamination and unnecessary use of antibiotics in viral conjunctivitis. Copyright © 2017 Sociedade Brasileira
Kahana, Shoshana Y; Jenkins, Richard A; Bruce, Douglas; Fernandez, Maria I; Hightow-Weidman, Lisa B; Bauermeister, Jose A
The authors examined associations between structural characteristics and HIV disease management among a geographically diverse sample of behaviorally and perinatally HIV-infected adolescents and young adults in the United States. The sample included 1891 adolescents and young adults living with HIV (27.8% perinatally infected; 72.2% behaviorally infected) who were linked to care through 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions Units. All completed audio computer-assisted self-interview surveys. Chart abstraction or blood draw provided viral load data. Geographic-level variables were extracted from the United States Census Bureau (e.g., socioeconomic disadvantage, percent of Black and Latino households, percent rural) and Esri Crime (e.g., global crime index) databases as Zip Code Tabulation Areas. AIDSVu data (e.g., prevalence of HIV among youth) were extracted at the county-level. Using HLM v.7, the authors conducted means-as-outcomes random effects multi-level models to examine the association between structural-level and individual-level factors and (1) being on antiretroviral therapy (ART) currently; (2) being on ART for at least 6 months; (3) missed HIV care appointments (not having missed any vs. having missed one or more appointments) over the past 12 months; and (4) viral suppression (defined by the corresponding assay cutoff for the lower limit of viral load at each participating site which denoted nondetectability vs. detectability). Frequencies for the 4 primary outcomes were as follows: current ART use (n = 1120, 59.23%); ART use for ≥6 months (n = 861, 45.53%); at least one missed HIV care appointment (n = 936, 49.50); and viral suppression (n = 577, 30.51%). After adjusting for individual-level factors, youth living in more disadvantaged areas (defined by a composite score derived from 2010 Census indicators including percent poverty, percent receiving public assistance, percent of female, single-headed households, percent
Shoshana Y Kahana
Full Text Available The authors examined associations between structural characteristics and HIV disease management among a geographically diverse sample of behaviorally and perinatally HIV-infected adolescents and young adults in the United States.The sample included 1891 adolescents and young adults living with HIV (27.8% perinatally infected; 72.2% behaviorally infected who were linked to care through 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions Units. All completed audio computer-assisted self-interview surveys. Chart abstraction or blood draw provided viral load data. Geographic-level variables were extracted from the United States Census Bureau (e.g., socioeconomic disadvantage, percent of Black and Latino households, percent rural and Esri Crime (e.g., global crime index databases as Zip Code Tabulation Areas. AIDSVu data (e.g., prevalence of HIV among youth were extracted at the county-level. Using HLM v.7, the authors conducted means-as-outcomes random effects multi-level models to examine the association between structural-level and individual-level factors and (1 being on antiretroviral therapy (ART currently; (2 being on ART for at least 6 months; (3 missed HIV care appointments (not having missed any vs. having missed one or more appointments over the past 12 months; and (4 viral suppression (defined by the corresponding assay cutoff for the lower limit of viral load at each participating site which denoted nondetectability vs. detectability.Frequencies for the 4 primary outcomes were as follows: current ART use (n = 1120, 59.23%; ART use for ≥6 months (n = 861, 45.53%; at least one missed HIV care appointment (n = 936, 49.50; and viral suppression (n = 577, 30.51%. After adjusting for individual-level factors, youth living in more disadvantaged areas (defined by a composite score derived from 2010 Census indicators including percent poverty, percent receiving public assistance, percent of female, single-headed households, percent
Ragni, M V; Sherman, K E; Jordan, J A
Despite continuous improvement in safety and purity of blood products for individuals with haemophilia, transmissible agents continue to affect individuals with haemophilia. This chapter addresses three viral pathogens with significant clinical impact: HIV, hepatitis C and parvovirus B19. Hepatitis C is the leading cause of chronic hepatitis and the major co-morbid complication of haemophilia treatment. Clinically, asymptomatic intermittent alanine aminotransferase elevation is typical, with biopsy evidence of advanced fibrosis currently in 25%. Current treatment is effective in up to 70%, and many new agents are in development. For those progressing to end-stage liver disease, liver transplantation outcomes are similar to those in non-haemophilia subjects, although pretransplant mortality is higher. HIV infection, the second leading co-morbid condition in haemophilia, is managed as a chronic infection with highly active antiretroviral therapy (HAART). HAART also slows hepatitis C virus (HCV) progression in those with HIV/HCV co-infection. Viral inactivation and recombinant technologies have effectively prevented transfusion-transmitted viral pathogens in haemophilia. Human parvovirus B19 infection, typically associated with anaemia or, rarely severe aplastic crisis, is a non-lipid enveloped virus, for which standard inactivation techniques are ineffective. Thus, nucleic acid testing (NAT) to screen the blood supply for B19 DNA is currently under consideration by the Food and Drug Administration. To the extent, viral inactivation, recombinant, and NAT technologies are available worldwide, and the lifespan for those with haemophilia is approaching that of the normal population. The purpose of this chapter is to provide an update on three clinically significant transfusion-transmitted viral pathogens.
Law, W. Phillip; Duncombe, Chris J.; Mahanontharit, Apicha; Boyd, Mark A.; Ruxrungtham, Kiat; Lange, Joep M. A.; Phanuphak, Praphan; Cooper, David A.; Dore, Gregory J.
OBJECTIVE: To examine the impact of viral hepatitis co-infection on HIV disease outcomes following commencement of combination antiretroviral therapy in a developing country setting. METHODS: HIV RNA suppression, CD4 cell count recovery, and HIV disease progression were examined within a cohort of
Ahlers, Laura R. H.; Goodman, Alan G.
Innate immunity refers to the body’s initial response to curb infection upon exposure to invading organisms. While the detection of pathogen-associated molecules is an ancient form of host defense, if dysfunctional, autoimmune disease may result. The innate immune response during pathogenic infection is initiated through the activation of receptors recognizing conserved molecular patterns, such as nucleic acids from a virus’ genome or replicative cycle. Additionally, the host’s own nucleic acids are capable of activating an immune response. Therefore, it follows that the nucleic acid-sensing pathways must be tightly controlled to avoid an autoimmune response from recognition of self, yet still be unimpeded to respond to viral infections. In this review, we will describe the nucleic acid sensing pathways and how they respond to virus infection. Moreover, we will discuss autoimmune diseases that develop when these pathways fail to signal properly and identify knowledge gaps that are prime for interrogation. PMID:27857881
Raberahona, Mihaja; Wackenheim, Chloe; Germi, Raphaele; Carré, Martin; Bulabois, Claude-Eric; Thiébaut, Anne; Lupo, Julien; Semenova, Touyana; Cahn, Jean-Yves; Morand, Patrice; Epaulard, Olivier
Epstein-Barr virus (EBV) displays oncogenic properties, particularly in the immunocompromised host. Notably, hematopoietic stem cell transplantation (HSCT) recipients with a detectable blood EBV viral load (BEBVL) are considered at higher risk of post-transplant lymphoproliferative diseases (PTLD). Therefore, BEBVL is monitored after HSCT, and preemptive rituximab may be used in patients with high values. However, little is known about post-HSCT BEBVL dynamics, and the threshold that should lead to anti-CD20 therapy is poorly defined. We retrospectively analyzed the post-HSCT BEBVL of 332 adult HSCT recipients in our center from 2005 to 2013, including the effect of rituximab. Detection of BEBVL >100, 1000, 5000, 10 000, and 50 000 copies/mL occurred in, respectively, 77.7%, 69.6%, 37.0%, 27.1%, and 7.5% of the patients after a respective median time of 9, 14, 15, 16, and 14 weeks. No BEBVL threshold was associated with an overall survival difference. Seventy-eight patients received rituximab, with a BEBVL decrease in most. Among patients with detectable BEBVL, long-term survival did not differ in rituximab treated and non-treated, except for patients with BEBVL ≥50 000. Only one case of PTLD was observed. BEBVL is frequently detectable after HSCT, but suggests no strong association with survival. Preemptive rituximab therapy threshold remains to be defined. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Huang, Pin-I; Chang, Ju-Fang; Kirn, David H; Liu, Ta-Chiang
Head and neck cancers usually present with advanced disease and novel therapies are urgently needed. Genetic therapy aims at restoring malfunctioned tumor suppressor gene(s) or introducing proapoptotic genes. Oncolytic virotherapeutics induce multiple cycles of cancer-specific virus replication, followed by oncolysis, virus spreading and infection of adjacent cancer cells. Oncolytic viruses can also be armed to express therapeutic transgene(s). Recent advances in preclinical and clinical studies are revealing the potential of both therapeutic classes for advanced head and neck cancers, including the approval of two products (Gendicine and H101) by a governmental agency. This review summarizes the available clinical data to date and discusses the challenges and future directions.
Barnett, Burton E.; Staupe, Ryan P.; Odorizzi, Pamela M.; Palko, Olesya; Tomov, Vesselin T.; Mahan, Alison E.; Gunn, Bronwyn; Chen, Diana; Paley, Michael A.; Alter, Galit; Reiner, Steven L.; Lauer, Georg M.; Teijaro, John; Wherry, E. John
The role of antibody and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. Here we demonstrate that B cell specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells not only controlled IgG2a production, but also mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a since T-bet in B cells was important even in the presence of virus-specific IgG2a. Our data supports a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages. PMID:27430722
Conclusions: It is very difficult in viral conjunctivitis to make clinical differentiation caused by different agents because of common clinical signs and symptoms. In routine clinical work, the viral conjunctivitis usually related with Adenovirus. But almost one fourth of the patients’ conjunctivitis were not related to Adenovirus, which shows the importance of the laboratory diagnostics. True diagnosis plays an important role on prevention of contamination and unnecessary use of antibiotics in viral conjunctivitis.
Patrício, Maria I; MacLaren, Robert E
As gene therapy of choroideremia is becoming a clinical reality, there is a need for reliable and sensitive assays to determine the expression of exogenously delivered Rab Escort Protein-1 (REP1), in particular to test new gene therapy vectors and as a quality control screen for clinical vector stocks. Here we describe an in vitro protocol to test transgene expression following AAV2/2-REP1 transduction of a human cell line. Gene augmentation can be confirmed by western blot and quantification of the fold-increase of human REP1 levels over untransduced controls.
Full Text Available The article considers issues of therapeutic tactics for virus infections of children. The authors explain the essence of changes, which take place in the immune system of body under this pathology. The article describes immuno pathogenesis of acute enteric infections and the effect of lactoprobiotics on immuno-competent cells. The findings prove the advisability of applying this group of medications for a complex therapy of children with acute diarrhea disturbance.Key words: acute enteric infections, immuno-pathogenesis, treatment, lacto probiotics, children.
Marro, Brett S; Blanc, Caroline A; Loring, Jeanne F; Cahalan, Michael D; Lane, Thomas E
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. While a broad range of therapeutics effectively reduce the incidence of focal white matter inflammation and plaque formation for patients with relapse-remitting forms of MS, a challenge within the field is to develop therapies that allow for axonal protection and remyelination. In the last decade, growing interest has focused on utilizing neural precursor cells (NPCs) to promote remyelination. To understand how NPCs function in chronic demyelinating environments, several excellent pre-clinical mouse models have been developed. One well accepted model is infection of susceptible mice with neurotropic variants of mouse hepatitis virus (MHV) that undergo chronic demyelination exhibiting clinical and histopathologic similarities to MS patients. Combined with the possibility that an environmental agent such as a virus could trigger MS, the MHV model of demyelination presents a relevant mouse model to assess the therapeutic potential of NPCs transplanted into an environment in which inflammatory-mediated demyelination is established.
Kelly B McClellan
Full Text Available B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL-specific B cells can contribute to the control of murine gamma-herpesvirus 68 (gammaHV68 latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell-/- mice during the early phase of gammaHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell-/- mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of gamma-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection.
This is the third installment of a 3 part series on bovine viral diarrhea (BVD), written for a lay publication whose core audience in dairy producers. Control of BVD in any dairy operation must rely on the implementation of an organized strategy combining biosecurity, surveillance and increased herd...
Stoica, Lorelei; Sena-Esteves, Miguel
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of upper and lower motor neurons. Mutations in superoxide dismutase 1 (SOD1) are a leading cause of ALS, responsible for up to 20% of familial cases. Although the exact mechanism by which mutant SOD1 causes disease remains unknown, multiple studies have shown that reduction of the mutant species leads to delayed disease onset and extension of lifespan of animal models. This makes SOD1 an ideal target for gene therapy coupling adeno associated virus vector (AAV) gene delivery with RNAi molecules. In this review we summarize the studies done thus far attempting to decrease SOD1 gene expression, using AAV vectors as delivery tools, and RNAi as therapeutic molecules. Current hurdles to be overcome, such as the need for widespread gene delivery through the entire central nervous system (CNS), are discussed. Continued efforts to improve current AAV delivery methods and capsids will accelerate the application of these therapeutics to the clinic.
Mazzola, Alessandra; Tran Minh, Margherita; Charlotte, Frédéric; Hdiji, Aisha; Bernard, Denis; Wendum, Dominique; Calmus, Yvon; Conti, Filomena
Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.
Fairlie, Lee; Karalius, Brad; Patel, Kunjal; van Dyke, Russell B; Hazra, Rohan; Hernán, Miguel A; Siberry, George K; Seage, George R; Agwu, Allison; Wiznia, Andrew
This study compared 12-month CD4 and viral load outcomes in HIV-infected children and adolescents with virological failure, managed with four treatment switch strategies. This observational study included perinatally HIV-infected (PHIV) children in the Pediatric HIV/AIDS Cohort Study (PHACS) and Pediatric AIDS Clinical Trials (PACTG) Protocol 219C. Treatment strategies among children with virologic failure were compared: continue failing combination antiretroviral therapy (cART); switch to new cART; switch to drug-sparing regimen; and discontinue all ART. Mean changes in CD4% and viral load from baseline (time of virologic failure) to 12 months follow-up in each group were evaluated using weighted linear regression models. Virologic failure occurred in 939 out of 2373 (40%) children. At 12 months, children switching to new cART (16%) had a nonsignificant increase in CD4% from baseline, 0.59 percentage points [95% confidence interval (95% CI) -1.01 to 2.19], not different than those who continued failing cART (71%) (-0.64 percentage points, P = 0.15) or switched to a drug-sparing regimen (5%) (1.40 percentage points, P = 0.64). Children discontinuing all ART (7%) experienced significant CD4% decline -3.18 percentage points (95% CI -5.25 to -1.11) compared with those initiating new cART (P = 0.04). All treatment strategies except discontinuing ART yielded significant mean decreases in log10VL by 12 months, the new cART group having the largest drop (-1.15 log10VL). In PHIV children with virologic failure, switching to new cART was associated with the best virological response, while stopping all ART resulted in the worst immunologic and virologic outcomes and should be avoided. Drug-sparing regimens and continuing failing regimens may be considered with careful monitoring.
Glass, Elizabeth J; Baxter, Rebecca; Leach, Richard J; Jann, Oliver C
Farm animals remain at risk of endemic, exotic and newly emerging viruses. Vaccination is often promoted as the best possible solution, and yet for many pathogens, either there are no appropriate vaccines or those that are available are far from ideal. A complementary approach to disease control may be to identify genes and chromosomal regions that underlie genetic variation in disease resistance and response to vaccination. However, identification of the causal polymorphisms is not straightforward as it generally requires large numbers of animals with linked phenotypes and genotypes. Investigation of genes underlying complex traits such as resistance or response to viral pathogens requires several genetic approaches including candidate genes deduced from knowledge about the cellular pathways leading to protection or pathology, or unbiased whole genome scans using markers spread across the genome. Evidence for host genetic variation exists for a number of viral diseases in cattle including bovine respiratory disease and anecdotally, foot and mouth disease virus (FMDV). We immunised and vaccinated a cattle cross herd with a 40-mer peptide derived from FMDV and a vaccine against bovine respiratory syncytial virus (BRSV). Genetic variation has been quantified. A candidate gene approach has grouped high and low antibody and T cell responders by common motifs in the peptide binding pockets of the bovine major histocompatibility complex (BoLA) DRB3 gene. This suggests that vaccines with a minimal number of epitopes that are recognised by most cattle could be designed. Whole genome scans using microsatellite and single nucleotide polymorphism (SNP) markers has revealed many novel quantitative trait loci (QTL) and SNP markers controlling both humoral and cell-mediated immunity, some of which are in genes of known immunological relevance including the toll-like receptors (TLRs). The sequencing, assembly and annotation of livestock genomes and is continuing apace. In
Fray, M D; Paton, D J; Alenius, S
Bovine viral diarrhoea virus (BVDV) is a major reproductive pathogen in cattle. Infection of the bull can lead to a fall in semen quality and the isolation of infectious virus in the ejaculate, while infection in the cow leads to poor conception rates, abortions and congenital defects. BVDV also reduces the animal's resistance to other respiratory and enteric pathogens. The prevalence of BVDV is primarily due to the efficiency with which the virus crosses the placenta of susceptible females. Calves that survive infection during the first trimester of pregnancy are born with a persistent and lifelong infection. These persistently infected (PI) animals represent between 1.0% and 2.0% of the cattle population and continuously shed infectious virus. The availability of reliable diagnostic ELISA and PCR techniques, which can test milk or serum samples for virus or antibodies, has simplified BVDV surveillance and improved the prospects for control. Although PI animals are the principal vectors within and between herds, they can be readily identified and removed. By contrast, cows carrying a PI foetus are particularly problematic. These animals have been compared to 'Trojan Horses' because they are virus-negative and antibody-positive but they deliver PI calves. In general, acutely infected cattle are much less efficient vectors but infections at the onset of puberty have resulted in a localised and persistent infection within the testes. Under these circumstances, virus shedding into the semen may remain undetected. Transmission of BVDV can be controlled through vaccination or eradication. BVDV vaccine technology has been developing over the past 30 years, but currently available vaccines are still of the conventional inactivated or attenuated sort. In general, vaccination has not been applied with sufficient rigor to make a significant impact on the level of circulating virus, unlike the national and regional eradication programmes established in areas such as
Full Text Available Mannose polyethylenimine with a molecular weight of 25 k (Man-PEI25k was synthesized via a phenylisothiocyanate bridge using mannopyranosylphenyl isothiocyanate as a coupling reagent, and characterized by 1H NMR (nuclear magnetic resonance and FT-IR (Fourier transform infrared spectroscopy analysis. Spherical nanoparticles were formed with diameters of 80–250 nm when the copolymer was mixed with DNA at various charge ratios of copolymer/DNA (N/P. Gel electrophoresis demonstrated that the DNA had been condensed and retained by the PEI derivates at low N/P ratios. The Man-PEI25k/DNA complexes were less cytotoxic than the PEI complexes with a molecular weight of 25 k (PEI25k at the same N/P ratio. Laser scan confocal microscopy and flow cytometry confirmed that the Man-PEI25k/DNA complexes gave higher cell uptake efficiency in (Dendritic cells DC2.4 cells than HeLa cells. The transfection efficiency of Man-PEI25k was higher than that of PEI25k towards DC2.4 cells. These results indicated that Man-PEI25k could be used as a potential DC-targeting non-viral vector for gene therapy.
Chu, Heng-Cheng; Hsieh, Chung-Bao; Hsu, Kuo-Feng; Fan, Hsiu-Lung; Hsieh, Tsai-Yuan; Chen, Teng-Wei
Simultaneous splenectomy in liver transplantation (LT) is selectively indicated because of splenoportal venous thromboses and increased sepsis. Therefore, its impact should be further investigated. Of the 160 liver transplant patients, only 40 underwent simultaneous splenectomy. Clinicopathologic characteristics and outcomes were compared between the splenectomy and non-splenectomy group using retrospective analysis. Although the groups were similar and had no significant difference in the intra- and postoperative data, non-splenectomy group had more male patients. However, splenectomy group showed significantly higher platelet and leukocyte counts at 1 month and 6 months after the transplantation and higher hepatitis C virus anti-viral therapy completion. Furthermore, 3 patients developed portal or splenic vein thrombosis during the postoperative follow-up, but the overall survival rate did not significantly differ between these groups. Simultaneous splenectomy in LT can be safely performed, particularly in patients with hepatitis C virus cirrhosis, small-for-size grafts, hypersplenism, and ABO blood group incompatible (ABO - incompatible) LT. Copyright © 2015 Elsevier Inc. All rights reserved.
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Neuzil, Petr; Merkely, Béla; Erglis, Andrejs; Marinskis, Germanas; de Groot, Joris R; Schmidinger, Herwig; Rodriguez Venegas, Manuel; Voskuil, Michiel; Sturmberger, Thomas; Petru, Jan; Jongejan, Niels; Aichinger, Josef; Kamzola, Ginta; Aidietis, Audrius; Gellér, Laszlo; Mraz, Tomas; Osztheimer, Istvan; Mika, Yuval; Evans, Steven; Burkhoff, Daniel; Kuck, Karl-Heinz
Many patients requiring a pacemaker have persistent hypertension with systolic blood pressures above recommended levels. We evaluated a pacemaker-based Programmable Hypertension Control (PHC) therapy that uses a sequence of variably timed shorter and longer atrioventricular intervals. Patients indicated for dual-chamber pacing with office systolic blood pressure (oSBP) >150 mm Hg despite stable medical therapy were implanted with a Moderato™ pulse generator that delivers PHC therapy. Patients were followed for 1 month (Run-In period) with conventional pacing; those with persistent oSBP >140 mm Hg were included in the study and had PHC therapy activated. The co-primary efficacy end points were changes in 24-hour ambulatory systolic blood pressure and oSBP between baseline and 3 months. Safety was assessed by tracking adverse events. Thirty-five patients met the initial inclusion criteria and underwent Moderato implantation. At 1 month, oSBP was URL: http://www.clinicaltrials.gov. Unique identifier: NCT02282033. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
Galivo, F; Diaz, R M; Wongthida, P; Thompson, J; Kottke, T; Barber, G; Melcher, A; Vile, R
A fully intact immune system would be expected to hinder the efficacy of oncolytic virotherapy by inhibiting viral replication. Simultaneously, however, it may also enhance antitumor therapy through initiation of proinflammatory, antiviral cytokine responses at the tumor site. The aim of this study was to investigate the role of a fully intact immune system on the antitumor efficacy of an oncolytic virus. In this respect, injection of oncolytic vesicular stomatitis virus (VSV) into subcutaneous B16ova melanomas in C57Bl/6 mice leads to tumor regression, but it is not associated with viral replicative burst in the tumor. In contrast, intratumoral delivery of VSV induces an acute proinflammatory reaction, which quickly resolves concomitantly with virus clearance. Consistent with the hypothesis that therapy may not be dependent on the ability of VSV to undergo progressive rounds of replication, a single-cycle VSV is equally effective as a fully replication-competent VSV, whereas inactivated viruses do not generate therapy. Even though therapy is dependent on host CD8+ and natural killer cells, these effects are not associated with interferon-gamma-dependent responses against either the virus or tumor. There is, however, a strong correlation between viral gene expression, induction of proinflammatory reaction in the tumor and in vivo therapy. Overall, our results suggest that acute innate antiviral immune response, which rapidly clears VSV from B16ova tumors, is associated with the therapy observed in this model. Therefore, the antiviral immune response to an oncolytic virus mediates an intricate balance between safety, restriction of oncolysis and, potentially, significant immune-mediated antitumor therapy.
A. L. Zaplatnikov
intoxication signs. Almost every one in three children in both groups had catarrhal signs completely resolved by the end of the treatment, in 70% and 65% cases in groups 1 and 2 severity of catarrhal syndrome did not exceed rank 1 (2, p > 0.05. No adverse effects associated with the study scheme components have been reported during the study. Efficacy and tolerability evaluation by the doctors using CGI in group 1 was 3.37 ± 0.65 (M ± SD, 95% CI 3.22-3.53 vs. 3.23 ± 0.77 (M ± SD, 95%CI 3.08—3.39 in group 2 (Т-test, p = 0.38. In group 1 maximum rating (4 scores was assigned by the doctors in 46%, minimum one (2 scores — in 9%, while in group 2 the equivalent proportions were 40% and 16%, respectively (p = 0.44 for maximum score and p = 0.17 for minimum score. Therapeutic efficacy evaluation by parents in group 1 was 3.73 ± 0.57 (M ± SD, 95% CI 3.59-3.87 vs. 3.35 ± 0.72 (M ± SD, 95%CI 3.20—3.50 in group 2; Т-test, p = 0.04. According to frequency assessment, positive scoring (4-5 scores was more prevalent among parents in group 1: 71% vs. 44% (group 2, 2 test, p = 0.001, minimum scoring (2 scores was less common in group 1: 1.5% vs. 12% (group 2,?2 test, p = 0.02. Evaluation of therapeutic tolerability by parents in group 1 (4.04 ± 0.53, 95%CI 3.91—4.18 was higher as compared to group 2 (3.82 ± 0.53, 95%CI 3.71—3.93; Т-test, p = 0.01. Maximum scoring (5 scores was obtained in group 1 in 16% cases, in group 2 — 6% (2 test, p = 0.03. Analysis of additional drug prescriptions revealed that 3.6 ± 1.2 prescriptions have been made on average in group 1 vs. 5.0 ± 1.2 in group 2 (Т-test, р = 0.01. Proportion of children receiving more than 5 drugs was 18% in group 1 vs. 32% in group 2 (2 test, p = 0.05. Seven drugs were given to 3% children in group 1 and 12% — in group 2 (exact Fisher’s test, p = 0.067. Duration of therapy with H1-histamine blockers in group 1 was 5 days (Me: 5.0 (5.0; 6.0 vs. 8.5 days (Me: 8.5 (7.5; 10.0 in
Full Text Available Abstract Background Cervical cancer and infection with human immunodeficiency virus (HIV are both important public health problems in South Africa (SA. The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs, high-risk human papillomavirus (HR-HPV, HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV therapy. Methods A cross-sectional survey was conducted at an anti-retroviral (ARV treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2 test was used to detect HR-HPV. Relative light units (RLU were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology. Results The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene, the median HPV viral load was 181.1 RLU (HC2 positive samples only and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL. The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 – 57.7 for those that were HC2 positive and had a viral load of ≤ 181.1 RLU (the median HPV viral load, and 33.8 (95% CI 6.4 – 178.9 for those that were HC2 positive with a HPV viral load > 181.1 RLU. Conclusion Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need
Caldeira, Daniel; Lopes, Luís R; Vaz-Carneiro, António; Costa, João
The causes of myocarditis are diverse, but a viral etiology is the most common. In this systematic review by the Cochrane Collaboration, the authors assessed the efficacy of corticosteroid therapy in patients with viral myocarditis. Eight randomized controlled trials with 719 patients (two trials in pediatric populations) were included for analysis. Pooled results did not show significant differences in mortality with the use of corticosteroids. Patients on corticosteroid therapy had significantly higher post-treatment left ventricular ejection fraction values compared to control. These results are limited by the significant heterogeneity associated with clinical trials. The best available evidence does not support the routine use of corticosteroids in patients with viral myocarditis. Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.
Iorio, R; Pensati, P; Botta, S; Moschella, S; Impagliazzo, N; Vajro, P; Vegnente, A
Interferon (IFN) is standard therapy for chronic viral hepatitis in children. The aim of this study was to evaluate the side effects of alpha-interferon (IFN) in 94 consecutive children (58 males; age range, 3 to 14 years) affected by chronic viral hepatitis treated with different schedules ranging from 3 to 10 MU and from 3 to 12 months, and the impact of this therapy on health-related quality of life. Side effects were evaluated with clinical and laboratory examinations and were recorded on a diary card. The health-related quality of life was evaluated with a modified version of the Sickness Impact Profile. All patients experienced at least one adverse reaction to IFN treatment; 80% had more than five side effects. There were no life-threatening reactions. Three children experienced severe reactions (febrile seizure, severe hypertransaminasemia and relapsing episodes of epistaxis, respectively) that required permanent IFN withdrawal. Another child had a febrile seizure requiring temporary IFN withdrawal. In seven children the neutrophil count fell below 1000/mm3 and promptly increased when IFN was temporarily discontinued. The remaining children had mild or moderate clinical and/or laboratory adverse reactions. Age, sex, viral etiology of chronic hepatitis and response to therapy were not significantly associated with the appearance of side effects. The pre-IFN health-related quality of life was good in all children; it deteriorated significantly during IFN therapy and returned to basal standards within 3 months after IFN withdrawal. No patient required suspension of IFN therapy because of worsening of health-related quality of life. Children have a low risk of developing severe IFN-induced side effects. Adverse reactions and worsening of health-related quality of life were tolerable and did not seem to be a limiting factor for IFN therapy in young candidates.
Emilia García-Menor MD
Full Text Available This randomized, open-label study evaluated the additional benefits of the synbiotic Prodefen® in the clinical management of acute diarrhea of suspected viral origin in children between 6 months and 12 years of age. Study outcomes included the duration of diarrhea, the recovery from diarrhea, and the tolerability and acceptance of the treatment. The proportion of patients without diarrhea over the study period was greater in the synbiotic group than in the control group at all study time points, showing a statistically significant difference on the fifth day (95% vs 79%, p < 0.001. The duration of diarrhea (median and interquartile range was reduced by 1 day in the synbiotic-treated patients (3 [2-5] vs 4 [3-5], p = 0.377. The tolerability of the treatment regimen, as evaluated by the parents, was significantly better in those receiving the synbiotic than in the control group. Overall, 96% of the parents of children receiving the synbiotic reported being satisfied to very satisfied with the treatment regimen. The results of this study indicate that the addition of the synbiotic Prodefen® is a well-tolerated and well-accepted approach that provides an additional benefit to the standard supportive therapy in the management of acute viral diarrhea in children.
Cade, A; Brownlee, K G; Conway, S P; Haigh, D; Short, A; Brown, J; Dassu, D; Mason, S A; Phillips, A; Eglin, R; Graham, M; Chetcuti, A; Chatrath, M; Hudson, N; Thomas, A; Chetcuti, P A
To evaluate short and long term effects of giving nebulised budesonide early in respiratory syncytial viral (RSV) bronchiolitis. A multicentre randomised double blind placebo controlled trial. Infants admitted to hospital with their first episode of RSV positive bronchiolitis. Randomisation to receive either 1 mg of nebulised budesonide (Bud) or placebo (Pla) twice daily from admission until 2 weeks after discharge. Follow up was for 12 months. Duration of hospital admission, time taken to become symptom free, re-admission rates, general practitioner consultation rates, and use of anti-wheeze medication during follow up. 161 infants were studied. Both arms were similar with respect to initial clinical severity, age, sex, socioeconomic class, and tobacco exposure. Median time from first nebulisation to discharge: Bud and Pla, 2 days. Median number of days for 50% of infants to be symptom free for 48 hours: Bud, 10 days; Pla, 12 days. Respiratory re-admission rates in the 12 month follow up: Bud, 16%; Pla, 18%; median difference (95% confidence interval (CI)), -2 (-14 to 10). Median respiratory related general practitioner attendances: Bud, 4.0; Pla, 4.5; median difference (95% CI), -1 (-2 to 0). Percentage of infants receiving at least one prescription for anti-wheeze medication during follow up, corticosteroids: Bud, 50%; Pla, 60%; difference (95% CI), -10 (-26 to 6); bronchodilators: Bud, 60%; Pla, 67%; difference (95% CI), -7 (-22 to 8). There are no short or long term clinical benefits from the administration of nebulised corticosteroids in the acute phase of RSV bronchiolitis.
Schneider, U; Martin, A; Schwemmle, M; Staeheli, P
Persistence of RNA viruses is frequently associated with non-uniform terminal nucleotide deletions at both ends of the viral genome, which are believed to restrict viral replication and transcription during persistent infection. Borna disease virus (BDV), a negative strand RNA virus with no recognizable acute phase, quickly establishes persistence. We recently demonstrated that the vast majority of BDV genomes and antigenomes possess uniformly trimmed 5' termini, even if the virus is recovered from complementary DNA encoding a hypothetical full-length viral genome. Here we discuss different mechanisms which might lead to the selective 5'-terminal trimming of the BDV genome and subsequent retrieval of the lost genetic information. We further discuss possible benefits of genome trimming in the light of recent findings that terminal RNA structures are recognized by intracellular sensors which trigger innate immunity. We hypothesize that 5'-terminal genome trimming might represent a smart strategy of BDV to evade the antiviral host response.
V. F. Uchaikin
Full Text Available We observed 43 patients with cholestasis (21 — with acute viral hepatitis A and B and 22 — with chronic viral hepatitis B and C. Etiological diagnosis was based on the identification of specific markers of the spectrum. These 43 patients in addition to basic therapy ursodeoxycholic acid as a drug Ursosan of company «PRO.MED.CS Praha a.s.» (CzechRepublic. The control group consisted of 17 patients with acute viral hepatitis. Clinical signs are jaundice and itching of the skin, abdominal pain, significant hepatomegaly. Serum bilirubin level rises due to the conjugated fraction, alkaline phosphatase, gamma-glutamyltranspeptidase. When ultrasound revealed dilated bile ducts in the liver parenchyma, reactive edema of the gallbladder wall, signs gipomotornoy dyskinesia. Appointment ursosan in acute and chronic viral hepatitis occurring with cholestasis leads to the clinical and biochemical effects, and has a beneficial effect on the state of the liver and gall bladder.
Full Text Available BACKGROUND: Hepatitis C virus (HCV infection is highly prevalent in renal transplant (RT recipients. Currently, interferon-based (IFN-based antiviral therapies are the standard approach to control HCV infection. In a post-transplantation setting, however, IFN-based therapies appear to have limited efficacy and their use remains controversial. The present study aimed to evaluate the efficacy and safety of IFN-based therapies for HCV infection post RT. METHODS: We searched Pubmed, Embase, Web of Knowledge, and The Cochrane Library (1997-2013 for clinical trials in which transplant patients were given Interferon (IFN, pegylated interferon (PEG, interferon plus ribavirin (IFN-RIB, or pegylated interferon plus ribavirin (PEG-RIB. The Sustained Virological Response (SVR and/or drop-out rates were the primary outcomes. Summary estimates were calculated using the random-effects model of DerSimonian and Laird, with heterogeneity and sensitivity analysis. RESULTS: We identified 12 clinical trials (140 patients in total. The summary estimate for SVR rate, drop-out rate and graft rejection rate was 26.6% (95%CI, 15.0-38.1%, 21.1% (95% CI, 10.9-31.2% and 4% (95%CI: 0.8%-7.1%, respectively. The overall SVR rate in PEG-based and standard IFN-based therapy was 40.6% (24/59 and 20.9% (17/81, respectively. The most frequent side-effect requiring discontinuation of treatment was graft dysfunction (14 cases, 45.1%. Meta-regression analysis showed the covariates included contribute to the heterogeneity in the SVR logit rate, but not in the drop-out logit rate. The sensitivity analyses by the random model yielded very similar results to the fixed-effects model. CONCLUSIONS: IFN-based therapy for HCV infection post RT has poor efficacy and limited safety. PEG-based therapy is a more effective approach for treating HCV infection post-RT than standard IFN-based therapy. Future research is required to develop novel strategies to improve therapeutic efficacy and
Gorar, Zulfikar A; Butt, Zahid A.; Aziz, Imrana
Objectives A high prevalence of viral hepatitis B and C was found among healthcare workers during a province-wide screening in Sindh Province, Pakistan. A follow-up study was undertaken to identify risk factors for this high prevalence in healthcare workers. Design Population based case–control design. Setting Public sector healthcare facilities in a rural district of Pakistan. Participants Healthcare workers who were screened for hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV...
Olesen, Niels Jørgen; Skall, Helle Frank
This chapter covers the genetics (genotypes and serotypes), clinical signs, host species, transmission, prevalence, diagnosis, control and prevention of viral haemorrhagic septicaemia virus.......This chapter covers the genetics (genotypes and serotypes), clinical signs, host species, transmission, prevalence, diagnosis, control and prevention of viral haemorrhagic septicaemia virus....
Full Text Available Abstract Background The optimal stage for initiating antiretroviral therapies in HIV-1 bearing patients is still a matter of debate. Methods We present computer simulations of HIV-1 infection aimed at identifying the pro et contra of immediate as compared to deferred Highly Active Antiretroviral Therapy (HAART. Results Our simulations highlight that a prompt specific CD8+ cytotoxic T lymphocytes response is detected when therapy is delayed. Compared to very early initiation of HAART, in deferred treated patients CD8+ T cells manage to mediate the decline of viremia in a shorter time and, at interruption of therapy, the virus experiences a stronger immune pressure. We also observe, however, that the immunological effects of the therapy fade with time in both therapeutic regimens. Thus, within one year from discontinuation, viral burden recovers to the value at which it would level off in the absence of therapy. In summary, simulations show that immediate therapy does not prolong the disease-free period and does not confer a survival benefit when compared to treatment started during the chronic infection phase. Conclusion Our conclusion is that, since there is no therapy to date that guarantees life-long protection, deferral of therapy should be preferred in order to minimize the risk of adverse effects, the occurrence of drug resistances and the costs of treatment.
Marcus Tulius T Silva
Full Text Available While systemic viral infections are exceptionally common, symptomatic viral infections of the brain parenchyma itself are very rare, but a serious neurologic condition. It is estimated that viral encephalitis occurs at a rate of 1.4 cases per 100.000 inhabitants. Geography is a major determinant of encephalitis caused by vector-borne pathogens. A diagnosis of viral encephalitis could be a challenge to the clinician, since almost 70% of viral encephalitis cases are left without an etiologic agent identified. In this review, the most common viral encephalitis will be discussed, with focus on ecology, diagnosis, and clinical management.
Terpstra, C.; Kroese, A.H.
This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of
Bonnaud, Emilie M; Szelechowski, Marion; Bétourné, Alexandre; Foret, Charlotte; Thouard, Anne; Gonzalez-Dunia, Daniel; Malnou, Cécile E
Understanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which viral origin is suspected. Borna disease virus (BDV) represents an ideal model to analyze the molecular mechanisms of viral persistence in neurons and its consequences for neuronal homeostasis. It is now established that BDV ensures its long-term maintenance in infected cells through a stable interaction of viral components with the host cell chromatin, in particular, with core histones. This has led to our hypothesis that such an interaction may trigger epigenetic changes in the host cell. Here, we focused on histone acetylation, which plays key roles in epigenetic regulation of gene expression, notably for neurons. We performed a comparative analysis of histone acetylation patterns of neurons infected or not infected by BDV, which revealed that infection decreases histone acetylation on selected lysine residues. We showed that the BDV phosphoprotein (P) is responsible for these perturbations, even when it is expressed alone independently of the viral context, and that this action depends on its phosphorylation by protein kinase C. We also demonstrated that BDV P inhibits cellular histone acetyltransferase activities. Finally, by pharmacologically manipulating cellular acetylation levels, we observed that inhibiting cellular acetyl transferases reduces viral replication in cell culture. Our findings reveal that manipulation of cellular epigenetics by BDV could be a means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction. Persistent DNA viruses often subvert the mechanisms that regulate cellular chromatin dynamics, thereby benefitting from the resulting epigenetic changes to create a favorable milieu for their latent and persistent states. Here, we reasoned that Borna disease virus (BDV), the only RNA virus known to
Kim, Eddo; Kliger, Yossef
Viruses and developers of anti-inflammatory therapies share a common interest in proteins that manipulate the immune response. Large double-stranded DNA viruses acquire host proteins to evade host defense mechanisms. Hence, viral pirated proteins may have a therapeutic potential. Although dozens of viral piracy events have already been identified, we hypothesized that sequence divergence impedes the discovery of many others. We developed a method to assess the number of viral/human homologs and discovered that at least 917 highly diverged homologs are hidden in low-similarity alignment hits that are usually ignored. However, these low-similarity homologs are masked by many false alignment hits. We therefore applied a filtering method to increase the proportion of viral/human homologous proteins. The homologous proteins we found may facilitate functional annotation of viral and human proteins. Furthermore, some of these proteins play a key role in immune modulation and are therefore therapeutic protein candidates.
Klein, Marina B; Yang, Hong; DelBalso, Lina; Carbonneau, Julie; Frost, Eric; Boivin, Guy
To determine the spectrum of pathogens causing acute febrile respiratory illness in human immunodeficiency virus (HIV)-infected adults, we re-analyzed data from a prospective surveillance study involving 50 outpatients (90% of whom received highly active antiretroviral therapy). Nasopharyngeal samples were tested for 23 respiratory viruses by multiplex reverse-transcriptase polymerase chain reaction (PCR) and for atypical bacteria by PCR. Sputum cultures and serological testing were performed. Viruses accounted for 64% of infections. After influenza (22 cases), human metapneumovirus infection (6 cases) was most common and was associated with bronchospasm. Bacterial infections occurred in 6 patients (3 of whom had concurrent viral infection). Over 80% of patients received antibiotics. Rapid testing to identify specific viral pathogens could aid in patient management and reduce unnecessary antibiotic exposure.
Franz J Zemp
Full Text Available Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1 (+/- Trp53 (+/- mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV. These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models.
Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing; Maxwell, Lori; Reilly, Karlyne M; McFadden, Grant; Yong, V Wee; Forsyth, Peter A
Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1 (+/-) Trp53 (+/-) mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models.
Kirk, Ole; Pedersen, Court; Law, Matthew
to ITT/s=f, 22-70% of the patients starting a HAART regimen in a RCT experienced a virological response at week 48. Only two RCTs had complete follow-up data (n=424): between 29 and 62% achieved a virological response at week 48 in the six treatment arms evaluated in the studies according to ITT...... confirmed virological failure: 63 vs 33%), varied largely across regimens and were not associated with the discontinuation rate. CONCLUSIONS: Discontinuation of follow-up at switch from the therapy to be evaluated remains common in antiretroviral treatment trials, but leads to an imprecise and incomplete......SIDA) starting their first HAART regimen. METHODS: Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified...
Wang, Mandy; Barasheed, Osamah; Rashid, Harunor; Booy, Robert; El Bashir, Haitham; Haworth, Elizabeth; Ridda, Iman; Holmes, Edward C; Dwyer, Dominic E; Nguyen-Van-Tam, Jonathan; Memish, Ziad A; Heron, Leon
Cost-effective interventions are needed to control the transmission of viral respiratory tract infections (RTIs) in mass gatherings. Facemasks are a promising preventive measure, however, previous studies on the efficacy of facemasks have been inconclusive. This study proposes a large-scale facemask trial during the Hajj pilgrimage in Saudi Arabia and presents this protocol to illustrate its feasibility and to promote both collaboration with other research groups and additional relevant studies. A cluster-randomised controlled trial is being conducted to test the efficacy of standard facemasks in preventing symptomatic and proven viral RTIs among pilgrims during the Hajj season in Mina, Mecca, Saudi Arabia. The trial will compare the 'supervised use of facemasks' versus 'standard measures' among pilgrims over several Hajj seasons. Cluster-randomisation will be done by accommodation tents with a 1:1 ratio. For the intervention tents, free facemasks will be provided to be worn consistently for 7days. Data on flu-like symptoms and mask use will be recorded in diaries. Nasal samples will be collected from symptomatic recruits and tested for nucleic acid of respiratory viruses. Data obtained from questionnaires, diaries and laboratory tests will be analysed to examine whether mask use significantly reduces the frequency of laboratory-confirmed respiratory viral infection and syndromic RTI as primary outcomes. This trial will provide valuable evidence on the efficacy of standard facemask use in preventing viral respiratory tract infections at mass gatherings. This study is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: ACTRN12613001018707 (http://www.anzctr.org.au). Copyright © 2014 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.
Milavetz, Barry I; Balakrishnan, Lata
DNA tumor viruses including members of the polyomavirus, adenovirus, papillomavirus, and herpes virus families are presently the subject of intense interest with respect to the role that epigenetics plays in control of the virus life cycle and the transformation of a normal cell to a cancer cell. To date, these studies have primarily focused on the role of histone modification, nucleosome location, and DNA methylation in regulating the biological consequences of infection. Using a wide variety of strategies and techniques ranging from simple ChIP to ChIP-chip and ChIP-seq to identify histone modifications, nuclease digestion to genome wide next generation sequencing to identify nucleosome location, and bisulfite treatment to MeDIP to identify DNA methylation sites, the epigenetic regulation of these viruses is slowly becoming better understood. While the viruses may differ in significant ways from each other and cellular chromatin, the role of epigenetics appears to be relatively similar. Within the viral genome nucleosomes are organized for the expression of appropriate genes with relevant histone modifications particularly histone acetylation. DNA methylation occurs as part of the typical gene silencing during latent infection by herpesviruses. In the simple tumor viruses like the polyomaviruses, adenoviruses, and papillomaviruses, transformation of the cell occurs via integration of the virus genome such that the virus's normal regulation is disrupted. This results in the unregulated expression of critical viral genes capable of redirecting cellular gene expression. The redirected cellular expression is a consequence of either indirect epigenetic regulation where cellular signaling or transcriptional dysregulation occurs or direct epigenetic regulation where epigenetic cofactors such as histone deacetylases are targeted. In the more complex herpersviruses transformation is a consequence of the expression of the viral latency proteins and RNAs which again can
The aim of my thesis is to provide a comprehensive overview of the viral marketing and to analyze selected viral campaigns. There is a description of advantages and disadvantages of this marketing tool. In the end I suggest for which companies viral marketing is an appropriate form of the promotion.
Erik M Volz
Full Text Available Viral phylodynamics is defined as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viralphylogenies. Since the coining of the term in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts. Many viruses, especially RNA viruses, rapidly accumulate genetic variation because of short generation times and high mutation rates. Patterns of viral genetic variation are therefore heavily influenced by how quickly transmission occurs and by which entities transmit to one another. Patterns of viral genetic variation will also be affected by selection acting on viral phenotypes. Although viruses can differ with respect to many phenotypes, phylodynamic studies have to date tended to focus on a limited number of viral phenotypes. These include virulence phenotypes, phenotypes associated with viral transmissibility, cell or tissue tropism phenotypes, and antigenic phenotypes that can facilitate escape from host immunity. Due to the impact that transmission dynamics and selection can have on viral genetic variation, viral phylogenies can therefore be used to investigate important epidemiological, immunological, and evolutionary processes, such as epidemic spread, spatio-temporal dynamics including metapopulation dynamics, zoonotic transmission, tissue tropism, and antigenic drift. The quantitative investigation of these processes through the consideration of viral phylogenies is the central aim of viral phylodynamics.
Full Text Available Abstract Background Hepatitis B and C are silent killers not yet recognized as major public health challenges in many developing countries with huge disease burden. In Ethiopia, Hepatitis B is endemic with an average prevalence of 10.8 %, and the prevalence of Hepatitis C is 2 %. The prevalence of both infections, however, is likely to be underreported due to the lack of diagnostic facilities and appropriate surveillance systems. Ethiopia is also among the many Sub-Sahara African countries lacking a coordinated and systematic national response to chronic viral hepatitis. The objective of this study is to examine the current level of response to viral Hepatitis B & C in Ethiopia with the aim to bring identified gaps to the attention of relevant stakeholders and policy makers. Methods This cross-sectional qualitative study was based on semi-structured in-depth interviews with 21 key informants from health facilities, health offices, pharmaceutical companies, regulatory bodies, professional association and blood bank units. Participants were selected purposively based on their role in the national hepatitis response. The investigators also reviewed available policy and strategy documents, standards of practice and surveys, and paid visits to pharmaceutical premises to check the availability of antiviral drugs. Thematic analysis was employed to make sense of the data. During the data analysis process, all the authors critically read the materials, and data was triangulated by source, interpreter view and thematic perspective to ensure accurate representation and comprehensiveness, and validation of the interviewees’ responses. Once each investigator reviewed the data independently, the team reached a common understanding of the scope and contexts of the information attained. Data were subsequently reduced to key concepts, and case stories were taken with successive revisions. The key concepts were later coded into most basic meaningful
FitzSimons, David W
The Viral Hepatitis Prevention Board and the European Liver Patients Association jointly organized a meeting (Lucca, Italy, 13-14 March 2008) to review the role and impact of patients' organizations and advocacy groups in Europe and the USA on the prevention and control of viral hepatitis. The national and international groups described a wide variety of organizational structures, means of funding, services and activities. Participants reported numerous obstacles and difficulties, ranging from limited funding, weak governmental support and the lack of a high-profile lobby to residual prejudice against people with viral hepatitis and cultural barriers. The groups' experiences formed an impressive list of strengths and achievements, including international and national campaigns, networking, building of excellent relations with the media, support from and respect of professional bodies, greater respect of patients' human rights, improved access to counselling and treatment, and influence on national and international policies. The meeting highlighted opportunities, for example, to complete programmes of immunization against hepatitis B, to convince governments of the economic value of public health interventions, and raise awareness of the value of a healthy liver.
Full Text Available Control of chronic viral infections by CD8 T cells is critically dependent on CD4 help. In particular, helper-derived IL-21 plays a key role in sustaining the CD8 T cell response; however, the molecular pathways by which IL-21 sustains CD8 T cell immunity remain unclear. We demonstrate that IL-21 causes a phenotypic switch of transcription factor expression in CD8 T cells during chronic viral infection characterized by sustained BATF expression. Importantly, BATF expression during chronic infection is both required for optimal CD8 T cell persistence and anti-viral effector function and sufficient to rescue “unhelped” CD8 T cells. Mechanistically, BATF sustains the response by cooperating with IRF4, an antigen-induced transcription factor that is also critically required for CD8 T cell maintenance, to preserve Blimp-1 expression and thereby sustain CD8 T cell effector function. Collectively, these data suggest that CD4 T cells “help” the CD8 response during chronic infection via IL-21-induced BATF expression.
Mosepele, Mosepele; Hemphill, Linda C; Moloi, Walter; Moyo, Sikhulile; Nkele, Isaac; Makhema, Joseph; Bennett, Kara; Triant, Virginia A; Lockman, Shahin
Human immune deficiency virus (HIV) is associated with increased cardiovascular disease (CVD) risk, yet the relationship between HIV and carotid atherosclerosis / monocyte activation among virally suppressed HIV-infected patients in sub-Saharan Africa is not well understood. We measured traditional CVD risk factors, bilateral distal common carotid intima media thickness (cIMT), presence of carotid plaque and plasma sCD163 levels among virally suppressed HIV-infected adults and HIV-uninfected controls, in a cross-sectional study in Gaborone, Botswana. The associations between HIV status, traditional CVD risk factors, sCD163 and outcome of cIMT were assessed in univariate and multivariate linear regression models. We enrolled 208 HIV-infected adults (55% Female, mean age 39 years) who had undetectable HIV-1 RNA on antiretroviral therapy and 224 HIV-uninfected controls (47% Female, mean age 37 years). There was no difference in cIMT between study groups, with mean cIMT 0.607mm and 0.599mm in HIV-infected and HIV-uninfected, respectively (p = 0.37). Plasma sCD163 was significantly higher in HIV-infected versus HIV-uninfected persons (1917ng/ml vs 1593ng/ml, p = 0.003), but was not associated with cIMT (p = 0.43 among all, p = 0.72 for HIV-infected only). In the final multivariate model, increased cIMT was associated with older age, being treated for hypertension, and higher non-HDL cholesterol among all (polder age and waist-hip ratio in HIV-infected participants (p = 0.02 & p = 0.02 respectively). Carotid plaque was present in a significantly higher proportion of HIV-infected adults (RR 2.15, 95% CI 1.22, 3.81). HIV-infected participants aged 30-50 years who have achieved viral suppression did not have increased cIMT when compared to HIV-uninfected controls in Botswana. However, well-controlled HIV was associated with excess monocyte activation. Future work should explore the impact of subclinical atherosclerosis on CVD events among HIV-infected and -uninfected adults
Full Text Available Human immune deficiency virus (HIV is associated with increased cardiovascular disease (CVD risk, yet the relationship between HIV and carotid atherosclerosis / monocyte activation among virally suppressed HIV-infected patients in sub-Saharan Africa is not well understood.We measured traditional CVD risk factors, bilateral distal common carotid intima media thickness (cIMT, presence of carotid plaque and plasma sCD163 levels among virally suppressed HIV-infected adults and HIV-uninfected controls, in a cross-sectional study in Gaborone, Botswana. The associations between HIV status, traditional CVD risk factors, sCD163 and outcome of cIMT were assessed in univariate and multivariate linear regression models.We enrolled 208 HIV-infected adults (55% Female, mean age 39 years who had undetectable HIV-1 RNA on antiretroviral therapy and 224 HIV-uninfected controls (47% Female, mean age 37 years. There was no difference in cIMT between study groups, with mean cIMT 0.607mm and 0.599mm in HIV-infected and HIV-uninfected, respectively (p = 0.37. Plasma sCD163 was significantly higher in HIV-infected versus HIV-uninfected persons (1917ng/ml vs 1593ng/ml, p = 0.003, but was not associated with cIMT (p = 0.43 among all, p = 0.72 for HIV-infected only. In the final multivariate model, increased cIMT was associated with older age, being treated for hypertension, and higher non-HDL cholesterol among all (p<0.001, p = 0.03, p<0.001 respectively, and with older age and waist-hip ratio in HIV-infected participants (p = 0.02 & p = 0.02 respectively. Carotid plaque was present in a significantly higher proportion of HIV-infected adults (RR 2.15, 95% CI 1.22, 3.81.HIV-infected participants aged 30-50 years who have achieved viral suppression did not have increased cIMT when compared to HIV-uninfected controls in Botswana. However, well-controlled HIV was associated with excess monocyte activation. Future work should explore the impact of subclinical atherosclerosis
Styer, Linda M; Miller, Thomas T; Parker, Monica M
Human immunodeficiency virus type 2 (HIV-2) is distantly related to the more widespread HIV-1. Although HIV-2 infection is rare in the U.S., cases are concentrated in the Northeast. No FDA-approved HIV-2 viral load assays exist. A clinically validated laboratory-developed assay is currently available in the U.S., however it is not currently approved for use on New York State patients. To develop a sensitive viral load assay to quantify HIV-2 RNA in plasma and to validate it for clinical use. The real-time RT-PCR assay simultaneously amplifies HIV-2 and a whole virus internal control, added during the lysis step. Two extraction volumes can be used. Results are reported in HIV-2 RNA International Units (IU). The assay has a limit of detection of 7 IU/mL and a lower limit of quantification of 29 IU/mL. The assay detects multiple strains of HIV-2 group A and B and generates reproducible results. Samples exchanged with a comparator laboratory produced similar viral load results, with 74% of positives differing by loads (range: 1.63-5.14 log10 IU/mL), 10 (19%) were positive but not quantifiable, and 14 were negative. HIV-2 RNA was detected in at least one specimen from 19 of 25 (76%) individuals tested. We developed a sensitive and accurate HIV-2 viral load assay. Validation data indicate the assay is suitable for clinical use and its availability in New York State will improve clinical monitoring of HIV-2 infected patients. Copyright © 2013 Elsevier B.V. All rights reserved.
Maujean, Annick; Pepping, Christopher A.; Kendall, Elizabeth
This review article examines current knowledge about the efficacy of art therapy based on the findings of 8 randomized controlled trials (RCTs) conducted with adult populations from 2008-2013 that met a high standard of rigor. Of these studies, all but one reported beneficial effects of art therapy. Review findings suggest that art therapy may…
Ebrahimi, Mahyar, E-mail: firstname.lastname@example.org
In self-controlling hyperthermia therapy, once the desired temperature is reached, the heat generation ceases and overheating is prevented. In order to design a system that generates sufficient heat without thermal ablation of surrounding healthy tissue, a good understanding of temperature distribution and its change with time is imperative. This study is conducted to extend our understanding about the heat generation and transfer, temperature distribution and temperature rise pattern in the tumor and surrounding tissue during self-controlling magnetic hyperthermia. A model consisting of two concentric spheres that represents the tumor and its surrounding tissue is considered and temperature change pattern and temperature distribution in tumor and surrounding tissue are studied. After describing the model and its governing equations and constants precisely, a typical numerical solution of the model is presented. Then it is showed that how different parameters like Curie temperature of nanoparticles, magnetic field amplitude and nanoparticles concentration can affect the temperature change pattern during self-controlling magnetic hyperthermia. The model system herein discussed can be useful to gain insight on the self-controlling magnetic hyperthermia while applied to cancer treatment in real scenario and can be useful for treatment strategy determination. - Highlights: • Temperature change pattern in tumor and surrounding tissue are studied. • The model system herein can be useful for treatment strategy determination. • In the work described herein, emphasis is on the effect of low Curie temperature. • If the equilibrium temperature can be tuned appropriately, the stay time will be infinite.
Aust, W; Wichmann, G; Dietz, A
In Germany anaphylactic reactions after insect stings are mostly caused by honey bee (Apis mellifera) and wasp (Vespula vulgaris, Vespula germanica). In the majority of cases venom immunotherapy is a successful therapy and protects patients from recurrent systemic anaphylactic reaction. In some patients persistent severe reactions after insect sting can even occur in spite of venom therapy, as a sign of therapy failure. It is important to identify these patients, who do not benefit from venom immunotherapy, in an early stage of therapy. In this case dose rate of venom immunotherapy must be adjusted for a successful therapy outcome. Up to now skin prick tests, specific IgE-antibodies and in vitro diagnostics are not suitable for detecting therapy failure. Patients with treatment failure can be diagnosed by insect sting test and almost all of them will become fully protected by increasing the maintenance dose. © Georg Thieme Verlag KG Stuttgart · New York.
Full Text Available Cyclin-dependent kinases (CDKs are key regulators of the cell cycle and RNA polymerase II mediated transcription. Several pharmacological CDK inhibitors are currently in clinical trials as potential cancer therapeutics and some of them also exhibit antiviral effects. Olomoucine II and roscovitine, purine-based inhibitors of CDKs, were described as effective antiviral agents that inhibit replication of a broad range of wild type human viruses. Olomoucine II and roscovitine show high selectivity for CDK7 and CDK9, with important functions in the regulation of RNA polymerase II transcription. RNA polymerase II is necessary for viral transcription and following replication in cells. We analyzed the effect of inhibition of CDKs by olomoucine II on gene expression from viral promoters and compared its effect to widely-used roscovitine. We found that both roscovitine and olomoucine II blocked the phosphorylation of RNA polymerase II C-terminal domain. However the repression of genes regulated by viral promoters was strongly dependent on gene localization. Both roscovitine and olomoucine II inhibited expression only when the viral promoter was not integrated into chromosomal DNA. In contrast, treatment of cells with genome-integrated viral promoters increased their expression even though there was decreased phosphorylation of the C-terminal domain of RNA polymerase II. To define the mechanism responsible for decreased gene expression after pharmacological CDK inhibitor treatment, the level of mRNA transcription from extrachromosomal DNA was determined. Interestingly, our results showed that inhibition of RNA polymerase II C-terminal domain phosphorylation increased the number of transcribed mRNAs. However, some of these mRNAs were truncated and lacked polyadenylation, which resulted in decreased translation. These results suggest that phosphorylation of RNA polymerase II C-terminal domain is critical for linking transcription and posttrancriptional
Full Text Available The use of non-viral procedures, together with CRISPR/Cas9 genome-editing technology, allows the insertion of single-copy therapeutic genes at pre-determined genomic sites, overcoming safety limitations resulting from random gene insertions of viral vectors with potential for genome damage. In this study, we demonstrate that combination of non-viral gene delivery and CRISPR/Cas9-mediated knockin via homology-directed repair can replace the use of viral vectors for the generation of genetically modified therapeutic cells. We custom-modified human adipose mesenchymal stem cells (hAMSCs, using electroporation as a transfection method and CRISPR/Cas9-mediated knockin for the introduction and stable expression of a 3 kb DNA fragment including the eGFP (selectable marker and a variant of the herpes simplex virus 1 thymidine kinase genes (therapeutic gene, under the control of the human elongation factor 1 alpha promoter in exon 5 of the endogenous thymidine kinase 2 gene. Using a U87 glioma model in SCID mice, we show that the therapeutic capacity of the new CRISPR/Cas9-engineered hAMSCs is equivalent to that of therapeutic hAMSCs generated by introduction of the same therapeutic gene by transduction with a lentiviral vector previously published by our group. This strategy should be of general use to other applications requiring genetic modification of therapeutic cells.
Full Text Available Epstein-Barr virus (EBV encoded transcription factor Zta (BZLF1, ZEBRA, EB1 is the prototype of a class of transcription factor (including C/EBPalpha that interact with CpG-containing DNA response elements in a methylation-dependent manner. The EBV genome undergoes a biphasic methylation cycle; it is extensively methylated during viral latency but is reset to an unmethylated state following viral lytic replication. Zta is expressed transiently following infection and again during the switch between latency and lytic replication. The requirement for CpG-methylation at critical Zta response elements (ZREs has been proposed to regulate EBV replication, specifically it could aid the activation of viral lytic gene expression from silenced promoters on the methylated genome during latency in addition to preventing full lytic reactivation from the non-methylated EBV genome immediately following infection. We developed a computational approach to predict the location of ZREs which we experimentally assessed using in vitro and in vivo DNA association assays. A remarkably different binding motif is apparent for the CpG and non-CpG ZREs. Computational prediction of the location of these binding motifs in EBV revealed that the majority of lytic cycle genes have at least one and many have multiple copies of methylation-dependent CpG ZREs within their promoters. This suggests that the abundance of Zta protein coupled with the methylation status of the EBV genome act together to co-ordinate the expression of lytic cycle genes at the majority of EBV promoters.
May, Margaret T.; Gompels, Mark; Delpech, Valerie; Porter, Kholoud; Orkin, Chloe; Kegg, Stephen; Hay, Phillip; Johnson, Margaret; Palfreeman, Adrian; Gilson, Richard; Chadwick, David; Martin, Fabiola; Hill, Teresa; Walsh, John; Post, Frank; Fisher, Martin; Ainsworth, Jonathan; Jose, Sophie; Leen, Clifford; Nelson, Mark; Anderson, Jane; Sabin, Caroline
Objective: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). Methods: Patients aged more than 20 years who started ART during 2000–2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4+ cell count and viral load before ART and in each of years 1–5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4+ cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20–85 years. Results: Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 person-years. At start of ART, expected age at death [95% confidence interval (CI)] of 35-year-old men with CD4+ cell count less than 200, 200–349, at least 350 cells/μl was 71 (68–73), 78 (74–82) and 77 (72–81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five-year-old men who increased their CD4+ cell count in the first year of ART from less than 200 to 200–349 or at least 350 cells/μl and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48–61) (CD4+ cell count <200 cells/μl and no viral suppression) to 80 (76–83) years (CD4+ cell count ≥350 cells/μl and viral suppression). Conclusion: Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4+ cell count significantly improve their life expectancy if they have a good CD4+ cell count response and undetectable viral load. PMID:24556869
Kamwesiga, Julius; Mutabazi, Vincent; Kayumba, Josephine; Tayari, Jean-Claude K; Uwimbabazi, Jean Claude; Batanage, Gad; Uwera, Grace; Baziruwiha, Marcel; Ntizimira, Christian; Murebwayire, Antoinette; Haguma, Jean Pierre; Nyiransabimana, Julienne; Nzabandora, Jean Bosco; Nzamwita, Pascal; Mukazayire, Ernestine
To examine the effect of selenium supplementation on CD4 T-cell counts, viral suppression, and time to antiretroviral therapy (ART) initiation in ART-naive HIV-infected patients in Rwanda. A multicenter, double-blinded, placebo-controlled, randomized clinical trial was conducted. Eligible patients were HIV-infected adults (≥21 years) who had a CD4 cell count between 400 and 650 cells/μl (ART eligibility was ≤350 cells/μl throughout the trial), and were willing to practice barrier methods of birth control. Patients were randomized to receive once-daily 200 μg selenium tablets or identical placebo. They were followed for 24 months with assessments every 6 months. Declines in CD4 cell counts were modeled using linear regressions with generalized estimating equations and effect modification, and the composite outcome (ART eligible or ART initiation) using Cox proportional-hazards regression, both conducted with intention to treat. Of the 300 participants, 149 received selenium, 202 (67%) were women, and median age was 33.5 years. The rate of CD4 depletion was reduced by 43.8% [95% confidence interval (CI) 7.8-79.8% decrease] in the treatment arm - from mean 3.97 cells/μl per month to mean 2.23 cells/μl per month. We observed 96 composite outcome events - 45 (47%) in the treatment arm. We found no treatment effect for the composite outcome (hazard ratio 1.00, 95% CI 0.66-1.54) or viral suppression (odds ratio 1.18, 95% CI 0.71-1.94). The trial was underpowered for the composite outcome due to a lower-than-anticipated event rate. Adverse events were comparable throughout. This randomized clinical trial demonstrated that 24-month selenium supplementation significantly reduces the rate of CD4 cell count decline among ART-naive patients.
Singh Ravesh; Gaiha Gaurav; Werner Lise; McKim Kevin; Mlisana Koleka; Luban Jeremy; Walker Bruce D; Karim Salim S Abdool; Brass Abraham L; Ndung'u Thumbi; CAPRISA 002 Acute Infection Study Team
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV 1 acquisition and viral control during primary HIV 1 infection. We measured IFN a IFN ß myxovirus resistance protein A (MxA) human TRIM5a (huTR...
Singh, Ravesh; Gaiha, Gaurav; Werner, Lise; McKim, Kevin; Mlisana, Koleka; Luban, Jeremy; Bruce D. Walker; Karim, Salim S. Abdool; Brass, Abraham L; Ndung'u, Thumbi
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-α, IFN-β, myxovirus resistance protein A (MxA), human TRIM5α (...
Perkins, Matthew J; Bradley, William P; Lalani, Tahaniyat; Agan, Brian K; Whitman, Timothy J; Ferguson, Tomas M; Okulicz, Jason F; Ganesan, Anuradha
Posttreatment control of HIV infection is a rare phenomenon primarily described among those initiating treatment with antiretroviral therapy (ART) during early/acute HIV infection. We examined a large, well-characterized cohort of HIV-infected Department of Defense beneficiaries for the presence of posttreatment controllers (PTCs) whom we defined as individuals with sustained viral suppression for ≥6 months after discontinuation of ART. We defined those who became viremic within 6 months of discontinuing ART as rapid viremics (RVs) and compared demographic and clinical characteristics, CD4 counts, and viral loads prior, during, and after ART discontinuation between the 2 groups. From a cohort of 6070 patients, we identified 95 who had been treated with ART for 2 years or more who subsequently discontinued ART and had viral load assessments available after discontinuation. Four (4.2%) of these 95 met our definition of PTC. The duration of viral suppression off of ART ranged from 267 to 1058 days with 1 of the 4 restarting ART without having redeveloped a significant viremia. All 4 patients initiated ART during chronic HIV infection. Demographic and clinical characteristics of PTCs were similar to RVs. While posttreatment control has predominantly been described among individuals who initiated ART in early/acute HIV infection, we identified 4 PTCs who started ART during chronic infection suggesting that posttreatment control also occurs among such patients. The rarity of PTCs identified in our cohort is consistent with reports from previous studies.
education, self-blood glucose monitoring and titration algorithms. Weight gain and hypoglycaemia can be significant complications of insulin therapy. Glitazones (thiazolidenediones) are not recommended therapies. Specialist referral is appropriate at any stage if glycaemic targets are not met. Refer to full text guideline ...
Bissig, Christin; Lenoir, Marc; Velluz, Marie-Claire; Kufareva, Irina; Abagyan, Ruben; Overduin, Michael; Gruenberg, Jean
ALIX plays a role in nucleocapsid release during viral infection, as does lysobisphosphatidic acid (LBPA). However, the mechanism remains unclear. Here we report that LBPA is recognized within an exposed site in ALIX Bro1 domain predicted by MODA, an algorithm for discovering membrane-docking areas in proteins. LBPA interactions revealed a strict requirement for a structural calcium tightly bound near the lipid interaction site. Unlike other calcium- and phospholipid-binding proteins, the all-helical triangle-shaped fold of the Bro1 domain confers selectivity for LBPA via a pair of hydrophobic residues in a flexible loop, which undergoes a conformational change upon membrane association. Both LBPA and calcium binding are necessary for endosome association and virus infection, as are ALIX ESCRT binding and dimerization capacity. We conclude that LBPA recruits ALIX onto late endosomes via the calcium-bound Bro1 domain, triggering a conformational change in ALIX to mediate the delivery of viral nucleocapsids to the cytosol during infection. Copyright © 2013 Elsevier Inc. All rights reserved.
Nash, William T.; Teoh, Jeffrey; Wei, Hairong; Gamache, Awndre; Brown, Michael G.
Natural killer (NK) cells provide essential protection against viral infections. One of the defining features of this lymphocyte population is the expression of a wide array of variable cell surface stimulatory and inhibitory NK receptors (sNKR and iNKR, respectively). The iNKR are particularly important in terms of NK-cell education. As receptors specific for MHC class I (MHC I) molecules, they are responsible for self-tolerance and adjusting NK-cell reactivity based on the expression level of self-MHC I. The end result of this education is twofold: (1) inhibitory signaling tunes the functional capacity of the NK cell, endowing greater potency with greater education, and (2) education on self allows the NK cell to detect aberrations in MHC I expression, a common occurrence during many viral infections. Many studies have indicated an important role for iNKR and MHC I in disease, making these receptors attractive targets for manipulating NK-cell reactivity in the clinic. A greater understanding of iNKR and their ability to regulate NK cells will provide a basis for future attempts at translating their potential utility into benefits for human health. PMID:24795719
Superinfection exclusion, a phenomenon in which a preexisting viral infection prevents a secondary infection with the same or a closely related virus, has been described for various viruses, including important pathogens of humans, animals, and plants. The phenomenon was initially used to test the relatedness of plant viruses. Subsequently, purposeful infection with a mild isolate has been implemented as a protective measure against virus isolates that cause severe disease. In the medical and veterinary fields, superinfection exclusion was found to interfere with repeated applications of virus-based vaccines to individuals with persistent infections and with the introduction of multicomponent vaccines. In spite of its significance, our understanding of this phenomenon is surprisingly incomplete. Recently, it was demonstrated that superinfection exclusion of Citrus tristeza virus (CTV), a positive-sense RNA closterovirus, occurs only between isolates of the same strain, but not between isolates of different strains of the virus. In this study, I show that superinfection exclusion by CTV requires production of a specific viral protein, the p33 protein. Lack of the functional p33 protein completely eliminated the ability of the virus to exclude superinfection by the same or a closely related virus. Remarkably, the protein appeared to function only in a homology-dependent manner. A cognate protein from a heterologous strain failed to confer the exclusion, suggesting the existence of precise interactions of the p33 protein with other factors involved in this complex phenomenon. PMID:22398285
Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.
Brunna M. Alves
Full Text Available Increased access to highly active antiretroviral therapy (HAART by human immunodeficiency virus postive (HIV+ individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can influence virus persistence and pathogenicity, representing a challenge to treatment. However, the clinical relevance of minority quasispecies is still uncertain. In this study, we have determined the archived proviral sequences, viral subtype and drug resistance mutations from a cohort of HIV+ patients with undetectable viral load undergoing HAART as first-line therapy using next-generation sequencing for near full-length virus genome (NFLG assembly. HIV-1 consensus sequences representing NFLG were obtained for eleven patients, while for another twelve varying genome coverage rates were obtained. Phylogenetic analysis showed the predominance of subtype B (83%; 19/23. Considering the minority variants, 18 patients carried archived virus harboring at least one mutation conferring antiretroviral resistance; for six patients, the mutations correlated with the current ARVs used. These data highlight the importance of monitoring HIV minority drug resistant variants and their clinical impact, to guide future regimen switches and improve HIV treatment success.
Negahban, Hossein; Rezaie, Solmaz; Goharpey, Shahin
The primary aim was to investigate the comparative effects of massage therapy and exercise therapy on patients with multiple sclerosis. The secondary aim was to investigate whether combination of both massage and exercise has an additive effect. Randomized controlled pilot trial with repeated measurements and blinded assessments. Local Multiple Sclerosis Society. A total of 48 patients with multiple sclerosis were randomly assigned to four equal subgroups labelled as massage therapy, exercise therapy, combined massage-exercise therapy and control group. The treatment group received 15 sessions of supervised intervention for five weeks. The massage therapy group received a standard Swedish massage. The exercise therapy group was given a combined set of strength, stretch, endurance and balance exercises. Patients in the massage-exercise therapy received a combined set of massage and exercise treatments. Patients in the control group were asked to continue their standard medical care. Pain, fatigue, spasticity, balance, gait and quality of life were assessed before and after intervention. Massage therapy resulted in significantly larger improvement in pain reduction (mean change 2.75 points, P = 0.001), dynamic balance (mean change, 3.69 seconds, P = 0.009) and walking speed (mean change, 7.84 seconds, P = 0.007) than exercise therapy. Patients involved in the combined massage-exercise therapy showed significantly larger improvement in pain reduction than those in the exercise therapy (mean change, 1.67 points, P = 0.001). Massage therapy could be more effective than exercise therapy. Moreover, the combination of massage and exercise therapy may be a little more effective than exercise therapy alone.
D. A. Meira
Full Text Available Seventy-nine HIV-1 infected patients were studied in three groups: Group G1 - 11 patients with no antiretroviral therapy; G2 - 40 patients undergoing antiretroviral therapy, 33 with only two nucleoside reverse transcriptase inhibitors (NRTI, and seven with two NRTI and one protease inhibitor (PI, all with viral load (VL equal or higher than 80 copies of plasma RNA/ml; Group G3 - 28 patients, 23 on highly active antiretroviral therapy (HAART, 18 with two NRTI and one PI, and five with two NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI, the remaining five with combination of two NRTI. All G3 patients had undetectable viral load for at least the past six months. The control group (Gc included 20 normal blood donors without clinical complaints or signs of disease and negative for anti-HIV-1/2 antibodies. Serum cytokine levels pg/ml (TNF-alpha, INF-gamma, IL-2, IL-4, and IL-10 were determined in all patients including controls. CD4+ T and CD8+ T lymphocyte counts were made in the 79 patients by flow cytometry; VL determination was by NASBA technology. Analysis of results showed that the number of CD4+ T and CD8+ T lymphocytes were higher in G2 than G1, while VL was 0.5 log lower. G3 patients had similar lymphocyte values to G2, however they were chosen for G3 because their VL was undetectable, different by 4.0 log to G2. These results show the effect of antiretroviral treatment in G2 and G3 patients with better performance in the latter. Statistical difference was seen between the three groups and controls for serum cytokine behavior: TNF-alpha [H=48.323; pGc]; INF-gamma[H=28.992; pGc]; IL-4[H=48.323; pGc]; IL-10[H=47.256; pGc. There was no statistical difference in IL-2 values between all groups (H=6.071; p>0.10; G1=G2=G3=Gc. In absolute values however, G3 showed slightly lower TNF-alpha, IL-4, and IL-10, and higher INF-gamma and IL-2, to G1 and G2. This suggests a better performance in G3 patients, especially in IL-2 behavior
Marysabel Pinto Telis Silveira
Full Text Available Factors associated with undetectable viral load ( or = 95% of adherence (CI 95% 1,80-13,28; CI 95% 1,73-9,53, compared with less than 60% adherence; it was greater for less than 6 months in treatment (OR = 3.37; CI 95% 1.09-10.46; and smaller for viral load previous to adherence measurement > or = 5.2 log10 (OR = 0.19; CI95% 0.06-0.58, adjusted for these variables and sex, age, clinical status, current immune status, group of drugs and interval between the two measurements of viral load. The crude odds were lower for age 16-24 years and use of Nucleoside Analog Reverse Transcriptase Inhibitors only, but these effects were not significant in the multivariate model. There was no evidence of effect of sex, clinical status, current immune status, and changes in treatment regimen. Treatment adherence gave the largest effect. Motivational interventions directed at adherence may improve treatment effectiveness.
Situmorang, James Rianto
Viral marketing is an extremely powerful and effective form of internet marketing. Itis a new form of word-of-mouth through internet. In viral marketing, someone passeson a marketing message to someone else and so on. Viral marketing proposes thatmessages can be rapidly disseminated from consumer to consumer leading to largescale market acceptance. The analogy of a virus is used to described the exponentialdiffusion of information in an electronic environment and should not be confusedwith th...
Berenguer, Marina; Ortíz-Cantó, Cecilia; Abellán, Juan José; Aguilera, Victoria; Rubín, Angel; Prieto, Martín; López-Labrador, F Xavier
Predictors of sustained virological response (SVR) to antiviral therapy post-liver transplantation (LT) for chronic hepatitis C are needed. In non-transplanted patients, viral kinetics can predict SVR. To determine the early viral kinetics in LT recipients with different immunosuppression (tacrolimus - Tac- vs. cyclosporine - CsA-) during treatment with peg-IFN+RBV. Prospective pilot study in HCV-1b infected patients: (LT CsA n=8; Tac n=8; non-LT n=4), treated with IFN α-2a vs. α-2b (180 μg or 1.5 μg/kg, respectively) once weekly plus weight-based RBV. Median CsA or Tac baseline trough levels were 141 and 7.70 ng/mL, respectively. HCV-RNA was quantified before treatment and after 3, 6, 12h; days 1-6; and weeks 4, 12, 24, 48 and 78 (follow-up). Different kinetics were observed: early viral load declines with shoulder phase (n=12), delayed monophasic without first phase (n=5, all CsA), and biphasic (n=1) or flat (n=1), without influence of IL28B rs12979860 donor/recipient alleles. In LT, median declines (log(10)UI/mL) at week 4 were -3.62 and -1.49 for Tac vs. CsA; and -2.10 vs.-1.50 for IFN α-2a vs. α-2b (NS), with a trend for faster declines in Tac patients. Generalized additive models suggested a cut-off for predicting response in LT patients of 30 days for Tac, but beyond day 40 for CsA. In LT, the viral kinetics during peg-IFN+RBV treatment is delayed. HCV-RNA at 48 h. may not be predictive of response, and CsA-immunosupressed patients with delayed monophasic declines may potentially achieve ETVR and SVR despite unfavourable or absent early viral load declines. Copyright Â© 2011 Elsevier B.V. All rights reserved.
Hecker, James G
Appropriate gene delivery systems are essential for successful gene therapy in clinical medicine. Cationic lipid-mediated delivery is an alternative to viral vector-mediated gene delivery. Lipid-mediated delivery of DNA or mRNA is usually more rapid than viral-mediated delivery, offers a larger payload, and has a nearly zero risk of incorporation. Lipid-mediated delivery of DNA or RNA is therefore preferable to viral DNA delivery in those clinical applications that do not require long-term expression for chronic conditions. Delivery of RNA may be preferable to non-viral DNA delivery in some clinical applications, because transit across the nuclear membrane is not necessary and onset of expression with RNA is therefore even faster than with DNA, although both are faster than most viral vectors. Here, we describe techniques for cationic lipid-mediated delivery of nucleic acids encoding reporter genes in a variety of cell lines. We describe optimized formulations and transfection procedures that we previously assessed by bioluminescence and flow cytometry. RNA transfection demonstrates increased efficiency relative to DNA transfection in non-dividing cells. Delivery of mRNA results in onset of expression within 1 h after transfection and a peak in expression 5-7 h after transfection. Duration of expression in eukaryotic cells after mRNA transcript delivery depends on multiple factors, including transcript stability, protein turnover, and cell type. Delivery of DNA results in onset of expression within 5 h after transfection, a peak in expression 24-48 h after transfection, and a return to baseline that can be as long as several weeks after transfection. In vitro results are consistent with our in vivo delivery results, techniques for which are described as well. RNA delivery is suitable for short-term transient gene expression due to its rapid onset, short duration of expression and greater efficiency, particularly in non-dividing cells, while the longer duration and
Au, Hilda H T; Jan, Eric
Viral genomes are compact and encode a limited number of proteins. Because they do not encode components of the translational machinery, viruses exhibit an absolute dependence on the host ribosome and factors for viral messenger RNA (mRNA) translation. In order to recruit the host ribosome, viruses have evolved unique strategies to either outcompete cellular transcripts that are efficiently translated by the canonical translation pathway or to reroute translation factors and ribosomes to the viral genome. Furthermore, viruses must evade host antiviral responses and escape immune surveillance. This review focuses on some recent major findings that have revealed unconventional strategies that viruses utilize, which include usurping the host translational machinery, modulating canonical translation initiation factors to specifically enhance or repress overall translation for the purpose of viral production, and increasing viral coding capacity. The discovery of these diverse viral strategies has provided insights into additional translational control mechanisms and into the viral host interactions that ensure viral protein synthesis and replication. © 2014 John Wiley & Sons, Ltd.
S.O. Kramariov; I.V. Shpak; A.I. Markov
Purpose of the study. Іmproving the treatment of acute viral hepatitis in children accompanied by cholestasis. Material and methods. We observed 40 children with acute viral hepatitis type A and B aged from 4 months old to 18 years old. The patients were randomized into 2 groups: the first group of children (a control one, n = 27) received basic therapy of acute viral hepatitis, the children of the second group (a main one, n = 13) received basic therapy of acute viral hepatitis in combina...
Manuel, Edwin R; Yeh, Wendy W; Balachandran, Harikrishnan; Clarke, Ryon H; Lifton, Michelle A; Letvin, Norman L
It has been suggested that vaccination prior to infection may direct the mutational evolution of human immunodeficiency virus type 1 (HIV-1) to a less fit virus, resulting in an attenuated course of disease. The present study was initiated to explore whether prior immunization might prevent the reversion of the virus to the wild-type form. Mamu-A*01 monkeys were vaccinated to generate a cytotoxic T-lymphocyte response to the immunodominant Gag p11C epitope and were then challenged with a cloned pathogenic CXCR4-tropic simian-human immunodeficiency virus (SHIV) expressing a mutant Gag p11C sequence (Δp11C SHIV). The epitopic and extraepitopic compensatory mutations introduced into gag of Δp11C SHIV resulted in attenuated replicative capacity and eventual reversions to the wild-type Gag p11C sequence in naïve rhesus monkeys. However, in vaccinated rhesus monkeys, no reversions of the challenge virus were observed, an effect that may have been a consequence of significantly decreased viral replication rather than a redirection of the mutational evolution of the virus. These findings highlight the multifactorial pressures that affect the evolution of primate immunodeficiency viruses.
Use this algorithm only if the patient does NOT have features of severe decompensation.1 Progress down this algorithm within three months if HbA1C remains above 7% (or individualised target). Choose therapies that are likely to produce the HbA1C reduction required to achieve the target.2. Do not proceed with drug ...
D.D. Drabek (Dubravka)
textabstractGene therapy is a procedure in which exogenous genetic material is introduced into the cells of a patient in order to correct an genetic error or to provide the cells of the patient with a new functional property. Correction can be achieved by gene targeting via homologous recombination,
Domingues, Renan Barros
Several viruses may cause central nervous system diseases with a broad range of clinical manifestations. The time course of the viral encephalitis can be acute, subacute, or chronic. Pathologically there are encephalitis with direct viral entry into the CNS in which brain parenchyma exhibits neuronal damaging and viral antigens and there are postinfectious autoimmune encephalitis associated with systemic viral infections with brain tissue presenting perivascular aggregation of immune cells and myelin damaging. Some virus affect previously healthy individuals while others produce encephalitis among imunocompromised ones. Factors such evolving lifestyles and ecological changes have had a considerable impact on the epidemiology of some viral encephalitis [e.g. West-Nile virus, and Japanese B virus]. Citomegalovirus and JC virus are examples of infections of the brain that have been seen more frequently because they occur in immunocompromised patients. In the other hand many scientific achievements in neuroimaging, molecular diagnosis, antiviral therapy, immunomodulatory treatments, and neurointensive care have allowed more precise and earlier diagnoses and more efficient treatments, resulting in improved outcomes. In this article, we will present the current drug options in the management of the main acute and chronic viral infection of the central nervous system of immunocompetent and immunocompromised adults, focusing on drugs mechanisms of action, efficacy, and side effects. The early diagnosis and correct management of such diseases can reduce mortality and neurological sequelae; however, even with recent treatment advances, potentially devastating outcomes are still possible.
Conclusion: Our preliminary experience demonstrated the effectiveness of insulin pump therapy for both type 1 and type 2 diabetic patients. The reduction in their HbA1C values was both statistically and clinically significant. This treatment should be considered for patients poorly controlled by subcutaneous insulin injection therapy.
Pociask, Fredrick D.; Morrison, Gary R.
In this study, we examined the effectiveness of instructional materials designed to control redundancy and split attention in the teaching of complex orthopedic physical therapy skills. Participants included 41 first-year physical therapy students. The modified instruction group received a modified unit of instruction designed to reduce cognitive…
Mocroft, Amanda; Bannister, Wendy P; Kirk, Ole
The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression....
Zhang, Tian-Yuan; Huang, Bing; Yuan, Zhong-Yue; Hu, Yu-Lan; Tabata, Yasuhiko; Gao, Jian-Qing
One of the main limitations of anti-tumor gene therapy is the lack of an effective way to deliver therapeutic genes to tumor sites. Bone marrow mesenchymal stem cells (BMSCs) have been proposed as cellular delivery vehicles to tumor sites in tumor-targeted cancer gene therapy. Here, we investigated the therapeutic effects of cytomegalovirus-thymidine kinase expressing BMSCs (TK-BMSCs) on pulmonary melanoma metastasis combined with prodrug ganciclovir. BMSCs were successfully engineered through a non-viral gene vector. The gene recombinant BMSCs migrated to the pulmonary area and were found to have the tendency to target tumor nodules after systemic delivery. In vitro results demonstrate that the engineered BMSCs have significant suicide effects in the presence of ganciclovir in a dose-dependent manner and can exert a sufficient bystander effect on B16F10 tumor cells in co-culture experiments. In vivo studies confirmed the therapeutic effects of TK-BMSCs/ganciclovir on the metastasis tumor model. This study investigates the possibility of gene transfer via bone marrow mesenchymal stem cells in anti-cancer gene therapy using a metastatic melanoma model and cytomegalovirus-thymidine kinase expressing stem cells, demonstrating clear therapeutic effects. © 2013.
Campbell, Melissa; Decker, Kathleen P.; Kruk, Kerry; Deaver, Sarah P.
This randomized controlled trial was designed to determine if art therapy in conjunction with Cognitive Processing Therapy (CPT) was more effective for reducing symptoms of combat posttraumatic stress disorder (PTSD) than CPT alone. Veterans (N = 11) were randomized to receive either individual CPT, or individual CPT in conjunction with individual…
Hoving, Jan Lucas; Koes, Bart W.; de Vet, Henrica C. W.; van der Windt, Danielle A. W. M.; Assendelft, Willem J. J.; van Mameren, Henk; Devillé, Walter L. J. M.; Pool, Jan J. M.; Scholten, Rob J. P. M.; Bouter, Lex M.
BACKGROUND: Neck pain is a common problem, but the effectiveness of frequently applied conservative therapies has never been directly compared. OBJECTIVE: To determine the effectiveness of manual therapy, physical therapy, and continued care by a general practitioner. DESIGN: Randomized, controlled
Hoving, J.L.; Koes, B.W.; Vet, H.C.W. de; Windt, D.A.W.M. van der; Assendelft, W.J.J.; Mameren, H. van; Devillé, W.L.J.M.; Pool, J.J.M.; Scholten, R.J.P.M.; Bouter, L.M.
BACKGROUND: Neck pain is a common problem, but the effectiveness of frequently applied conservative therapies has never been directly compared. OBJECTIVE: To determine the effectiveness of manual therapy, physical therapy, and continued care by a general practitioner. DESIGN: Randomized, controlled
Kwon, SeungWon; Shin, KyoungHo; Jung, WooSang; Moon, SangKwan; Cho, KiHo
We report the cases of eight military patients with fever (≥38°C) induced by viral upper respiratory tract infection (URTI) who requested treatment with acupuncture in the military medical service room. All patients were treated immediately after diagnosis with classical acupuncture (GV14, GB20, TE8 points) and a new type of acupuncture, equilibrium acupuncture (Feibing and Ganmao points). After one treatment session (20 min), reduction of body temperature was confirmed in all patients. Accompanying symptoms such as headache, myalgia and nasal obstruction also showed a tendency to decrease. Within 3 days of treatment, six of the eight patients had recovered from the URTI. No adverse effects of acupuncture treatment were reported. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Covington, Matthew F; Curiel, Clara N; Lattimore, Lois; Avery, Ryan J; Kuo, Phillip H
61-year-old woman with stage IIIa (T3a N1a M0) left lower leg melanoma with lesions suggestive of in-transit metastases 8 months following wide local excision and femoral nodal dissection. FDG-PET/CT demonstrated 5 FDG-avid in-transit nodal metastases in the distal left leg, confirmed on biopsy. Talimogene laherparepvec (T-VEC) oncolytic immunotherapy consisting of intralesional injections of modified herpes simplex virus-expressing granulocyte-macrophage colony-stimulating factor was completed over 6 months. Subsequent FDG-PET/CT demonstrated reduced or resolved FDG activity in the treated in-transit metastases and a new FDG-avid left thigh in-transit metastasis. FDG-PET/CT can monitor response to T-VEC and potentially other novel viral immunotherapies.
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Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M; Palko, Olesya; Tomov, Vesselin T; Mahan, Alison E; Gunn, Bronwyn; Chen, Diana; Paley, Michael A; Alter, Galit; Reiner, Steven L; Lauer, Georg M; Teijaro, John R; Wherry, E John
The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages. Copyright © 2016 by The American Association of Immunologists, Inc.
Damsgaard, Jesper; Hjerrild, Simon; Renvillard, Signe Groth; Leutscher, Peter Derek Christian
Viral meningitis is considered to be a benign illness with only mild symptoms. In contrast to viral encephalitis and bacterial meningitis, the prognosis is usually good. However, retrospective studies have demonstrated that patients suffering from viral meningitis may experience cognitive impairment following the acute course of infection. Larger controlled studies are needed to elucidate the potential neuropsychiatric adverse outcome of viral meningitis.
Martínez Aguilar, N E; Guido Bayardo, R; Vargas Camaño, M E; Compañ González, D; Miranda Feria, A J
Viruses have been implicated in vasculitis. To determine activity of viral infection associated with vasculitis. 17 patients with vasculitis had been in immunological and antiviral antibodies evaluation. Twenty five healthy controls sex and age matched with hematic biometry (BH) and AA. All subjects were negative to HIV and HBV. Viral activity was demonstrated in eight patients; vascular purpura (5), Takayasu disease (1), polyarteritis nodosa (1), erythema nodosum (1). None subject of control group had IgM activity. Antibodies response of IgG in patients were of lesser intensity than in control group. 14 abnormalities in BH were found in patients and 4 in control group. Immune response in patients, measured by lymphocyte subpopulations and circulating immune complexes was abnormal. In conclusion 47% showed viral activity, but the dominant feature was abnormal immune response in 82%.
Degli Stefani, Mario; Biasutti, Michele
Objective: Framed in the patients’ engagement perspective, the current study aims to determine the effects of group music therapy in addition to drug care in comparison with drug care in addition to other non-expressive group activities in the treatment of psychiatric outpatients. Method: Participants (n = 27) with ICD-10 diagnoses of F20 (schizophrenia), F25 (schizoaffective disorders), F31 (bipolar affective disorder), F32 (depressive episode), and F60 (specific personality disorders) were randomized to receive group music therapy plus standard care (48 weekly sessions of 2 h) or standard care only. The clinical measures included dosages of neuroleptics, benzodiazepines, mood stabilizers, and antidepressants. Results: The participants who received group music therapy demonstrated greater improvement in drug dosage with respect to neuroleptics than those who did not receive group music therapy. Antidepressants had an increment for both groups that was significant only for the control group. Benzodiazepines and mood stabilizers did not show any significant change in either group. Conclusion: Group music therapy combined with standard drug care was effective for controlling neuroleptic drug dosages in adult psychiatric outpatients who received group music therapy. We discussed the likely applications of group music therapy in psychiatry and the possible contribution of music therapy in improving the psychopathological condition of adult outpatients. In addition, the implications for the patient-centered perspective were also discussed. PMID:27774073
Degli Stefani, Mario; Biasutti, Michele
Objective: Framed in the patients' engagement perspective, the current study aims to determine the effects of group music therapy in addition to drug care in comparison with drug care in addition to other non-expressive group activities in the treatment of psychiatric outpatients. Method: Participants ( n = 27) with ICD-10 diagnoses of F20 (schizophrenia), F25 (schizoaffective disorders), F31 (bipolar affective disorder), F32 (depressive episode), and F60 (specific personality disorders) were randomized to receive group music therapy plus standard care (48 weekly sessions of 2 h) or standard care only. The clinical measures included dosages of neuroleptics, benzodiazepines, mood stabilizers, and antidepressants. Results: The participants who received group music therapy demonstrated greater improvement in drug dosage with respect to neuroleptics than those who did not receive group music therapy. Antidepressants had an increment for both groups that was significant only for the control group. Benzodiazepines and mood stabilizers did not show any significant change in either group. Conclusion: Group music therapy combined with standard drug care was effective for controlling neuroleptic drug dosages in adult psychiatric outpatients who received group music therapy. We discussed the likely applications of group music therapy in psychiatry and the possible contribution of music therapy in improving the psychopathological condition of adult outpatients. In addition, the implications for the patient-centered perspective were also discussed.
Mario Degli Stefani
Full Text Available Objective: Framed in the patients’ engagement perspective, the current study aims to determine the effects of group music therapy in addition to drug care in comparison with drug care in the treatment of psychiatric outpatients. Method: Participants (n = 27 with ICD-10 diagnoses of F20 (schizophrenia, F25 (schizoaffective disorders, F31 (bipolar affective disorder, F32 (depressive episode and F60 (specific personality disorders were randomised to receive group music therapy plus standard care (48 weekly sessions of two hours or standard care only. The clinical measures included dosages of neuroleptics, benzodiazepines, mood stabilisers and antidepressants. Results: The participants who received group music therapy demonstrated greater improvement in drug dosage relative to neuroleptics than those who did not receive group music therapy. Antidepressants had an increment for both groups that was significant only for the control group. Benzodiazepines and mood stabilisers did not show any significant change in either group. Conclusions: Group music therapy combined with standard drug care is effective for controlling neuroleptic drug dosages in adult psychiatric outpatients who received group music therapy. We discuss the likely applications of group music therapy in psychiatry and the possible contribution of music therapy in improving the psychopathological condition of adult outpatients. In addition, the implications for the patient-centred perspective were also discussed.
Full Text Available In this pilot study (RibaC, 58 hepatitis C virus (HCV genotype 1 infected treatment-naïve patients were randomized to (i 2 weeks ribavirin double dosing concomitant with pegylated interferon-α (pegIFN-α, (ii 4 weeks ribavirin mono-therapy prior to adding pegIFN-α, or (iii standard-of-care (SOC ribavirin dosing concurrent with pegIFN-α. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10 IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10 IU/mL for CC and CT/TT respectively; P = 0.006, increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-α and thus shortened treatment duration (P<0.05, and decreased median IP-10 concentration from 550 to 345 pg/mL (P<0.001. Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03. Conclusion: Ribavirin down-regulates IP-10, and may have an anti-viral effect differently regulated across IL28B genotypes.
Kirk, Ole; Pedersen, Court; Law, Matthew
OBJECTIVES: To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle. MATERIAL: Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (EuroSIDA) star......OBJECTIVES: To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle. MATERIAL: Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (Euro......SIDA) starting their first HAART regimen. METHODS: Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified...... to ITT/s=f, 22-70% of the patients starting a HAART regimen in a RCT experienced a virological response at week 48. Only two RCTs had complete follow-up data (n=424): between 29 and 62% achieved a virological response at week 48 in the six treatment arms evaluated in the studies according to ITT...
Chang, Qing; Wang, Jianjun; Li, Qi; Kim, Yeunjung; Zhou, Binfei; Wang, Yunfeng; Li, Huawei; Lin, Xi
Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1(-/-) mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0-P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner's membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1(-/-) mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
Peters, Brandon; Dirscherl, Sara; Dantzer, Jessica; Nowacki, Jonathan; Cross, Scott; Li, Xiaoman; Cornetta, Kenneth; Dinauer, Mary C.; Mooney, Sean D.
Research in gene therapy involving genome integrating vectors, now often includes analysis of vector integration sites across the genome using methods such as ligation mediated (LM)-PCR or linear amplification-mediated (LAM)-PCR. To help researchers analyze these sites and the functions of nearby genes, we have developed SeqMap (http://seqmap.compbio.iupui.edu/) a secure, web-based comprehensive vector integration site management tool that automatically analyzes and annotates large numbers of...
Iizuka, Shunsuke; Sakurai, Fuminori; Tachibana, Masashi; Ohashi, Kazuo; Mizuguchi, Hiroyuki
Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX). An adenovirus (Ad) vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX) (Ad-E4-122aT-AHAFIX) maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.
Full Text Available Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX. An adenovirus (Ad vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX (Ad-E4-122aT-AHAFIX maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.
Vaccination is a commonly used tool for the control of both low pathogenic and highly pathogenic avian influenza viruses. Traditionally inactivated adjuvanted vaccines made from a low pathogenic field strain has been used for vaccination, but advances in molecular biology has allowed a number of di...
Aravinthan, Aloysious; Gelson, William; Limbu, Anita; Brais, Rebecca; Richardson, Paul
Hepatic sarcoidosis is usually asymptomatic but rarely leads to adverse liver-related outcome. Co-existence of viral hepatitis and hepatic sarcoidosis is a rare, but recognised phenomenon. Obtaining a balance between immune suppression and anti-viral therapy may be problematic. Immunosuppression in the presence of viral hepatitis can lead to rapid deterioration of liver disease. Similarly, anti-viral therapy may exacerbate granulomatous hepatitis. Here we present two cases of viral hepatitis ...
Cruz, Maria L S; Cardoso, Claudete A A; Darmont, Mariana Q; Souza, Edvaldo; Andrade, Solange D; D'Al Fabbro, Marcia M; Fonseca, Rosana; Bellido, Jaime G; Monteiro, Simone S; Bastos, Francisco I
To evaluate treatment adherence among perinatally-infected pediatric human immunodeficiency virus (HIV) patients followed in pediatric centers in Brazil. This was a cross-sectional multicenter study. Medical records were reviewed and adherence scale, assessment of caregivers' quality of life (WHOQOL-BREF), anxiety, depression, and alcohol/substances use/abuse were assessed. Outcomes included self-reported 100% adherence in the last three days and HIV viral load (VL)<50 copies/mL. Statistical analyses included contingency tables and respective statistics, and multivariable logistic regression. 260 subjects were enrolled: 78% children and 22% adolescents; 93% of caregivers for the children and 77% of adolescents reported 100% adherence; 57% of children and 49% of adolescents had VL<50 copies/mL. In the univariate analyses, HIV diagnosis for screening due to maternal infection, lower caregiver scores for anxiety, and higher scores in physical and psychological domains of WHOQOL-BREF were associated with 100% adherence. Shorter intervals between pharmacy visits were associated with VL<50 copies/mL (p ≤ 0.01). Multivariable regression demonstrated that caregivers who did not abuse alcohol/other drugs (OR=0.49; 95% CI: 0.27-0.89) and median interval between pharmacy visits<33 days (OR=0.97; 95% CI: 0.95-0.98) were independently associated with VL<50 copies/mL; whereas lower caregiver scores for anxiety (OR=2.57; 95% CI: 1.27-5.19) and children's HIV diagnosis for screening due to maternal infection (OR=2.25; 95% CI: 1.12-4.50) were found to be independently associated with 100% adherence. Pediatric HIV programs should perform routine assessment of caregivers' quality of life, and anxiety and depression symptoms. In this setting, pharmacy records are essential to help identify less-than-optimal adherence. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.
Maria L.S. Cruz
Full Text Available OBJECTIVE: To evaluate treatment adherence among perinatally-infected pediatric human immunodeficiency virus (HIV patients followed in pediatric centers in Brazil. METHODS: This was a cross-sectional multicenter study. Medical records were reviewed and adherence scale, assessment of caregivers' quality of life (WHOQOL-BREF, anxiety, depression, and alcohol/substances use/abuse were assessed. Outcomes included self-reported 100% adherence in the last three days and HIV viral load (VL < 50 copies/mL. Statistical analyses included contingency tables and respective statistics, and multivariable logistic regression. RESULTS: 260 subjects were enrolled: 78% children and 22% adolescents; 93% of caregivers for the children and 77% of adolescents reported 100% adherence; 57% of children and 49% of adolescents had VL < 50 copies/mL. In the univariate analyses, HIV diagnosis for screening due to maternal infection, lower caregiver scores for anxiety, and higher scores in physical and psychological domains of WHOQOL-BREF were associated with 100% adherence. Shorter intervals between pharmacy visits were associated with VL < 50 copies/mL (p ≤ 0.01. Multivariable regression demonstrated that caregivers who did not abuse alcohol/other drugs (OR = 0.49; 95% CI: 0.27-0.89 and median interval between pharmacy visits < 33 days (OR = 0.97; 95% CI: 0.95-0.98 were independently associated with VL < 50 copies/mL; whereas lower caregiver scores for anxiety (OR = 2.57; 95% CI: 1.27-5.19 and children's HIV diagnosis for screening due to maternal infection (OR = 2.25; 95% CI: 1.12-4.50 were found to be independently associated with 100% adherence. CONCLUSIONS: Pediatric HIV programs should perform routine assessment of caregivers' quality of life, and anxiety and depression symptoms. In this setting, pharmacy records are essential to help identify less-than-optimal adherence.
Mangia, Alessandra; Bányai, Tivadar; De Bartolomeo, Giuseppe; Gervain, Judit; Habersetzer, François; Mulkay, Jean-Pierre; Ouzan, Denis; Parruti, Giustino; Passariello, Nicola; Remy, Andre-Jean; Rizzetto, Mario; Shiffman, Mitchell L; Tice, Alan D; Schmitz, Manuela; Tatsch, Fernando; Rodriguez-Torres, Maribel
PROPHESYS is a large, multinational, non-interventional prospective cohort study of chronic hepatitis C patients treated with peginterferon alfa/ribavirin. This subanalysis assesses rates of premature treatment discontinuation stratified by on-treatment virological response (VR). This PROPHESYS subanalysis is restricted to treatment-naive, hepatitis C virus (HCV) genotype (G)1/2/3 mono-infected patients who received peginterferon alfa-2a (40KD)/ribavirin with intended treatment duration of 48 (G1) or 24 weeks (G2/3). Early virological responses were classified into four mutually exclusive categories [rapid VR (RVR), complete early VR (cEVR), partial EVR (pEVR), no RVR/EVR], using standard criteria. The likelihood for shortening treatment owing to good efficacy was highest among patients with an RVR and HCV RNA≤400 000 IU/ml (G1 10.0%; G2/3 5.8%) whereas for poor efficacy, it was highest in G1 non-RVR/EVR patients with HCV RNA>400 000 IU/ml (56.6%). Factors significantly associated with early treatment discontinuation as a result of good efficacy in G1 patients included RVR vs. no RVR/EVR and, at baseline, lower HCV RNA, lower FIB-4 score, HCV infection via injection drug use. For G2/3 patients, factors included lower baseline HCV RNA and G2 vs. G3 infection. Most patients started with the recommended peginterferon alfa-2a dose, but a high proportion received a higher-than-recommended ribavirin dose. Despite international guidelines, few physicians used early viral kinetics to abbreviate treatment. Therefore, relatively few patients with an RVR and low baseline HCV RNA abbreviated treatment. In addition, there were deviations in ribavirin starting doses, suggesting that physicians tailor treatment according to local guidelines or previous experience. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Full Text Available Approaches to limiting exposure to antiretroviral therapy (ART drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms.Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1 three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1-8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4-8] wk, n = 21; p = 0.36. No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen.Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis
Full Text Available BACKGROUND: Generalizable data are needed on the magnitude and determinants of adherence and virological suppression among patients on antiretroviral therapy (ART in Africa. METHODS: We conducted a cross-sectional survey with chart abstraction, patient interviews and site assessments in a nationally representative sample of adults on ART for 6, 12 and 18 months at 20 sites in Rwanda. Adherence was assessed using 3- and 30-day patient recall. A systematically selected sub-sample had viral load (VL measurements. Multivariable logistic regression examined predictors of non-perfect (40 copies/ml. RESULTS: Overall, 1,417 adults were interviewed and 837 had VL measures. Ninety-four percent and 78% reported perfect adherence for the last 3 and 30 days, respectively. Eighty-three percent had undetectable VL. In adjusted models, characteristics independently associated with higher odds of non-perfect 30-day adherence were: being on ART for 18 months (vs. 6 months; younger age; reporting severe (vs. no or few side effects in the prior 30 days; having no documentation of CD4 cell count at ART initiation (vs. having a CD4 cell count of <200 cells/µL; alcohol use; and attending sites which initiated ART services in 2003-2004 and 2005 (vs. 2006-2007; sites with ≥600 (vs. <600 patients on ART; or sites with peer educators. Participation in an association for people living with HIV/AIDS; and receiving care at sites which regularly conduct home-visits were independently associated with lower odds of non-adherence. Higher odds of having a detectable VL were observed among patients at sites with peer educators. Being female; participating in an association for PLWHA; and using a reminder tool were independently associated with lower odds of having detectable VL. CONCLUSIONS: High levels of adherence and viral suppression were observed in the Rwandan national ART program, and associated with potentially modifiable factors.
Forsgren, Eva; Fries, Ingemar; de Miranda, Joachim R.
Honey bee (Apis mellifera) colonies are declining, and a number of stressors have been identified that affect, alone or in combination, the health of honey bees. The ectoparasitic mite Varroa destructor, honey bee viruses that are often closely associated with the mite, and pesticides used to control the mite population form a complex system of stressors that may affect honey bee health in different ways. During an acaricide treatment using Apistan (plastic strips coated with tau-fluvalinate), we analyzed the infection dynamics of deformed wing virus (DWV), sacbrood virus (SBV), and black queen cell virus (BQCV) in adult bees, mite-infested pupae, their associated Varroa mites, and uninfested pupae, comparing these to similar samples from untreated control colonies. Titers of DWV increased initially with the onset of the acaricide application and then slightly decreased progressively coinciding with the removal of the Varroa mite infestation. This initial increase in DWV titers suggests a physiological effect of tau-fluvalinate on the host's susceptibility to viral infection. DWV titers in adult bees and uninfested pupae remained higher in treated colonies than in untreated colonies. The titers of SBV and BQCV did not show any direct relationship with mite infestation and showed a variety of possible effects of the acaricide treatment. The results indicate that other factors besides Varroa mite infestation may be important to the development and maintenance of damaging DWV titers in colonies. Possible biochemical explanations for the observed synergistic effects between tau-fluvalinate and virus infections are discussed. PMID:22020517
Full Text Available The prevalence of bovine viral diarrhoea (BVD serologically positive animals in 18 dairy herds with clinical and pathological lesions suggestive of BVD infection, the post-vaccinal seroconversion rates in negative animals vaccinated twice with an inactivated BVD vaccine, and the control measures taken, are described. The pathological and histopathological findings in 6 necropsies performed on animals that died in 5 separate herds closely resembled published descriptions. Positive immunohistochemistry results in 3 cases confirmed the diagnosis in those animals. In 1 herd the prevalence of prevaccinal BVDantibodies was only 36.8 %, while the prevalence varied from 79.85 to 100 % in the remainder. Control measures taken included immunoprophylaxis with an inactivated vaccine, culling animals that were serologically negative after vaccination that were regarded as probably persistently infected (PI and the implementation of additional biosecurity measures. The prevalence of serologically negative PI animals in 10 herds varied from 0.38 to 4.04 %, with 8 herds less than 1 %and 2 herds at 2.79 %and 4.04 %, respectively. Methods based on vaccinating the herd, followed by serological testing and culling cattle that did not develop an antibody titre, are not reliable. The identification of PI animals should be confirmed by isolation of the virus or identification of the antigen.
Kamya Moses R
Full Text Available Abstract Background A proportion of individuals who start antiretroviral therapy (ART fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4 in an urban HIV research cohort in Kampala, Uganda Methods We analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I magnitude of CD4 cell increase (a CD4 count increase Results Of 559 patients initiating ART, 386 (69% were female. Median (IQR age and baseline CD4 counts were 38 yrs (33–44 and 98 cells/μl (21–163 respectively; 414 (74% started a d4T-based regimen (D4T+3TC+NVP and 145 (26% a ZDV-based regimen (ZDV+3TC+EFV. After 6, 12 and 24 months of ART, 380 (68%, 339 (61% and 309 (55% had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%, 151 (45% and 166 (54% respectively had SO-CD4 based on criteria I, and 165(43%, 143(42% and 58(19% respectively based on criteria II. With both criteria combined, 56 (15% and 129 (38% had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58% of those that had SO-CD4 at 6 months (using criteria I maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29] and without SO-CD4 [23/100PYO (19–28]. Conclusion Using criteria I, the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.
High viral load and elevated angiogenic markers associated with increased risk of preeclampsia among women initiating highly active antiretroviral therapy in pregnancy in the Mma Bana study, Botswana.
Powis, Kathleen M; McElrath, Thomas F; Hughes, Michael D; Ogwu, Anthony; Souda, Sajini; Datwyler, Saul A; von Widenfelt, Erik; Moyo, Sikhulile; Nádas, Marisa; Makhema, Joseph; Machakaire, Esther; Lockman, Shahin; Essex, Max; Shapiro, Roger L
Risk factors associated with preeclampsia in HIV-infected women remain largely unknown. Systemic angiogenic imbalance contributes to preeclampsia in HIV-uninfected women, but changes in angiogenic markers after highly active antiretroviral therapy (HAART) initiation have not been studied. The Mma Bana study randomized 560 HIV-infected, HAART-naive pregnant women with CD4 counts ≥ 200 cells per cubic millimeter between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine or abacavir/zidovudine/lamivudine. Another 170 participants with CD4 counts less than 200 cells per cubic millimeter initiated nevirapine/zidovudine/lamivudine between 18 and 34 weeks gestation. Characteristics of 11 women who developed preeclampsia were compared with the remaining 722 Mma Bana participants who delivered using logistic regression. Plasma samples drawn at HAART initiation and 1 month later from 60 women without preeclampsia and at HAART initiation for all 11 preeclamptic women were assayed for placental growth factor (PlGF) and soluble FMS toll-like tyrosine kinase-1 (sFlt-1). Pre-HAART viral load greater than 100,000 copies per milliliter was associated with preeclampsia (odds ratio: 5.8, 95% confidence interval: 1.8 to 19.4, P = 0.004). Median pre-HAART PlGF level was lower and sFlt-1 was higher in women who developed preeclampsia vs those who did not (130 vs 992 pg/mL, P = 0.001; 17.5 vs 9.4 pg/mL, P = 0.03, respectively). In multivariate analysis, PlGF and viral load remained significantly associated with preeclampsia. No significant changes in angiogenic factors were noted after 1 month of HAART treatment among non-preeclamptic women. Pre-HAART viral load greater than 100,000 copies per milliliter and PlGF predicted preeclampsia among women starting HAART in pregnancy. Among non-preeclamptic women, HAART treatment did not significantly alter levels of PlGF or sFlt-1 after 1 month of treatment.
Campbell, Melissa; Decker, Kathleen P.; Kruk, Kerry; Deaver, Sarah P.
This randomized controlled trial was designed to determine if art therapy in conjunction with Cognitive Processing Therapy (CPT) was more effective for reducing symptoms of combat posttraumatic stress disorder (PTSD) than CPT alone. Veterans (N = 11) were randomized to receive either individual CPT, or individual CPT in conjunction with individual art therapy. PTSD Checklist–Military Version and Beck Depression Inventory–II scores improved with treatment in both groups with no significant difference in improvement between the experimental and control groups. Art therapy in conjunction with CPT was found to improve trauma processing and veterans considered it to be an important part of their treatment as it provided healthy distancing, enhanced trauma recall, and increased access to emotions. PMID:29332989
Leong, Yew Ann; Chen, Yaping; Ong, Hong Sheng; Wu, Di; Man, Kevin; Deleage, Claire; Minnich, Martina; Meckiff, Benjamin J; Wei, Yunbo; Hou, Zhaohua; Zotos, Dimitra; Fenix, Kevin A; Atnerkar, Anurag; Preston, Simon; Chipman, Jeffrey G; Beilman, Greg J; Allison, Cody C; Sun, Lei; Wang, Peng; Xu, Jiawei; Toe, Jesse G; Lu, Hao K; Tao, Yong; Palendira, Umaimainthan; Dent, Alexander L; Landay, Alan L; Pellegrini, Marc; Comerford, Iain; McColl, Shaun R; Schacker, Timothy W; Long, Heather M; Estes, Jacob D; Busslinger, Meinrad; Belz, Gabrielle T; Lewin, Sharon R; Kallies, Axel; Yu, Di
During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.
Kim, W S; Geider, K
ABSTRACT A 3.3-kb fragment of genomic DNA from bacteriophage Phi-Ea1h encoding an amylovoran-directed depolymerase lyase was sequenced, and three open reading frames (ORFs) were detected. The first ORF could encode a lysozyme and the second a holin that may form a pore supporting cell lysis by the lysozyme. The third ORF encodes a protein of 657 amino acids and deletion mutation in this DNA fragment abolished extracellular polysaccharide (EPS)-degrading activity. A putative promoter and a ribosome binding sequence were located in front of the gene. A polymerase chain reaction product spanning the gene was inserted into multi copy plasmids including fusions with a Histidine-tagged sequence to facilitate its purification on a nickel nitrilotriacetic acid column. Maximal activity of the purified protein was observed between pH 4 and 5 at 52 degrees C. Visualized by staining with fluorescein isothiocyanate-labeled lectin from Abrus precatorious, the enzyme degraded the EPS-capsules of Erwina amylovora. In virulence assays, no symptoms were detected for a low inoculum of an E. amylovora strain when pear slices were soaked in a solution of depolymerase in contrast to control slices without addition of the enzyme. Furthermore, gfp- or lux-labeled E. amylovora cells were not propagated, when their amylovoran capsules were removed by the depolymerase. The enzyme could be a tool for biological control of fire blight.
Akpinar, E.; Berger, Jonah
Given recent interest in social media, many brands now create content that they hope consumers will view and share with peers. While some campaigns indeed go “viral,” their value to the brand is limited if they do not boost brand evaluation or increase purchase. Consequently, a key question is how
... help relieve the symptoms of viral gastroenteritis in adults: drinking plenty of liquids such as fruit juices, sports ... as the child is hungry giving infants breast milk or full strength ... solutions Older adults and adults with weak immune systems should also ...
Rehman, Hasan; Silk, Ann W; Kane, Michael P; Kaufman, Howard L
With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma. Herein, we review the development of T-VEC, and suggest how it fits into the in the current clinical treatment paradigm, and provide pearls for drug preparation, administration, and monitoring of response to therapy.
Höper, Dirk; Freuling, Conrad M; Müller, Thomas; Hanke, Dennis; von Messling, Veronika; Duchow, Karin; Beer, Martin; Mettenleiter, Thomas C
Vaccines are the most effective prophylactic public health tools. With the help of vaccines, prevention of infectious disease spread and, in concert with other measures, even eradication has become possible. Until now, licensing and quality control require the determination of consensus genome sequences of replication competent infectious agents contained in vaccines. Recent improvements in sequencing technologies now enable the sequencing of complete genomes and the genetic analysis of populations with high reliability and resolution. The latter is particularly important for RNA viruses, which consist of fluctuating heterogeneous populations rather than genetically stable entities. This information now has to be integrated into the existing regulatory framework, challenging both licensing authorities and vaccine producers to develop new quality control criteria. Commercially available modified-live oral rabies vaccines and their precursor strains were deep-sequenced to assess strain identity and relations between strains based on population diversity. Strain relations were inferred based on the Manhattan distances calculated between the compositions of the viral populations of the strains. We provide a novel approach to assess viral strain relations with high resolution and reliability by deep sequencing with subsequent analysis of the overall genetic diversity within the viral populations. A comparison of our novel approach of inferring strain relations based on population data with consensus sequence analysis clearly shows that consensus sequence analysis of diverse viral populations can be misleading. Therefore, for quality control of viral vaccines deep sequencing analysis is to be preferred over consensus sequence analysis. The presented methodology allows for routine integration of deep sequencing data in vaccine quality control and licensing for highly reliable assessment of strain identity and stability. Copyright © 2015 Elsevier Ltd. All rights reserved.
Nasher, Akram T; Al-Hebshi, Nezar N; Al-Moayad, Ebtisam E; Suleiman, Ahmed M
The role of qat chewing, tobacco (shammah) dipping, smoking, alcohol drinking, and oral viral infection as risk factors for oral squamous cell carcinoma (OSCC) in Yemen was assessed. A total of 60 cases of OSCC and 120 age- and gender-matched controls were analyzed with respect to demographic data, history of oral habits, and the presence of human papillomavirus (HPV)-16, HPV-18, or Epstein-Barr virus (EBV) as determined by Taqman quantitative polymerase chain reaction. Logistic regression analysis was used to identify independent predictors of the disease. Shammah use was the only risk factor for OSCC, with an odds ratio of 12.6 (CI, 3.3-48.2) and 39 (CI, 14-105) for the ex-users and current users, respectively. The association of shammah use alone with OSCC exceeded that of shammah use in combination with qat chewing, smoking, or both. EBV infection, smoking, and qat chewing showed no association with OSCC, while neither HPV-16 nor HPV-18 were detected in any sample. Shammah use is a major risk factor for oral cancer in Yemen. Copyright © 2014 Elsevier Inc. All rights reserved.
Hood, Iris V.; Berger, James M.
Replisome assembly requires the loading of replicative hexameric helicases onto origins by AAA+ ATPases. How loader activity is appropriately controlled remains unclear. Here, we use structural and biochemical analyses to establish how an antimicrobial phage protein interferes with the function of the
Zhang, Huawei; Zheng, Haixue; Qian, Ping; Xu, Jinfang; Yang, Xi; Zhou, Rui; Chen, Huanchun; Li, Xiangmin
Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals, and can cause severe economic loss. Interferon-induced transmembrane (IFITM) proteins constitute a family of viral restriction factors that can inhibit the replication of several types of viruses. Our previous study showed that overexpression of swine IFITM3 (sIFITM3) impeded replication of the FMD virus (FMDV) in BHK-21 cells and mice. In this study, sIFITM3-transgenic (TG) pigs were produced by handmade cloning. Results showed that sIFITM3 was highly overexpressed in many organs of sIFITM3-TG pigs compared to wild-type pigs. After a virulent FMDV strain (O/ES/2001) was intramuscularly inoculated, the sIFITM3-TG pigs showed slightly higher susceptibility to FMDV infection than wild-type pigs. Both groups displayed comparable degrees of clinical symptoms throughout the 14-day observation period. Therefore, the induction of systemic sIFITM3 expression does not protect pigs against FMDV infection. Based on these observations, we propose that a combination of interferons and vaccines be used to control FMDV infections and subsequent FMD outbreaks. Copyright © 2016 Elsevier B.V. All rights reserved.
Kolliopoulou, Anna; Taning, Clauvis N. T.; Smagghe, Guy; Swevers, Luc
RNAi is applied as a new and safe method for pest control in agriculture but efficiency and specificity of delivery of dsRNA trigger remains a critical issue. Various agents have been proposed to augment dsRNA delivery, such as engineered micro-organisms and synthetic nanoparticles, but the use of viruses has received relatively little attention. Here we present a critical view of the potential of the use of recombinant viruses for efficient and specific delivery of dsRNA. First of all, it requires the availability of plasmid-based reverse genetics systems for virus production, of which an overview is presented. For RNA viruses, their application seems to be straightforward since dsRNA is produced as an intermediate molecule during viral replication, but DNA viruses also have potential through the production of RNA hairpins after transcription. However, application of recombinant virus for dsRNA delivery may not be straightforward in many cases, since viruses can encode RNAi suppressors, and virus-induced silencing effects can be determined by the properties of the encoded RNAi suppressor. An alternative is virus-like particles that retain the efficiency and specificity determinants of natural virions but have encapsidated non-replicating RNA. Finally, the use of viruses raises important safety issues which need to be addressed before application can proceed. PMID:28659820
Vincent C Marconi
Full Text Available The impact of viral load (VL decay and cumulative VL on CD4 recovery and AIDS after highly-active antiretroviral therapy (HAART is unknown.Three virologic kinetic parameters (first year and overall exponential VL decay constants, and first year VL slope and cumulative VL during HAART were estimated for 2,278 patients who initiated HAART in the U.S. Military HIV Natural History Study. CD4 and VL trajectories were computed using linear and nonlinear Generalized Estimating Equations models. Multivariate Poisson and linear regression models were used to determine associations of VL parameters with CD4 recovery, adjusted for factors known to correlate with immune recovery. Cumulative VL higher than the sample median was independently associated with an increased risk of AIDS (relative risk 2.38, 95% confidence interval 1.56-3.62, p<0.001. Among patients with VL suppression, first year VL decay and slope were independent predictors of early CD4 recovery (p = 0.001 and overall gain (p<0.05. Despite VL suppression, those with slow decay during the first year of HAART as well as during the entire therapy period (overall, in general, gained less CD4 cells compared to the other subjects (133 vs. 195.4 cells/µL; p = 0.001 even after adjusting for potential confounders.In a cohort with free access to healthcare, independent of established predictors of AIDS and CD4 recovery during HAART, cumulative VL and virologic decay patterns were associated with AIDS and distinct aspects of CD4 reconstitution.
Chen, Shuqing; Hou, Chengxiang; Bi, Honglun; Wang, Yueqiang; Xu, Jun; Li, Muwang; James, Anthony A; Huang, Yongping; Tan, Anjiang
We developed a novel antiviral strategy by combining transposon-based transgenesis and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system for the direct cleavage of Bombyx mori nucleopolyhedrovirus (BmNPV) genome DNA to promote virus clearance in silkworms. We demonstrate that transgenic silkworms constitutively expressing Cas9 and guide RNAs targeting the BmNPV immediate early-1 ( ie-1 ) and me53 genes effectively induce target-specific cleavage and subsequent mutagenesis, especially large (∼7-kbp) segment deletions in BmNPV genomes, and thus exhibit robust suppression of BmNPV proliferation. Transgenic animals exhibited higher and inheritable resistance to BmNPV infection than wild-type animals. Our approach will not only contribute to modern sericulture but also shed light on future antiviral therapy. IMPORTANCE Pathogen genome targeting has shown its potential in antiviral research. However, transgenic CRISPR/Cas9 system-mediated viral genome targeting has not been reported as an antiviral strategy in a natural animal host of a virus. Our data provide an effective approach against BmNPV infection in a real-world biological system and demonstrate the potential of transgenic CRISPR/Cas9 systems in antiviral research in other species. Copyright © 2017 Chen et al.
Pilcher, Christopher D; Ospina-Norvell, Clarissa; Dasgupta, Aditi; Jones, Diane; Hartogensis, Wendy; Torres, Sandra; Calderon, Fabiola; Demicco, Erin; Geng, Elvin; Gandhi, Monica; Havlir, Diane V; Hatano, Hiroyu
Antiretroviral therapy (ART) is typically begun weeks after HIV diagnosis. We assessed the acceptability, feasibility, safety, and efficacy of initiating ART on the same day as diagnosis. We studied a clinic-based cohort consisting of consecutive patients who were referred with new HIV diagnosis between June 2013 and December 2014. A subset of patients with acute or recent infection (intensive, same-day appointment included social needs assessment; medical provider evaluation; and a first ART dose offered after laboratories were drawn. Patient acceptance of ART, drug toxicities, drug resistance, and time to viral suppression outcomes were compared between RAPID participants and contemporaneous patients (who were not offered the program), and with an historical cohort. Among 86 patients, 39 were eligible and managed on the RAPID protocol. Thirty-seven (94.9%) of 39 in RAPID began ART within 24 hours. Minor toxicity with the initial regimen occurred in 2 (5.1%) of intervention patients versus none in the nonintervention group. Loss to follow-up was similar in intervention (10.3%) and nonintervention patients (14.9%) during the study. Time to virologic suppression (Treatment for HIV infection can be started on the day of diagnosis without impacting the safety or acceptability of ART. Same-day ART may shorten the time to virologic suppression.
Brittain, Kirsty; Asafu-Agyei, Nana Akua; Hoare, Jacqueline; Bekker, Linda-Gail; Rabie, Helena; Nuttall, James; Roux, Paul; Stein, Dan J; Zar, Heather J; Myer, Landon
Accurate measurement of antiretroviral therapy (ART) adherence remains challenging and there are few data assessing the validity of self-reported adherence among perinatally HIV-infected adolescents. We examined adolescent and caregiver reports of adolescent adherence among perinatally-infected adolescents aged 9-14 years in Cape Town, South Africa, and explored factors that may modify associations between reported adherence and elevated viral load (VL). Among 474 adolescents (median age 12.0 years; median duration of ART use 7.5 years), elevated VL and caregiver- and adolescent-report of missed ART doses were common. Elevated VL was particularly prevalent among older, male adolescents. Low-moderate concordance was observed between caregiver and adolescent report. Among adolescents aged ≥ 12 years, caregiver- and adolescent-reported adherence was associated with elevated VL across most items assessed, but few significant associations were observed among adolescents adolescents who require adherence interventions are needed in this context.
Siberry, George K; Harris, D. Robert; Oliveira, Ricardo Hugo; Krauss, Margot R.; Hofer, Cristina B.; Tiraboschi, Adriana Aparecida; Marques, Heloisa; Succi, Regina C.; Abreu, Thalita; Negra, Marinella Della; Mofenson, Lynne M.; Hazra, Rohan
Background This study evaluated a wide range of viral load (VL) thresholds to identify a cut-point that best predicts new clinical events in children on stable highly-active antiretroviral therapy (HAART). Methods Cox proportional hazards modeling was used to assess the adjusted risk of World Health Organization stage 3 or 4 clinical events (WHO events) as a function of time-varying CD4, VL, and hemoglobin values in a cohort study of Latin American children on HAART ≥ 6 months. Models were fit using different VL cut-points between 400 and 50,000 copies/mL, with model fit evaluated on the basis of the minimum Akaike Information Criterion (AIC) value, a standard model fit statistic. Results Models were based on 67 subjects with WHO events out of 550 subjects on study. The VL cutpoints of > 2600 copies/mL and > 32,000 copies/mL corresponded to the lowest AIC values and were associated with the highest hazard ratios [2.0 (p = 0.015) and 2.1 (p = 0.0058), respectively] for WHO events. Conclusions In HIV-infected Latin American children on stable HAART, two distinct VL thresholds (> 2,600 copies/mL and > 32,000 copies/mL) were identified for predicting children at significantly increased risk of HIV-related clinical illness, after accounting for CD4 level, hemoglobin level, and other significant factors. PMID:22343177
Gorar, Zulfikar A; Butt, Zahid A; Aziz, Imrana
A high prevalence of viral hepatitis B and C was found among healthcare workers during a province-wide screening in Sindh Province, Pakistan. A follow-up study was undertaken to identify risk factors for this high prevalence in healthcare workers. Population based case-control design. Public sector healthcare facilities in a rural district of Pakistan. Healthcare workers who were screened for hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) antibodies. 178 healthcare workers employed at the public sector clinics and hospitals of the district were approached, of which 14 refused to participate. Cases had detectable serum antibodies against HCV and the presence of HBsAg. Healthcare workers non-reactive to HCV antibodies and with no HBsAg were controls. These were matched in a ratio of 1:1. Detectable serum HBsAg and HCV antibody titer were taken as outcome. OR for various exposures was calculated; those with paccident and emergency of a hospital (OR=5.5; CI95 1 to 28), female gender (OR=3.4; CI95 1 to 12) and more than 10 years of formal education (OR=0.25; CI95 0.07 to 0.8) were associated with hepatitis C. Hepatitis B was found to be associated with trying to bend or break a needle after use (OR=4.9; CI95 1 to 24). Healthcare workers in Pakistan are at additional risk of exposure to bloodborne pathogens. Bi-dimensional risk factors present at individual and broader health systems levels are responsible. Occupational safety, health trainings and redesigning of the curriculum for allied health professionals are required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Full Text Available Abstract Background Scale up of paediatric antiretroviral therapy in resource limited settings continues despite limited access to routine laboratory monitoring. We documented the weight and height responses in HIV infected Ugandan children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes. Methods A prospective cohort of HIV infected children were initiated on HAART and followed for 48 weeks. Body mass index for age z scores(BAZ, weight and height-for-age z scores (WAZ & HAZ were calculated: CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks. Treatment outcomes were classified according to; both virological and immunological success (VS/IS, virological failure and immunological success (VF/IS. virological success and immunological failure (VS/IF and both virological and immunological failure (VF/IF. Results From March 2004 until May 2006, 124 HIV infected children were initiated on HAART. The median age (IQR was 5.0 years (2.1 - 7.0 and 49% (61/124 were female. The median [95% confidence interval (CI] BAZ, WAZ and HAZ at baseline were 0.29 (-2.9, -1.2, -1.2 (-2.1, -0.5 and -2.06 (-2.9, -1.2 respectively. Baseline median CD4 cell % and log10 HIV-1 RNA were; 11.8% (7.5-18.0 and 5.6 (5.2-5.8 copies/ml. By 48 weeks, mean WAZ and HAZ in the VF/IS group, which was younger, increased from - 0.98 (SD 1.7 to + 1.22 (SD 1.2 and from -1.99 (1.7 to + 0.76 (2.4 respectively. Mean increase in WAZ and HAZ in the VS/IF group, an older group was modest, from -1.84 (1.3 to - 0.41 (1.2 and -2.25 (1.2 to -1.16 (1.3 respectively. Baseline CD4 cell % [OR 6.97 95% CI (2.6 -18.6], age [OR 4.6 95% CI (1.14 -19.1] and WHO clinical stage [OR 3.5 95%CI (1.05 -12.7] were associated with successful treatment outcome. Conclusions HIV infected Ugandan children demonstrated a robust increase in height and weight z scores during the first 48 weeks of HAART, including those who failed to
This paper examines the role of antiretroviral therapy (ART) programme on control of HIV transmission in order to assist and inform policy makers to design and implement effective ART programmes.The study used a crosssectional design involving ninety-three people living with HIV and AIDS (PLHIV). Descriptive statistics ...
South African Family Practice. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 56, No 1 (2014) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Glucose control: Non-insulin therapies. Editorial Office. Abstract. No Abstract.
Bahrami, K.; Kim, M.
This study deals with ways of curtailing the rapid growth of cancer cell populations. The performance functional that measures the size of the population at the terminal time as well as the control effort is devised. With use of the discrete maximum principle, the Hamiltonian for this problem is determined and the condition for optimal solutions are developed. The optimal strategy is shown to be a bang-bang control. It is shown that the optimal control for this problem must be on the vertices of an N-dimensional cube contained in the N-dimensional Euclidean space. An algorithm for obtaining a local minimum of the performance function in an orderly fashion is developed. Application of the algorithm to the design of antitumor drug and X-irradiation schedule is discussed.
Denlinger, Loren C; Manthei, David M.; Max A Seibold; Ahn, Kwangmi; Bleecker, Eugene; Boushey, Homer A; Calhoun, William J.; Castro, Mario; Chinchili, Vernon M.; Fahy, John V.; Hawkins, Greg A.; Icitovic, Nicolina; Israel, Elliot; Jarjour, Nizar N.; King, Tonya
Rationale: The function of the P2X7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied.
Full Text Available Deep brain stimulation (DBS is one of the effective treatments of epilepsy. Based on the Lyapunov stability theory combined with the method of the periodically intermittent control and adaptive control, the abnormal synchronization neural network models with high frequency oscillation are achieved with multilag synchronization in this paper. Some simple criteria are derived for the multilag synchronization of the coupled neural networks with coupling delays. The adaptive periodically intermittent control which we have obtained can cut down control cost. The sufficient conditions of this paper for abnormal neural network multilag synchronization are less conservative and can be applied in a wider area. Finally, simulation results show the effectiveness of the proposed control strategy. The design of controllers and control strategy may provide a potential electrical stimulation therapy on neurological diseases caused by abnormal synchronization. And they can provide technical support for epilepsy treatment apparatus research and development.
Fomsgaard, A.; Vinner, L.; Therrien, D.
To increase the understanding of mechanisms of HIV control we have genetically and immunologically characterized a full-length HIV-1 isolated from an acute infection in a rare case of undetectable viremia. The subject, a 43-year-old Danish white male (DK1), was diagnosed with acute HIV-1 infection...... after 1 year in Uganda. Following transient antiretroviral therapy DK1 maintained undetectable viral load for more than 10 years. His Ugandan wife (UG1) developed high viral load. HIV-1 sequences from both individuals were compared by bootscanning for recombination break points. Diversity plots......-gamma IC-FACS response in DK1 was detected against only one (Pol(476)) of 23 conserved epitopes. Neutralizing antibodies were induced only to the homologous isolate. These results indicate an A1D intersubtype recombination or transmission of a minor variant. Transient early antiretroviral therapy may have...
Pan, Jianqing; Wang, Hao; Liu, Xinmin; Hu, Jiliang; Song, Weijian; Luo, Jie; Jiang, Shan; Yan, Fei; Zhai, Baojin
Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog) promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373). Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk) driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.
Full Text Available Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373. Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.
Florin, Todd A; Plint, Amy C; Zorc, Joseph J
Viral bronchiolitis is a common clinical syndrome affecting infants and young children. Concern about its associated morbidity and cost has led to a large body of research that has been summarised in systematic reviews and integrated into clinical practice guidelines in several countries. The evidence and guideline recommendations consistently support a clinical diagnosis with the limited role for diagnostic testing for children presenting with the typical clinical syndrome of viral upper respiratory infection progressing to the lower respiratory tract. Management is largely supportive, focusing on maintaining oxygenation and hydration of the patient. Evidence suggests no benefit from bronchodilator or corticosteroid use in infants with a first episode of bronchiolitis. Evidence for other treatments such as hypertonic saline is evolving but not clearly defined yet. For infants with severe disease, the insufficient available data suggest a role for high-flow nasal cannula and continuous positive airway pressure use in a monitored setting to prevent respiratory failure. Copyright © 2017 Elsevier Ltd. All rights reserved.
Meta-analysis of two randomized controlled trials comparing combined zidovudine and didanosine therapy with combined zidovudine, didanosine, and nevirapine therapy in patients with HIV. INCAS study team.
Raboud, J M; Rae, S; Vella, S; Harrigan, P R; Bucciardini, R; Fragola, V; Ricciardulli, D; Montaner, J S
To extend the range of CD4 counts in which a plasma viral load nadir (pVL) 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir 400 copies/ml. We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression.
Considering the geographical asymmetric distribution of viral hepatitis A, B and E, having a much higher prevalence in the less developed world, travellers from developed countries are exposed to a considerable and often underestimated risk of hepatitis infection. In fact a significant percentage of viral hepatitis occurring in developed countries is travel related. This results from globalization and increased mobility from tourism, international work, humanitarian and religious missions or other travel related activities. Several studies published in Europe and North America shown that more than 50% of reported cases of hepatitis A are travel related. On the other hand frequent outbreaks of hepatitis A and E in specific geographic areas raise the risk of infection in these restricted zones and that should be clearly identified. Selected aspects related with the distribution of hepatitis A, B and E are reviewed, particularly the situation in Portugal according to the published studies, as well as relevant clinical manifestations and differential diagnosis of viral hepatitis. Basic prevention rules considering enteric transmitted hepatitis (hepatitis A and hepatitis E) and parenteral transmitted (hepatitis B) are reviewed as well as hepatitis A and B immunoprophylaxis. Common clinical situations and daily practice "pre travel" advice issues are discussed according to WHO/CDC recommendations and the Portuguese National Vaccination Program. Implications from near future availability of a hepatitis E vaccine, a currently in phase 2 trial, are highlighted. Potential indications for travellers to endemic countries like India, Nepal and some regions of China, where up to 30% of sporadic cases of acute viral hepatitis are caused by hepatitis E virus, are considered. Continued epidemiological surveillance for viral hepatitis is essential to recognize and control possible outbreaks, but also to identify new viral hepatitis agents that may emerge as important global health
Nordin, Linda; Rorsman, Ia
The aim of this study was to design a trial that could evaluate the effect of acceptance and commitment therapy as a group-intervention for multiple sclerosis patients with psychological distress. Randomized controlled trial with assessment at pretreatment, end of treatment, and at 3-month follow-up. Multiple sclerosis outpatients with elevated symptoms of anxiety and/or depression (n = 21). Patients were randomly assigned to acceptance and commitment therapy or relaxation training. Both treatments consisted of 5 sessions over 15 weeks containing didactic sessions, group discussions, and exercises. Outcome was assessed by self-rated symptoms of anxiety, depression, and a measure of acceptance. At 3-month follow-up, the relaxation training group had a significant decline in anxiety symptoms whereas the acceptance and commitment therapy group showed a maintained improvement in rated acceptance at follow-up. The results reflect the different emphases of the therapies. Acceptance and commitment therapy is aimed at living an active, valued life and increasing acceptance, while relaxation training focuses directly on coping strategies to handle emotional symptoms. The results are preliminary, but supportive of further study of brief group interventions for reducing psychological distress in patients with multiple sclerosis.
Full Text Available Viruses are among the most common causes of opportunistic infection after transplantation. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses have also affected outcomes. In some cases, preventive measures such as pretransplant screening, prophylactic antiviral therapy, or posttransplant viral monitoring may limit the impact of these infections. Recent advances in laboratory monitoring and antiviral therapy have improved outcomes. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections. This paper will summarize the major viral infections seen following transplant and discuss strategies for prevention and management of these potential pathogens.
Rawls, Renard A; Vega, Kenneth J
Viral hepatitis continues as an important public health concern in the United States. Available data indicate that acute and chronic viral hepatitis remains an important cause of morbidity and mortality in this country despite the availability of immunization for hepatitis A and B and pharmacologic therapy for chronic hepatitis B and C. Minority populations within the United States are disproportionately affected by acute and chronic viral hepatitis. Many diseases, for example, Barrett's esophagus, affect ethnic groups differently. Viral hepatitis A, B, and C may demonstrate ethnic variation with regard to their epidemiology, natural history, clinicopatholgic findings, complications, and treatment outcomes. This report will review the literature regarding these areas in hepatitis A, B, and C among the African American, Hispanic American, and Native American populations of the United States.
Kluth, L A; Rink, M; Ahyai, S A; Fisch, M; Shariat, S F; Dahm, P
Randomized controlled trials (RCTs) stopped prematurely for beneficial therapy effects are becoming increasingly more prevalent in the urological literature and often receive great attention in the public and medical media. Urologists who practice evidence-based medicine should be aware of the potential bias and the different reasons why and how early termination of RCTs can and will affect the results. This review provides insights into the challenges clinical urologists face by interpreting the results of prematurely terminated RCTs.
FINAL TECHNICAL REPORT Grant No. D15AP00024 “ Engineering Therapies that Evolve to Autonomously Control Epidemics” PI: Leor Weinberger...viruses could be engineered into therapeutics, known as Therapeutic Interfering Particles (’TIPs’), using the virus HIV as a model system. By engineering ... engineered TIPs could have indefinite, population-scale impact. To achieve this aim, we developed novel multi-scale models that connected the measured
Gautron, Laurent; Elmquist, Joel K.; Williams, Kevin W.
Recent insights into the neural circuits controlling energy balance and glucose homeostasis have rekindled the hope for development of novel treatments for obesity and diabetes. However, many therapies contribute relatively modest beneficial gains with accompanying side effects, and the mechanisms of action for other interventions remain undefined. This Review summarizes current knowledge linking the neural circuits regulating energy and glucose balance with current and potential pharmacother...
This thesis aims to give an insight into the ecology of the viral community in a shallow eutrophic lake. To achieve this, the population dynamics, diversity and control of the viral community in Lake Loosdrecht were studied, as well as the impact of the viral community on plankton mortality and
Sandaa, Ruth-Anne; Pree, Bernadette; Larsen, Aud; Våge, Selina; Töpper, Birte; Töpper, Joachim P; Thyrhaug, Runar; Thingstad, Tron Frede
Factors controlling the community composition of marine heterotrophic prokaryotes include organic-C, mineral nutrients, predation, and viral lysis. Two mesocosm experiments, performed at an Arctic location and bottom-up manipulated with organic-C, had very different results in community composition for both prokaryotes and viruses. Previously, we showed how a simple mathematical model could reproduce food web level dynamics observed in these mesocosms, demonstrating strong top-down control through the predator chain from copepods via ciliates and heterotrophic nanoflagellates. Here, we use a steady-state analysis to connect ciliate biomass to bacterial carbon demand. This gives a coupling of top-down and bottom-up factors whereby low initial densities of ciliates are associated with mineral nutrient-limited heterotrophic prokaryotes that do not respond to external supply of labile organic-C. In contrast, high initial densities of ciliates give carbon-limited growth and high responsiveness to organic-C. The differences observed in ciliate abundance, and in prokaryote abundance and community composition in the two experiments were in accordance with these predictions. Responsiveness in the viral community followed a pattern similar to that of prokaryotes. Our study provides a unique link between the structure of the predator chain in the microbial food web and viral abundance and diversity.
Full Text Available Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation. Adenoviruses, which breach the endosome upon entry, escape this fate by penetrating into the cytosol prior to autophagosome sequestration of the ruptured endosome. We show that virus induced membrane damage is recognized through Galectin-8 and sequesters the autophagy receptors NDP52 and p62. We further show that a conserved PPxY motif in the viral membrane lytic protein VI is critical for efficient viral evasion of autophagic sequestration after endosomal lysis. Comparing the wildtype with a PPxY-mutant virus we show that depletion of Galectin-8 or suppression of autophagy in ATG5-/- MEFs rescues infectivity of the PPxY-mutant virus while depletion of the autophagy receptors NDP52, p62 has only minor effects. Furthermore we show that wildtype viruses exploit the autophagic machinery for efficient nuclear genome delivery and control autophagosome formation via the cellular ubiquitin ligase Nedd4.2 resulting in reduced antigenic presentation. Our data thus demonstrate that a short PPxY-peptide motif in the adenoviral capsid permits multi-layered viral control of autophagic processes during entry.
Fanigliulo, A; Viggiano, A; Gualco, A; Crescenzi, A
Tomato spotted wilt disease is caused by Tomato Spotted Wilt Virus (TSWV) (Tospovirus, Bunyaviridae), a virus that severely damages and reduces the yield of many economically important plants worldwide and actually it is a major disease affecting the production of tomato and pepper in Italy. Due to the non-predictive nature of its outbreaks combined with the lack of forecasting, adoption of preventive measures have not always been practical, in fact the disease cycle has proven to be extremely difficult to break because of the wide and often overlapping host range of both the virus and the thrips vectors, which transmit the virus in a persistent, circulative, and propagative manner. Moreover recently, resistance breaking (RB) isolates of TSWV that overcome the resistance conferred by the Tsw gene in different pepper hybrids have been recovered in different locations in Italy and also in Brazil, USA, Spain and Australia, and this occurrence raises the question on the importance of a new approach of integrated pest management for TSWV management, including both control of its insect vector and the induction of the plant's resistance against viral infection. In this perspective, a study was performed in 2012 and 2013 with the purpose of evaluating the efficacy of the insecticide Cyantraniliprole alone or combined with Acibenzolar-S-Methyl (ASM), inducer of systemic acquired resistance, in the control of tomato spotted wilt disease in pepper. The experiment was performed in laboratory, in a thermo-conditioned greenhouse, into separate insect-proof cages and consisted of 5 treatments and 2 applications (plus a pre-transplant application for treatments were ASM was used. Variables were the mode of application of ASM in pre-transplant (by foliar or by drench) and the duration of the exposure time of the treated plants to viruliferous insects. Pepper cv. Corno di Toro, devoid of any resistance to TSWV, was used. Plants were observed daily to record any symptom induced by
Full Text Available Adequate knowledge on fish diseases caused by viruses is still lacking. Up until now, in fish which live their entire life cycle or part of it in the sea, some viral diseases have been determined (lymphoeytis, viral necrosis of crythrocytes, ciravosti cod syndrome, encephalitis, viral hemoragic septichemistry, viral hematopoetic necrosis, viral gusteraca necrosis, chum renviral infection, branchionephritis, rabdociral eel infection. Some of these diseases primarily occur in the freshwater phase of host development, although recordings exist that the virus is carried on in surving samples which succeed in making it to the sea. As the number of sea fish species increases in controlled culture a increasing number of pathological cases are observed, which is caused by viruses. Therefore, in this area it is necessary to emphasize future investigations.
Nichole R Klatt
Full Text Available While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV and late (day 177 post-SIV chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.
Comparação dos efeitos de duas técnicas fisioterapêuticas respiratórias em parâmetros cardiorrespiratórios de lactentes com bronquiolite viral aguda Comparison of the effects that two different respiratory physical therapy techniques have on cardiorespiratory parameters in infants with acute viral bronchiolitis
Melissa Karina Pupin
Full Text Available OBJETIVO: Comparar os efeitos das técnicas de aumento do fluxo expiratório (AFE e vibração associada à drenagem postural (DP nos parâmetros cardiorrespiratórios de frequência cardíaca (FC, frequência respiratória (FR e SpO2 de lactentes com bronquiolite viral aguda (BVA. MÉTODOS: Foram analisados lactentes com diagnóstico clínico e radiológico de BVA. A FC, FR e SpO2 foram registradas em quatro tempos: antes do procedimento e após 10, 30 e 60 min do término do procedimento. Os pacientes foram divididos em três grupos: submetido à AFE; submetido à vibração/DP; e controle. RESULTADOS: Foram incluídos no estudo 81 lactentes, 27 em cada grupo de estudo, com média de idade de 4,52 meses e peso médio de 6,56 kg. Na comparação por ANOVA, as médias da FR, FC e SpO2 nos grupos AFE e vibração/DP não apresentaram diferenças significantes em relação ao grupo controle (p > 0,05. Considerando somente os quatro tempos, houve queda significante dos valores médios de FR nos grupos AFE e vibração/DP em relação ao controle (p OBJECTIVE: To compare the expiratory flow increase technique (EFIT and vibration accompanied by postural drainage (PD in terms of their effects on the heart rate (HR, respiratory rate (RR and SpO2 of infants with acute viral bronchiolitis (AVB. METHODS: Infants with clinical and radiological diagnosis of AVB were analyzed. The HR, RR and SpO2 were registered at four time points: prior to the procedure; and at 10, 30 and 60 min after the procedure. The patients were divided into three groups: submitted to the EFIT; submitted to vibration/PD; and control. RESULTS: We included 81 infants, 27 per group, with a mean age of 4.52 years and a mean weight of 6.56 kg. Using ANOVA, we found that the EFIT and vibration/PD groups presented no significant differences in relation to the control group in terms of the mean values for HR, RR or SpO2 (p > 0.05. Considering only the four time points evaluated, the mean RR
de Bruin, E.J.; Bögels, S.M.; Oort, F.J.; Meijer, A.M.
Study Objectives: To investigate the efficacy of cognitive behavioral therapy for insomnia (CBTI) in adolescents. Design: A randomized controlled trial of CBTI in group therapy (GT), guided internet therapy (IT), and a waiting list (WL), with assessments at baseline, directly after treatment
Rohan, Kelly J.; Roecklein, Kathryn A.; Tierney Lindsey, Kathryn; Johnson, Leigh G.; Lippy, Robert D.; Lacy, Timothy J.; Barton, Franca B.
This first controlled psychotherapy trial for seasonal affective disorder (SAD) compared SAD-tailored cognitive-behavioral therapy (CBT), light therapy (LT), and their combination to a concurrent wait-list control. Adults (N = 61) with major depression, recurrent with seasonal pattern, were randomized to one of four 6-week conditions: CBT (1.5-hr…
Amanda L Blasius
Full Text Available Plasmacytoid dendritic cells (pDCs are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection.
Full Text Available T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT against human papillomavirus 16 (HPV16 E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2 by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women.
Jacobelli, Simon; Sanaa, Fedoua; Moyal-Barracco, Micheline; Pelisse, Monique; Berville, Sophie; Villefroy, Pascale; North, Marie Odile; Figueiredo, Suzanne; Charmeteau, Bénédicte; Clerici, Thierry; Plantier, Françoise; Arnold, Françoise; Touzé, Antoine; Dupin, Nicolas; Avril, Marie-Françoise; Guillet, Jean-Gérard; Cheynier, Rémi; Bourgault-Villada, Isabelle
T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT) against human papillomavirus 16 (HPV16) E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN) and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2) by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women.
Non-invasive Imaging of Sendai Virus Infection in Pharmacologically Immunocompromised Mice: NK and T Cells, but not Neutrophils, Promote Viral Clearance after Therapy with Cyclophosphamide and Dexamethasone.
Mostafa, Heba H; Vogel, Peter; Srinivasan, Ashok; Russell, Charles J
In immunocompromised patients, parainfluenza virus (PIV) infections have an increased potential to spread to the lower respiratory tract (LRT), resulting in increased morbidity and mortality. Understanding the immunologic defects that facilitate viral spread to the LRT will help in developing better management protocols. In this study, we immunosuppressed mice with dexamethasone and/or cyclophosphamide then monitored the spread of viral infection into the LRT by using a noninvasive bioluminescence imaging system and a reporter Sendai virus (murine PIV type 1). Our results show that immunosuppression led to delayed viral clearance and increased viral loads in the lungs. After cessation of cyclophosphamide treatment, viral clearance occurred before the generation of Sendai-specific antibody responses and coincided with rebounds in neutrophils, T lymphocytes, and natural killer (NK) cells. Neutrophil suppression using anti-Ly6G antibody had no effect on infection clearance, NK-cell suppression using anti-NK antibody delayed clearance, and T-cell suppression using anti-CD3 antibody resulted in no clearance (chronic infection). Therapeutic use of hematopoietic growth factors G-CSF and GM-CSF had no effect on clearance of infection. In contrast, treatment with Sendai virus-specific polysera or a monoclonal antibody limited viral spread into the lungs and accelerated clearance. Overall, noninvasive bioluminescence was shown to be a useful tool to study respiratory viral progression, revealing roles for NK and T cells, but not neutrophils, in Sendai virus clearance after treatment with dexamethasone and cyclophosphamide. Virus-specific antibodies appear to have therapeutic potential.
Mangraviti, Antonella; Tzeng, Stephany; Seng, Michael; Abbadi, Sara; Kozielski, Kristen; Schiapparelli, Paula; Wijesekera, Olindi; Sarabia-Estrada, Rachel; Brem, Henry; Tyler, Betty; Olivi, Alessandro; Green, Jordan; Quinones-Hinojosa, Alfredo
the tumor in a model of human glioma after local and systemic administration. NP-engineered BMP4-secreting hAMSCs can be a safe and effective alternative to viral transduction for stem cell-based anti-glioma gene therapies.
Zemp, Franz J.; McKenzie, Brienne A.; Lun, Xueqing; Maxwell, Lori; Reilly, Karlyne M.; McFadden, Grant; Yong, V. Wee; Forsyth, Peter A.
Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1+/−Trp53+/− mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models. PMID:23762429
Ahmed, J; Bouloy, M; Ergonul, O; Fooks, Ar; Paweska, J; Chevalier, V; Drosten, C; Moormann, R; Tordo, N; Vatansever, Z; Calistri, P; Estrada-Pena, A; Mirazimi, A; Unger, H; Yin, H; Seitzer, U
Arboviruses are arthropod-borne viruses, which include West Nile fever virus (WNFV), a mosquito-borne virus, Rift Valley fever virus (RVFV), a mosquito-borne virus, and Crimean-Congo haemorrhagic fever virus (CCHFV), a tick-borne virus. These arthropod-borne viruses can cause disease in different domestic and wild animals and in humans, posing a threat to public health because of their epidemic and zoonotic potential. In recent decades, the geographical distribution of these diseases has expanded. Outbreaks of WNF have already occurred in Europe, especially in the Mediterranean basin. Moreover, CCHF is endemic in many European countries and serious outbreaks have occurred, particularly in the Balkans, Turkey and Southern Federal Districts of Russia. In 2000, RVF was reported for the first time outside the African continent, with cases being confirmed in Saudi Arabia and Yemen. This spread was probably caused by ruminant trade and highlights that there is a threat of expansion of the virus into other parts of Asia and Europe. In the light of global warming and globalisation of trade and travel, public interest in emerging zoonotic diseases has increased. This is especially evident regarding the geographical spread of vector-borne diseases. A multi-disciplinary approach is now imperative, and groups need to collaborate in an integrated manner that includes vector control, vaccination programmes, improved therapy strategies, diagnostic tools and surveillance, public awareness, capacity building and improvement of infrastructure in endemic regions.
Gautron, Laurent; Elmquist, Joel K; Williams, Kevin W
Recent insights into the neural circuits controlling energy balance and glucose homeostasis have rekindled the hope for development of novel treatments for obesity and diabetes. However, many therapies contribute relatively modest beneficial gains with accompanying side effects, and the mechanisms of action for other interventions remain undefined. This Review summarizes current knowledge linking the neural circuits regulating energy and glucose balance with current and potential pharmacotherapeutic and surgical interventions for the treatment of obesity and diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.
Full Text Available Purpose of the study: Few clinical trials have compared non-nucleoside reverse transcriptase inhibitors (NNRTI and ritonavir-boosted protease inhibitors (PI/r as initial combined antiretroviral therapy (cART for HIV-1-infected patients with high plasma viral load (pVL, and non-conclusive results have been reported. We compared the effectiveness between NNRTI and PI/r as first-line cART for HIV-1-infected patients with high pVL. Methods: Observational retrospective study of 664 consecutive treatment-naïve HIV-1-infected patients with pVL (HIV-1 RNA >100,000 copies/mL who initiated NNRTI or PI/r-based cART between 2000–2010 in three University hospitals. Only currently preferred or alternative regimens in clinical guidelines were included. Primary endpoint: percentage of therapeutic failures at week 48. Virologic failure was defined as: a lack of virologic response (<1 log RNA HIV-1 decrease in first 3 months; b RNA HIV-1 >50 c/mL at week 48; c confirmed rebound >50 c/ml after a previous value <50 c/mL. Intent-to-treat (ITT noncompleter=failure and on-treatment (OT analyses were performed. Results: 62% of patients initiated NNRTI-regimens (83% efavirenz and 38% PI/r-regimens (62% lopinavir/. Baseline characteristics: male 83%; median age 39 yrs; median CD4 count: 212/µL (NNRTI 232 vs PI/r 177, p=0.028; pVL 5.83 log10 c/mL (NNRTI 5.43 vs PI/r 5.55, p=0.007; AIDS 24% (NNRTI 21% vs PI/r 29%, p=0.015. NRTI backbones were tenofovir plus 3TC or FTC in 72%. The percentage of therapeutic failure was higher in the PI/r group (ITT NC=F 26% vs 18%, p=0.012 with no differences in virologic failures (PI/r 5%, NNRTI 6%, p=0.688. The rate of treatment changes due to toxicity and/or voluntary discontinuations was higher in the PI/r group (15% vs 8%, p=0.008. A multivariate analysis adjusted for age, gender, CD4 count, VL and AIDS showed NNRTI vs PI/r as the only variable associated with treatment response (OR 0.61, 95% CI 0.41–0.88. Median pVL and rate of
Kim, Sujin; Kim, Min-Ji; Kim, Chang-Hoon; Kang, Ju Wan; Shin, Ha Kyung; Kim, Dong-Young; Won, Tae-Bin; Han, Doo Hee; Rhee, Chae Seo; Yoon, Joo-Heon; Kim, Hyun Jik
Here, we studied the IFN-regulated innate immune response against influenza A virus (IAV) infection in the mouse lung and the therapeutic effect of IFN-λ2/3 in acute IAV lung infection. For viral infections, IAV (WS/33, H1N1, PR8 H1N1, H5N1) were inoculated into wild-type mice by intranasal delivery, and IAV mRNA level and viral titer were measured. To compare the antiviral effect of IFNs in vivo in the lung, neutralizing antibodies and recombinant IFNs were used. After intranasal inoculation of IAV into mice, viral infection peaked at 7 days postinfection, and the IAV titer also reached its peak at this time. We found that IFN-β and IFN-λ2/3 were preferentially induced after IAV infection and the IFN-λ2/3-mediated innate immune response was specifically required for the induction of IFN-stimulated genes (ISGs) transcription in the mouse respiratory tract. Neutralization of secreted IFN-λ2/3 aggravated acute IAV lung infection in mice with intact IFN-β induction; consistent with this finding, the transcription of ISGs was significantly reduced. Intranasal administration of IFN-λ2/3 significantly suppressed various strains of IAV infection, including WS/33 (H1N1), PR (H1N1), and H5N1 in the mouse lung, and was accompanied by greater up-regulation of ISGs. Taken together, our data indicate that the IFN-λ2/3-mediated innate immune response is necessary to protect the lungs from IAV infection, and intranasally delivered IFN-λ2/3 has the potential to be a useful therapeutic strategy for treating acute IAV lung infection.
Full Text Available We summarized the most recent findings on the role of autophagy in antiviral immune response. We described how viruses have developed strategies to subvert the autophagic process. A particular attention has been given to Epstein-Barr and Kaposi’s sarcoma associated Herpesvirus, viruses studied for many years in our laboratory. These two viruses belong to γ-Herpesvirus subfamily and are associated with several human cancers. Besides the effects on the immune response, we have described how autophagy subversion by viruses may also concur to the enhancement of their replication and to viral tumorigenesis.
Fousteri, Georgia; Jofra, Tatiana; Di Fonte, Roberta; Kuka, Mirela; Iannacone, Matteo; Battaglia, Manuela
Ptpn22 is one of the most potent autoimmunity predisposing genes and strongly associates with type 1 diabetes (T1D). Previous studies showed that non-obese diabetic mice with reduced expression levels of Ptpn22 are protected from T1D due to increased number of T regulatory (Treg) cells. We report that lack of Ptpn22 exacerbates virally-induced T1D in female rat insulin promoter lymphocytic choriomeningitis virus (RIP-LCMV-GP) mice, while maintaining higher number of Treg cells throughout the antiviral response in the blood and spleen but not in the pancreatic lymph nodes. GP33-41-specific pentamer-positive cytotoxic lymphocytes (CTLs) are numerically reduced in the absence of Ptpn22 at the expansion and contraction phase but reach wild-type levels at the memory phase. However, they show similar effector function and even a subtle increase in the production of IL-2. In contrast, NP396-404-specific CTLs develop normally at all phases but display enhanced effector function. Lack of Ptpn22 also augments the memory proinflammatory response of GP61-80 CD4 T cells. Hence, lack of Ptpn22 largely augments antiviral effector T cell responses, suggesting that caution should be taken when targeting Ptpn22 to treat autoimmune diseases where viral infections are considered environmental triggers. Copyright © 2014 Elsevier Inc. All rights reserved.
Fomsgaard, Anders; Vinner, Lasse; Therrien, Dominic
To increase the understanding of mechanisms of HIV control we have genetically and immunologically characterized a full-length HIV-1 isolated from an acute infection in a rare case of undetectable viremia. The subject, a 43-year-old Danish white male (DK1), was diagnosed with acute HIV-1 infection...... after 1 year in Uganda. Following transient antiretroviral therapy DK1 maintained undetectable viral load for more than 10 years. His Ugandan wife (UG1) developed high viral load. HIV-1 sequences from both individuals were compared by bootscanning for recombination break points. Diversity plots...... homology in shared regions. Four of seven crossover points were identical; however, the env gene from UG1 was subtype D, but A1 in DK1. Both viruses encoded proteins of the expected length and replicated equally well in vitro. DK1 and UG1 shared the HLA-A02 tissue type. HLA-A02-restricted CD8(+) T cell IFN...
Klein, Marina B.; Althoff, Keri N.; Jing, Yuezhou; Lau, Bryan; Kitahata, Mari; Lo Re, Vincent; Kirk, Gregory D.; Hull, Mark; Kim, H. Nina; Sebastiani, Giada; Moodie, Erica E.M.; Silverberg, Michael J.; Sterling, Timothy R.; Thorne, Jennifer E.; Cescon, Angela
Despite increasing use of antiretrovirals, no clear reduction in end-stage liver disease events was observed in American human immunodeficiency virus–viral hepatitis–coinfected patients over 15 years. Direct-acting antivirals for hepatitis C and tenofovir-based regimens for hepatitis B should be prioritized.
Phillips, Andrew N; Pillay, Deenan; Miners, Alec H
: For patients on the first-line regimen of stavudine, lamivudine, and nevirapine the benefits of viral load or CD4 cell count monitoring over clinical monitoring alone are modest. Development of cheap and robust versions of these assays is important, but widening access to antiretrovirals-with or without...
Pijlman, G.P.; Suhrbier, A.; Khromykh, A.A.
The application of viral vectors for gene expression and delivery is rapidly evolving, with several entering clinical trials. However, a number of issues, including safety, gene expression levels, cell selectivity and antivector immunity, are driving the search for new vector systems. A number of
In his thesis, Legese A. Mekuria presents the results of a PhD study which was undertaken in 10 health-care facilities in Addis Ababa, Ethiopia. The overall aim was to estimate retention in HIV care, viral suppression, medication adherence and patients’ health-related quality of life (HRQoL). An
Janssen, Patricia; Shroff, Farah; Jaspar, Paula
Introduction Massage is a time-honored method by which women have received comfort throughout the millennia, yet it has not been rigorously evaluated in the modern day delivery suite. No study to date that we are aware of has evaluated the effect of massage therapy by a regulated massage therapist on labor pain. The purpose of this study was to evaluate the effectiveness of massage therapy provided by registered massage therapists in managing pain among women in active labor. Methods BC Women’s Hospital, Vancouver, BC. Research Design: a randomized controlled trial. Participants: 77 healthy nulliparous women presenting in spontaneous labor. Intervention: Swedish massage administered for up to five hours by a registered massage therapist during labor vs. standard care. Main outcome measures include: cervical dilation at the time of administration of epidural, compared using estimated marginal means in an analysis of covariance. We also compared perception of pain at three time periods during labor according to cervical dilation at 3–4 cm, 5–7 cm, and 8–10 cm using the McGill Present Pain Intensity Scale. Results The mean cervical dilation at the time of epidural insertion after adjustment for station of the presenting part, cervical dilation, and status of membranes on admission to hospital was 5.9 cm (95% CI 5.2–6.7) compared to 4.9 in the control group (95% CI 4.2–5.8). Scores on the McGill Pain Scale were consistently lower in the massage therapy group (13.3 vs. 16.9 at 3–4 cm, 13.3 vs. 15.8 at 5–6 cm, and 19.4 vs. 28.3 at 7–8 cm), although these differences were not statistically significant. Conclusions Our findings from this pilot study suggest that massage therapy by a registered massage therapist has the potential to be an effective means of pain management that may be associated with delayed use of epidural analgesia. It may therefore have the potential to reduce exposure to epidural analgesia during labor and decrease rates of associated
Althoff, Keri N.; Buchacz, Kate; Hall, H. Irene; Zhang, Jinbing; Hanna, David B.; Rebeiro, Peter; Gange, Stephen J.; Moore, Richard D.; Kitahata, Mari; Gebo, Kelly A.; Martin, Jeffrey; Justice, Amy C.; Horberg, Michael; Hogg, Robert S.; Sterling, Timothy R.; Cescon, Angela; Klein, Marina B.; Thorne, Jennifer; Crane, Heidi; Mugavero, Michael J.; Napravnik, Sonia; Kirk, Gregory D.; Jacobson, Lisa P.; Brooks, John T.
Background The U.S. National HIV/AIDS Strategy targets for 2015 include increasing access to care and improving health outcomes for persons living with HIV in the United States (PLWH-US). Objective To demonstrate the utility of the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) for monitoring trends in the HIV epidemic in the United States and to present trends in HIV treatment and related health outcomes. Design Trends from annual cross-sectional analyses comparing patients from pooled, multicenter, prospective, clinical HIV cohort studies with PLWH-US, as reported to national surveillance systems in 40 states. Setting U.S. HIV outpatient clinics. Patients HIV-infected adults with 1 or more HIV RNA plasma viral load (HIV VL) or CD4 T-lymphocyte (CD4) cell count measured in any calendar year from 1 January 2000 to 31 December 2008. Measurements Annual rates of antiretroviral therapy use, HIV VL, and CD4 cell count at death. Results 45 529 HIV-infected persons received care in an NA-ACCORD–participating U.S. clinical cohort from 2000 to 2008. In 2008, the 26 030 NA-ACCORD participants in care and the 655 966 PLWH-US had qualitatively similar demographic characteristics. From 2000 to 2008, the proportion of participants prescribed highly active antiretroviral therapy increased by 9 percentage points to 83% (P < 0.001), whereas the proportion with suppressed HIV VL (≤2.7 log10 copies/mL) increased by 26 percentage points to 72% (P < 0.001). Median CD4 cell count at death more than tripled to 0.209 × 109 cells/L (P < 0.001). Limitation The usual limitations of observational data apply. Conclusion The NA-ACCORD is the largest cohort of HIV-infected adults in clinical care in the United States that is demographically similar to PLWH-US in 2008. From 2000 to 2008, increases were observed in the percentage of prescribed HAART, the percentage who achieved a suppressed HIV VL, and the median CD4 cell count at death. Primary Funding Source
Full Text Available Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs of two EBOV species, Marburg virus (MARV and avian influenza H5 (FLU-H5. We confirm the ability of chloroquine (CQ to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We propose CQ as a priority candidate to consider for treatment of EBOV.
Wang, Shuo; Zhou, Ya; Yu, Shi; Ran, Li-Wen; Liu, Xiang-Ping; Chen, Yu-Fei
Objective: This study tested the efficacy of Acceptance and Commitment Therapy (ACT), compared with Cognitive-Behavioral Therapy (CBT), in alleviating academic procrastination. Method: A total of 60 (53.3% male) undergraduates suffering from academic procrastination were randomly assigned to two treatment groups (ACT and CBT) and a control group.…
Anny Armas Cayarga
Full Text Available Human immunodeficiency virus type-1 (HIV-1 viral load is useful for monitoring disease progression in HIV-infected individuals. We generated RNA standards of HIV-1 and internal control (IC by in vitro transcription and evaluated its performance in a quantitative reverse transcription polymerase chain reaction (qRT-PCR assay. HIV-1 and IC standards were obtained at high RNA concentrations, without DNA contamination. When these transcripts were included as standards in a qRT-PCR assay, it was obtained a good accuracy (±0.5 log10 unit of the expected results in the quantification of the HIV-1 RNA international standard and controls. The lower limit detection achieved using these standards was 511.0 IU/mL. A high correlation (=0.925 was obtained between the in-house qRT-PCR assay and the NucliSens easyQ HIV-1 test (bioMerieux for HIV-1 RNA quantitation with clinical samples (=14. HIV-1 and IC RNA transcripts, generated in this study, proved to be useful as standards in an in-house qRT-PCR assay for determination of HIV-1 viral load.
Gan, Lu; O'Hanlon, Terrance P; Lai, Zhennan; Fannin, Rick; Weller, Melodie L; Rider, Lisa G; Chiorini, John A; Miller, Frederick W
Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups-probands with SAID, their unaffected twins, and matched, unrelated healthy controls-using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID.
Full Text Available Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART. It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger, we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI of: 0.35 (0.30-0.40 for counts <200 cells/µl, 0.81 (0.71-0.92 for counts 200 to <350 cells/µl, 0.74 (0.66-0.83 for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99 for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl.Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl.
Deluca, Stephanie C; Echols, Karen; Law, Charles R; Ramey, Sharon L
A randomized crossover trial of a new form of pediatric rehabilitation was conducted with 18 children with hemiparesis. Half were randomly assigned to receive pediatric constraint-induced therapy involving constraint of the functional upper extremity and intensive therapy with the hemiparetic upper extremity. Controls received conventional physical and occupational therapy and then were crossed over to receive pediatric constraint-induced therapy. Pediatric constraint-induced therapy produced significantly greater gains than conventional rehabilitation services.
Bayu, Belete; Tariku, Amare; Bulti, Abera Balcha; Habitu, Yohannes Ayanaw; Derso, Terefe; Teshome, Destaw Fetene
Viral load monitoring is used as an important biomarker for diagnosing treatment failure in patients with HIV infection/AIDS. Ethiopia has started targeted viral load monitoring. However, factors leading to virological failure are not well understood and studied. Thus, the aim of this study was to identify the determinants of virological failure among HIV-infected patients on highly active antiretroviral therapy at the University of Gondar Referral Hospital, Northwest Ethiopia. A case-control study was conducted from May to June 2015. Cases were subjects who had already experienced virological failure; controls were those without virological failure. Data were extracted from 153 cases and 153 controls through chart review. A multivariate logistic regression analysis was carried out to identify factors associated with virological failure, and variables with a p-value failure was observed among patients aged failure. Therefore, evidence-based intervention should be implemented to improve adherence to ART, which in turn helps to boost immunity (CD4) and suppresses viral replication and load. Moreover, attention should be given to younger patients who have had ART for longer periods.
Background Low levels of serum selenium are associated with increased risk of mortality among HIV+ patients in East Africa. We aim to assess the effect of selenium supplementation on CD4 cell count, HIV viral load, opportunistic infections, and quality of life in HIV-infected patients in Rwanda. Methods and Design A 24-month, multi-centre, patient and provider-blinded, randomized, placebo-controlled clinical trial involving 300 pre-antiretroviral therapy (ART) HIV-infected patients will be carried out at two sites in Rwanda. Patients ≥ 21 years of age with documented HIV infection, CD4 cell count of 400-650 cells/mm3, and not yet on ART will be recruited. Patients will be randomized at each study site using a randomized block design to receive either the selenium micronutrient supplement or an identically appearing placebo taken once daily. The primary outcome is a composite of time from baseline to reduction of CD4 T lymphocyte count below 350 cells/mm3 (confirmed by two measures at least one week apart), or start of ART, or the emergence of a documented CDC-defined AIDS-defining illness. An intention-to-treat analysis will be conducted using stepwise regression and structural equation modeling. Discussion Micronutrient interventions that aim to improve CD4 cell count, decrease opportunistic infections, decrease HIV viral load, and ultimately delay initiation of more costly ART may be beneficial, particularly in resource-constrained settings, such as sub-Saharan Africa. Additional trials are needed to determine if micro-supplementation can delay the need for more costly ART among HIV-infected patients. If shown to be effective, selenium supplementation may be of public health importance to HIV-infected populations, particularly in sub-Saharan Africa and other resource-constrained settings. Trial Registration NCT01327755 PMID:21838913
Baize, Sylvain; Marianneau, Philippe; Loth, Philippe; Reynard, Stéphanie; Journeaux, Alexandra; Chevallier, Michèle; Tordo, Noël; Deubel, Vincent; Contamin, Hugues
Lassa virus causes a hemorrhagic fever endemic in West Africa. The pathogenesis and the immune responses associated with the disease are poorly understood, and no vaccine is available. We followed virological, pathological, and immunological markers associated with fatal and nonfatal Lassa virus infection of cynomolgus monkeys. The clinical picture was characterized by fever, weight loss, depression, and acute respiratory syndrome. Transient thrombocytopenia and lymphopenia, lymphadenopathy, splenomegaly, infiltration of mononuclear cells, and alterations of the liver, lungs, and endothelia were observed. Survivors exhibited fewer lesions and a lower viral load than nonsurvivors. Although all animals developed strong humoral responses, antibodies appeared more rapidly in survivors and were directed against GP1, GP2, and NP. Type I interferons were detected early after infection in survivors but only during the terminal stages in fatalities. The mRNAs for CXCL10 (IP-10) and CXCL11 (I-TAC) were abundant in peripheral blood mononuclear cells and lymph nodes from infected animals, but plasma interleukin-6 was detected only in fatalities. In survivors, high activated-monocyte counts were followed by a rise in the total number of circulating monocytes. Activated T lymphocytes circulated in survivors, whereas T-cell activation was low and delayed in fatalities. In vitro stimulation with inactivated Lassa virus induced activation of T lymphocytes from all infected monkeys, but only lymphocytes from survivors proliferated. Thus, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterized by major alterations of the blood formula and, in organs, weak immune responses and uncontrolled viral replication. PMID:19297492
Baize, Sylvain; Marianneau, Philippe; Loth, Philippe; Reynard, Stéphanie; Journeaux, Alexandra; Chevallier, Michèle; Tordo, Noël; Deubel, Vincent; Contamin, Hugues
Lassa virus causes a hemorrhagic fever endemic in West Africa. The pathogenesis and the immune responses associated with the disease are poorly understood, and no vaccine is available. We followed virological, pathological, and immunological markers associated with fatal and nonfatal Lassa virus infection of cynomolgus monkeys. The clinical picture was characterized by fever, weight loss, depression, and acute respiratory syndrome. Transient thrombocytopenia and lymphopenia, lymphadenopathy, splenomegaly, infiltration of mononuclear cells, and alterations of the liver, lungs, and endothelia were observed. Survivors exhibited fewer lesions and a lower viral load than nonsurvivors. Although all animals developed strong humoral responses, antibodies appeared more rapidly in survivors and were directed against GP(1), GP(2), and NP. Type I interferons were detected early after infection in survivors but only during the terminal stages in fatalities. The mRNAs for CXCL10 (IP-10) and CXCL11 (I-TAC) were abundant in peripheral blood mononuclear cells and lymph nodes from infected animals, but plasma interleukin-6 was detected only in fatalities. In survivors, high activated-monocyte counts were followed by a rise in the total number of circulating monocytes. Activated T lymphocytes circulated in survivors, whereas T-cell activation was low and delayed in fatalities. In vitro stimulation with inactivated Lassa virus induced activation of T lymphocytes from all infected monkeys, but only lymphocytes from survivors proliferated. Thus, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterized by major alterations of the blood formula and, in organs, weak immune responses and uncontrolled viral replication.
Sterrantino, Gaetana; Zaccarelli, Mauro; Prati, Francesca; Boschi, Andrea; Sighinolfi, Laura; Borghi, Vanni
Introduction Assessing virological response of four-drugs antiretroviral regimen that include raltegravir (RAL) in naïve patients with high viral load (>500,000 copies/mL) selected from a multicentre Italian database. Methods Naïve patients with HIV RNA>500,000 copies/mL, who began standard antiretroviral regimens either based on non-nucleoside reverse transcriptase inhibitors (NNRTI) or boosted-PI (PI/r), or a standard regimen plus RAL between 2008 and 2013 were analyzed. Observation was censored at 12 months and the percentage of patients who achieved a viral load below the limit of detection (BLD) was calculated. Virological failure was defined as two consecutive viral loads>40 copies/mL. Results Overall, 179 patients were included (13% with primary HIV infection (PHI), and 42.5% with AIDS diagnosis). Of them, 156 started standard three-drugs antiretroviral regimen (75.6% PI/r-based, 24.4% NNRTI-based. Among patients with PHI, 23 patients (12.8%), 6 (25%) started a four-drugs antiretroviral regimen containing both RAL and PI/r. Patients’ characteristics were as follows: males 74%, median age 42 years (IQR 35–51), sexually transmission 75.1%, median CD4 count 156 cells/µL (IQR 47–368) and median HIV-RNA 6.1 log10 copies/mL (IQR 5.8–6.4). 91 of 179 patients (50.8%) reached BLD viral load during the twelve months of observation. Three patients (1.7%) who began regimens PI/r-based with three-drugs had virological rebound after reaching BLD viral load. By use of survival analysis, we show that those patients who added RAL to the standard regimen have reached the primary end point faster (mean 8.4 months (95% CI 7.2–9.6) vs 11.4 (95% CI 11.0–11.8) in PI group and 10.3 (95% CI 9.4–11.1) in NNRTI group; p500,000 copies/mL HIV-RNA had virological success at 12 months. The success was reached faster using the RAL-containing four-drugs regimen, suggesting that strengthening the initial regimen could be an option in patients with very high viral load to
, expression of endogenous SAgs leads to thymic deletion of responding T cells (bearing Vβ6-9+ TCR) due to self-tolerance induction during the fetal life, and protects the host against future exogenous MMTV infections. The SAg of rabies virus is the N protein found in nucleocapsid structure and stimulates Vβ8+TCR-bearing T cells. The SAg-induced polyclonal activation of T cells leads to turn-off the specific immune response, to enhance the immunopathogenesis and facilitates viral transmission from the initial site of infection (the muscle tissue) to the nerve endings. In case of EBV-associated SAg that activates Vβ13+TCR-bearing T cells, it was detected that the SAg activity was not encoded by EBV itself, but instead was due to the transactivation of HERV-K18 by EBV latent membrane proteins, whose env gene encodes the SAg (Sutkowski, et al. 2001). It has been denoted that EBV-induced SAg expression plays a role in the long-term persistence and latency of virus in memory B cells, in the development of autoimmune diseases and in the oncogenesis mechanisms. The proteins which are identified as SAgs of HIV are Nef and gp120. It is believed that, the massive activation of CD4+ T cells (selectively with Vβ-12+, Vβ-5.3+ and Vβ-18+ TCRs) in early stages of infection and clonal deletion, anergy and apoptosis of bystander T cells in the late stages may be due to SAg property of Nef protein, as well as the other mechanisms. However there are some studies indicating that Nef does not act as a SAg (Lapatschek, et al. 2001). HIV gp120 glycoprotein is a B-cell SAg that binds to VH3-expressing B cell receptors and causes polyclonal B cell activation. In addition, binding of gp120 to IgE on the surface of basophiles and mast cells causes activation of those cells, secretion of high level proinflammatory mediators leading to allergic reactions and tissue damage. In a recent study, the depletion (anergy or deletion) of T cell populations bearing Vβ12+, Vβ13+ and Vβ17+ TCR have been
Wang, Shujun; Wang, Weihong; Chu, Yunxiang; Teng, Guigen; Hu, Fulian
To compare the efficacies of non-bismuth quadruple therapy for 7 days versus standard triple therapy for 7 or 10 days in initial treatment of Helicobacter pylori (H.pylori) . A randomized, open-labeled, controlled trial comparing non-bismuth quadruple therapy with standard triple therapy was performed at Peking University First Hospital from August 2010 to July 2012. A total of 246 patients with a diagnosis of H.pylori infection by (13)C-urea breath test and receiving no eradication therapy were randomly divided into non-bismuth quadruple therapy and standard triple therapy for 7 or 10 days. There were 110 males and 136 females with an age range of 18-75 years. Among them, 81 patients received non-bismuth quadruple therapy (esomeprazole 20 mg, amoxicillin 1 000 mg, clarithromycin 500 mg and tinidazole 500 mg given twice daily for 7 days); 82 standard triple therapy (esomeprazole 20 mg, amoxicillin 1 000 mg and clarithromycin 500 mg given twice daily) for 7 days and 83 standard triple therapy for 10 days. The efficacies were examined at Week 4 post-therapy by (13)C-urea breath test. The incidence of adverse drug reactions was recorded. Among them, 242 patients completed the follow-up. The eradication rates for non-bismuth quadruple therapy and standard triple therapy for 7 or 10 days were 91.4% (74/81), 79.3% (65/82) and 79.5% (66/83) as determined by intention-to-treat analysis (ITT). The eradication rates were 92.5% (74/80), 81.3% (65/80) and 80.5% (66/82) respectively as determined by per-protocol analysis (PP).Non-bismuth quadruple therapy was superior to standard triple therapy for 7 days (ITT analysis P = 0.029, PP analysis P = 0.035) and 10 days (ITT analysis P = 0.032, PP analysis P = 0.026). The differences for the eradication rates between standard triple therapy for 7 days and for 10 days were insignificant (ITT analysis P = 0.968, PP analysis P = 0.902): Adverse reaction rates for non-bismuth quadruple therapy (8.8%, 7/80) and standard triple therapy for
Thévenot, E.; Dufour, N.; Déglon, N.
The transfer of DNA into the nucleus of a eukaryotic cell (gene transfer) is a central theme of modern biology. The transfer is said to be somatic when it refers to non-germline organs of a developed individual, and germline when it concerns gametes or the fertilised egg of an animal, with the aim of transmitting the relevant genetic modification to its descendents . The efficient introduction of genetic material into a somatic or germline cell and the control of its expression over time have led to major advances in understanding how genes work in vivo, i.e., in living organisms (functional genomics), but also to the development of innovative therapeutic methods (gene therapy). The efficiency of gene transfer is conditioned by the vehicle used, called the vector. Desirable features for a vector are as follows: Easy to produce high titer stocks of the vector in a reproducible way. Absence of toxicity related to transduction (transfer of genetic material into the target cell, and its expression there) and no immune reaction of the organism against the vector and/or therapeutic protein. Stability in the expression of the relevant gene over time, and the possibility of regulation, e.g., to control expression of the therapeutic protein on the physiological level, or to end expression at the end of treatment. Transduction of quiescent cells should be as efficient as transduction of dividing cells. Vectors currently used fall into two categories: non-viral and viral vectors. In non-viral vectors, the DNA is complexed with polymers, lipids, or cationic detergents (described in Chap. 3). These vectors have a low risk of toxicity and immune reaction. However, they are less efficient in vivo than viral vectors when it comes to the number of cells transduced and long-term transgene expression. (Naked DNA transfer or electroporation is rather inefficient in the organism. This type of gene transfer will not be discussed here, and the interested reader is referred to the
Tsay, Feng-Woei; Wu, Deng-Chyang; Kao, Sung-Shuo; Tsai, Tzung-Jium; Lai, Kwok-Hung; Cheng, Jin-Shiung; Chan, Hoi-Hung; Wang, Huay-Min; Tsai, Wei-Lun; Tseng, Hui-Hwa; Peng, Nan-Jin; Hsu, Ping-I
Sequential therapy is a two-step therapy achieving a promising eradication rate for Helicobacter pylori infection. The rationale of sequential method has been proposed that amoxicillin weakens bacterial cell walls in the initial phase of treatment, preventing the development of drug efflux channels for clarithromycin and metronidazole used in the second phase. The aim of this prospective, randomized, controlled study was to investigate whether the efficacy of reverse sequential therapy was noninferior to sequential therapy in the treatment of H. pylori infection. From January 2009 to December 2010, consecutive H. pylori-infected patients were randomly assigned to receive either sequential therapy (a 5-day dual therapy with pantoprazole plus amoxicillin, followed by a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole) or reverse sequential therapy (a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole, followed by a 5-day dual therapy with pantoprazole plus amoxicillin). H. pylori status was examined 6 weeks after the end of treatment by rapid urease and histology or urea breath test. One hundred and twenty-two H. pylori-infected participants were randomized to receive sequential (n = 60) or reverse sequential therapy (n = 62). The eradication rates, by intention-to-treat analysis, were similar: 91.9% (95% confidence interval (CI): 85.1-98.7%) for sequential therapy and 96.7% (95% CI: 92.2-101.2%) for reverse sequential therapy (p = .44). Per-protocol analysis also showed similar results: 91.8% (95% CI: 84.9-98.7%) for sequential group and 96.7% (95% CI: 92.2-101.2%) for reverse sequential therapy (p = .43). The two treatments exhibited comparable frequencies of adverse events (11.3% vs 6.7%, respectively) and drug compliance (98.4% vs 100%, respectively). The overall resistance rates of antibiotics were clarithromycin 10.5%, amoxicillin 0%, and metronidazole 44.2% of patients, respectively. The dual
Loebbermann, J; Thornton, H; Durant, L; Sparwasser, T; Webster, K E; Sprent, J; Culley, F J; Johansson, C; Openshaw, P J
The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described “depletion of regulatory T cell” (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation. PMID:22236998
Kahan, Shannon M.; Wherry, E. John; Zajac, Allan J.
Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control. PMID:25620767
Schmidt, W; Schultze, C; Stachs, O; Allemann, R; Löbler, M; Sternberg, K; Hinze, U; Chichkov, B N; Guthoff, R; Schmitz, K-P
A pressure-controlled microstent could permanently normalise the intraocular pressure (IOP) for open-angle glaucoma therapy by drainage into the suprachoroidal space. The complex requirements demand new technical solutions as well as an improved understanding of specific cell biological processes at the implant's surface to develop effective local drug delivery (LDD) concepts and surface modifications. Fluid mechanical requirements were derived from physiological data and the analysis of commercial glaucoma implants. The technological basics for the production of suitable structures are refined ultra-short pulse laser technology and 2-photon polymerisation (2PP). All known glaucoma implants induce unwanted cell proliferation resulting in a loss of function. It is assumed that the activity of fibroblasts is low in the suprachoroidal space. However, it was seen that LDD concepts are required to control cell proliferation. Fibroblasts from sclera and choroidea were isolated und cultured as the most relevant cell types for in vitro investigation. Potential materials and drugs were investigated by cell viability tests for biocompatibility or suppression of cell viability. The fluid mechanical analysis leads to smallest stent lumina (ID = 50 µm) at anatomically suitable implant lengths (7 - 10 mm). Only pressure control can manage the individual conditions with changing IOP. Finite element analysis of valves showed the need for highly flexible structures. This can be achieved by combining basic structures with micromechanically active valves added by 2PP. The potential materials show perfect in vitro and in vivo biocompatibility. Ormocers which are best suited for 2PP are also highly biocompatible. The selected drugs paclitaxel and triamcinolon acetonide open a wide therapeutic window to impair fibroblast growth. The surgical procedure was established by implantation of prototypes in rabbit eyes, connecting the anterior chamber with the suprachoroidal space. Highly
Ramdass, Priya; Mullick, Sahil; Farber, Harold F
In the vast world of skin diseases, viral skin disorders account for a significant percentage. Most viral skin diseases present with an exanthem (skin rash) and, oftentimes, an accompanying enanthem (lesions involving the mucosal membrane). In this article, the various viral skin diseases are explored, including viral childhood exanthems (measles, rubella, erythema infectiosum, and roseola), herpes viruses (herpes simplex virus, varicella zoster virus, Kaposi sarcoma herpes virus, viral zoonotic infections [orf, monkeypox, ebola, smallpox]), and several other viral skin diseases, such as human papilloma virus, hand, foot, and mouth disease, molluscum contagiosum, and Gianotti-Crosti syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.
Aleksander Chaibi; Heidi Knackstedt; Peter J Tuchin; Michael Bjorn Russell
.... Thus, non-pharmacological management is warranted. Our objective was therefore to investigate the efficacy of chiropractic spinal manipulative therapy versus placebo (sham manipulation) and control...
Vuković Vuk R.
Full Text Available Background/Aim. Hepatitis C is an important sociomedical problem worldwide due to frequent progression to chronic disease, occurrence of liver cirrhosis and hepatocellular carcinoma. Standard pegylated interferon alfa 2a plus ribavirin therapy results in resolution of infection only in 50% of patients. The aim of this study was to determine the association of various factors with response to the therapy in patients with chronic hepatitis C virus (HCV infection. Age and sex of patients, inoculation risk factors, histopathological changes in the liver, viral load and HCV genotype were analyzed. Methods. The study included a group of 121 patients with chronic HCV infection. The treatment was carried out 24 weeks for virus genotype 2 and 3, and 48 weeks for genotype 1 and 4. The degree of histopathological changes in the liver was determined by hematoxylin and eosin staining, whereas polimerase chain reaction was used for HCV genotyping. Results. In the group of non-responding patients genotype 1 was represented with 100%, while in the other groups, although predominantly present, its percentage was lower. Unresponsiveness to therapy and relapse of disease were associated with higher viral load and advanced fibrosis. Intravenous use of psychoactive substances, as a risk factor, was present in a high percentage in the group of patients with sustained response, while blood transfusion and dialysis were leading risk factors in the group of relapse responders and non-responders. Conclusion. The results of our study showed that the treatment outcome of chronic HCV infection was associated with baseline HCV ribonucleic acid, HCV genotype, route of infection and the degree of histopathological changes in the liver. [Projekat Ministarstva nauke Republike Srbije, br. III41010
Weber, E P Scott
Viral dermatopathies of fish bear clinical signs similar to those of dermatopathies from other causes. This article offers an overview to approaching dermatologic presentations in fish, with an emphasis on sampling, diagnosis, and management of viral dermatopathies, building on previous publications. It is vital to recognize clinical signs associated with viral dermatopathies because there are currently no treatments available. Avoidance and prevention is the key to controlling viral diseases in fish. Optimizing husbandry practices and providing appropriate quarantine procedures can help prevent viral disease outbreaks in collection and aquaculture stocks. Copyright © 2013 Elsevier Inc. All rights reserved.
Marques, Cristiano Corrêa de Azevedo; Carvalheiro, José da Rocha
to assess the performance of the diagnostic network in the implementation process of the Program for Viral Hepatitis Prevention and Control in São Paulo State, Brazil, from 1997 to 2012. evaluation study based on documentary research and structured interviews, combined with a historical series analysis of indicators developed to assess the implementation process of the program, using data from the Department of the Brazilian National Health System. from 1997 to 2012, the serology, biopsy and molecular biology diagnostic networks showed an increase in the coefficients of coverage of 7.4, 7.3, and 62.0 times, respectively, with an increase in cases detection and treatment access. despite the effective implementation of the diagnostic network, there is a need to review the search strategy for new cases, and access to liver biopsy, still insufficient to the program demand.
Persistent humoral immune defect in highly active antiretroviral therapy-treated children with HIV-1 infection: loss of specific antibodies against attenuated vaccine strains and natural viral infection
Bekker, Vincent; Scherpbier, Henriëtte; Pajkrt, Dasja; Jurriaans, Suzanne; Zaaijer, Hans; Kuijpers, Taco W.
OBJECTIVE: In the pre-highly active antiretroviral therapy era, a loss of specific antibodies was seen. Our objective with this study was to describe the loss of specific antibodies during treatment with highly active antiretroviral therapy. METHODS: In a prospective, single-center, cohort study of
Guna Serrano, María del Remedio; Orta Mira, Nieves; Latorre Martínez, José-Carlos; Ovies, María Rosario; Poveda, Marta; Ruiz de Gopegui, Enrique; Gimeno Cardona, Concepción
Human immunodeficiency virus type 1 (HIV-1) and hepatitis B (HBV) and C virus (HCV) viral load determinations are among the most relevant markers for the follow up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of results obtained by microbiology laboratories. This article summarized the results obtained from the 2012 SEIMC External Quality Control Programme for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of five standards were sent. One standard consisted in seronegative human plasma, while the remaining four contained plasma from three different viremic patients, in the range of 2-5 log10 copies/mL; two of these standards were identical aiming to determine repeatability. A significant proportion of the laboratories (22.3% on average) obtained values out of the accepted range (mean±0.25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was excellent, with up to 98.9% of laboratories reporting results within the limits (Δ load contents. Most of the participants, 84% in the case of HCV and 88% in the HBV, obtained all the results within the accepted range (mean±1.96 SD log10 UI/mL). Data from this analysis reinforce the utility of proficiency programmes to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase on the overall quality. Due to the remarkable interlaboratory variability, it is advisable to use the same method and the same laboratory for patient follow up. Copyright © 2014 Elsevier España, S.L. All rights reserved.
Orta Mira, Nieves; Del Remedio Guna Serrano, María; Latorre Martínez, José-Carlos; Medina González, Rafael; Rosario Ovies, María; Poveda, Marta; Ruiz de Gopegui, Enrique; Gimeno Cardona, Concepción
Human immunodeficiency virus type 1 (HIV-1) and hepatitis B (HBV) and C virus (HCV) viral load determinations are among the most relevant markers for the follow up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of results obtained by microbiology laboratories. This article summarized the results obtained from the 2013 SEIMC External Quality Control Programme for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of five standards were sent. One standard consisted in seronegative human plasma, while the remaining four contained plasma from three different viremic patients, in the range of 2-5 log10 copies/mL; two of these standards were identical aiming to determine repeatability. A significant proportion of the laboratories (25% on average) obtained values out of the accepted range (mean ± 0.25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was excellent, with up to 98.9% of laboratories reporting results within the limits (D load contents. Most of the participants, 82% in the case of HCV and 78% in the HBV, obtained all the results within the accepted range (mean ± 1.96 SD log10 UI/mL). Data from this analysis reinforce the utility of proficiency programmes to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase on the overall quality. Due to the remarkable interlaboratory variability, it is advisable to use the same method and the same laboratory for patient follow up. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.
Orta Mira, Nieves; del Remedio Guna Serrano, María; Martínez, José-Carlos Latorre; Ovies, María Rosario; Poveda, Marta; de Gopegui, Enrique Ruiz; Pérez, José L; Cardona, Concepción Gimeno
Human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) viral load determinations are among the most important markers in the follow-up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of the results obtained by microbiology laboratories. This article summarizes the results obtained from the SEIMC's External Quality Control Program for HIV-1 and HCV viral loads in 2009. In the HIV-1 program, a total of five standards were sent. One standard consisted of seronegative human plasma, while the remaining four contained plasma from three different viremic patients, in the range of 2-5 log(10) copies/mL; two of these standards were identical, aiming to determine repeatability. A significant proportion of the laboratories (21.5% on average) obtained values outside the accepted range (mean ± 0.2 log(10) copies/mL), depending on the standard and on the method used for quantification. Repeatability was very good, with up to 95 % of laboratories reporting results within the accepted limits (Δload contents. Most of the participants (79.7%) obtained results within the accepted range (mean ± 1.96 SD log(10) UI/mL). Data from this analysis reinforce the utility of proficiency programs to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase in overall quality. Due to marked interlaboratory variability, use of the same method and the same laboratory for patient follow-up is advisable. Copyright © 2011 Elsevier España S.L. All rights reserved.
Medina González, Rafael; Orta Mira, Nieves; Guna Serrano, María Del Remedio; Latorre Martínez, José-Carlos; Gopegui, Enrique Ruiz de; Rosario Ovies, María; Poveda, Marta; Gimeno Cardona, Concepción
Human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV) viral load determinations are among the most relevant markers for the follow up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of results obtained by microbiology laboratories. This article summarizes the results obtained from the 2014 SEIMC (Spanish Society of Infectious Diseases and Clinical Microbiology) External Quality Control Programme for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of 5 standards were sent. One standard consisted in seronegative human plasma, while the remaining 4 contained plasma from 3 different viremic patients, in the range of 2-5 log10 copies/mL; 2 of these standards were identical aiming to determine repeatability. A significant proportion of the laboratories (30.8% on average) obtained values out of the accepted range (mean ± 0.25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was excellent, with up to 95.8% of laboratories reporting results within the limits (Δ load contents. Most of the participants, 83.7% in the case of HCV and 87.9% in the HBV, obtained all the results within the accepted range (mean ± 1.96 standard deviations log10 IU/mL). Data from this analysis reinforce the utility of proficiency programmes to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase on the overall quality. Due to the remarkable interlaboratory variability, it is advisable to use the same method and the same laboratory for patient follow up. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.
Orta Mira, Nieves; Guna Serrano, María del Remedio; Latorre Martínez, José-Carlos; Ovies, María Rosario; Poveda, Marta; Ruiz de Gopegui, Enrique; Gimeno Cardona, Concepción
Human immunodeficiency virus type 1 (HIV-1) and hepatitis B (HBV) and C virus (HCV) viral load determinations are among the most important markers in the follow-up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of the results obtained by microbiology laboratories. This article summarizes the results of the 2011 SEIMC External Quality Control Program for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of five standards were sent. One standard consisted of seronegative human plasma, while the remaining four contained plasma from three different viremic patients in the range of 2-5 log10 copies/mL; to determine repeatability, two of these standards were identical. A significant proportion of the laboratories (52.1% on average) obtained values outside the accepted range (mean ± 0,25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was very good, with up to 94.9% of laboratories reporting results within the accepted range (Δload contents. In most of the participating laboratories (90% in the case of HCV and 86% in that of HBV), all the results were within the accepted range (mean ± 1.96 SD log10UI/mL). Data from this analysis reinforce the utility of proficiency programs to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase in overall quality. Due to the marked interlaboratory variability found, use of the same method and the same laboratory for patient follow-up is advisable. Copyright © 2013 Elsevier España, S.L. All rights reserved.
Hua, Stéphane; Lécuroux, Camille; Sáez-Cirión, Asier; Pancino, Gianfranco; Girault, Isabelle; Versmisse, Pierre; Boufassa, Faroudy; Taulera, Olivier; Sinet, Martine; Lambotte, Olivier; Venet, Alain
HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38-/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. We compared CD38-/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. Compared to CD38+/HLA-DR+ cells, CD38-/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134-462] vs 638 [307-747], P = 0.001), higher frequency of polyfunctional cells (15% [7%-33%] vs 21% [16%-43%], P = 0.0003), greater proliferative capacity (0-fold [0-2] vs 3-fold -, P = 0.007), and higher cytotoxicity in vitro (7% [3%-11%] vs 13% [6%-22%], P = 0.02). The CD38-/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. These data highlight the role of CD38-/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies.
Hua, Stéphane; Lécuroux, Camille; Sáez-Cirión, Asier; Pancino, Gianfranco; Girault, Isabelle; Versmisse, Pierre; Boufassa, Faroudy; Taulera, Olivier; Sinet, Martine; Lambotte, Olivier; Venet, Alain
Background HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38−/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. Materials and Methods We compared CD38−/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. Results Compared to CD38+/HLA-DR+ cells, CD38−/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134–462] vs 638 [307–747], P = 0.001), higher frequency of polyfunctional cells (15% [7%–33%] vs 21% [16%–43%], P = 0.0003), greater proliferative capacity (0-fold [0–2] vs 3-fold –, P = 0.007), and higher cytotoxicity in vitro (7% [3%–11%] vs 13% [6%–22%], P = 0.02). The CD38−/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. Conclusions These data highlight the role of CD38−/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies. PMID:25000587
Browning, Diana L.; Collins, Casey P.; Hocum, Jonah D.; Leap, David J.; Rae, Dustin T.; Trobridge, Grant D.
Retroviral vector-mediated gene therapy is promising, but genotoxicity has limited its use in the clinic. Genotoxicity is highly dependent on the retroviral vector used, and foamy viral (FV) vectors appear relatively safe. However, internal promoters may still potentially activate nearby genes. We developed insulated FV vectors, using four previously described insulators: a version of the well-studied chicken hypersensitivity site 4 insulator (650cHS4), two synthetic CCCTC-binding factor (CTCF)-based insulators, and an insulator based on the CCAAT box-binding transcription factor/nuclear factor I (7xCTF/NF1). We directly compared these insulators for enhancer-blocking activity, effect on FV vector titer, and fidelity of transfer to both proviral long terminal repeats. The synthetic CTCF-based insulators had the strongest insulating activity, but reduced titers significantly. The 7xCTF/NF1 insulator did not reduce titers but had weak insulating activity. The 650cHS4-insulated FV vector was identified as the overall most promising vector. Uninsulated and 650cHS4-insulated FV vectors were both significantly less genotoxic than gammaretroviral vectors. Integration sites were evaluated in cord blood CD34+ cells and the 650cHS4-insulated FV vector had fewer hotspots compared with an uninsulated FV vector. These data suggest that insulated FV vectors are promising for hematopoietic stem cell gene therapy. PMID:26715244
Full Text Available Introduction: Prevalence of violence is highly occur in mental disorders clients at psychiatric hospitals. The impact is injure to others. This research aims to examine the effectiveness of music therapy and RECBT to sign and symptom and ability to control violent behaviour. Methods: Quasi-experimental research design with a sample of 64 respondents. Result: The study found a decrease symptoms of violent behaviour, ability to control violent behavior include relaxation, change negative thingking, irational belief, and negative behavior have increased significantly than the clients that did not receiving therapy. Discussion: Music therapy and RECBT is recommended as a therapeutic nursing at the client’s violent behaviour. Key Word: violent, sign and simptom, ability, music therapy, RECBT
Award Number: W81XWH-11-1-0387 TITLE: Viral Oncolytic Therapeutics for Neoplastic Meningitis PRINCIPAL INVESTIGATOR: Mikhail Papisov, PhD...SUBTITLE Viral Oncolytic Therapeutics for Neoplastic Meningitis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0387 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...for neoplastic meningitis ( meningeal metastasis of breast cancer). The proposed therapy will be based on direct (intrathecal) administration of
Full Text Available Abstract Background Previous research has shown positive effects of music therapy for people with schizophrenia and other mental disorders. In clinical practice, music therapy is often offered to psychiatric patients with low therapy motivation, but little research exists about this population. The aim of this study is to examine whether resource-oriented music therapy helps psychiatric patients with low therapy motivation to improve negative symptoms and other health-related outcomes. An additional aim of the study is to examine the mechanisms of change through music therapy. Methods 144 adults with a non-organic mental disorder (ICD-10: F1 to F6 who have low therapy motivation and a willingness to work with music will be randomly assigned to an experimental or a control condition. All participants will receive standard care, and the experimental group will in addition be offered biweekly sessions of music therapy over a period of three months. Outcomes will be measured by a blind assessor before and 1, 3, and 9 months after randomisation. Discussion The findings to be expected from this study will fill an important gap in the knowledge of treatment effects for a patient group that does not easily benefit from treatment. The study's close link to clinical practice, as well as its size and comprehensiveness, will make its results well generalisable to clinical practice.
Lopez, Alexander M; Weintraub, Daniel; Claassen, Daniel O
Impulsive and compulsive behaviors in Parkinson's disease (PD) patients are most often attributed to dopamine agonist therapy; dysregulation of the mesocorticolimbic system accounts for this behavioral phenotype. The clinical presentation is commonly termed impulse control disorder (ICD): Behaviors include hypersexuality, compulsive eating, shopping, pathological gambling, and compulsive hobby participation. However, not all PD individuals taking dopamine agonists develop these behavioral changes. In this review, the authors focus on the similarities between the phenotypic presentation of ICDs with that of other reward-based behavioral disorders, including binge eating disorder, pathological gambling, and substance use disorders. With this comparison, we emphasize that the transition from an impulsive to compulsive behavior likely follows a ventral to dorsal striatal pattern, where an altered dopaminergic reward system underlies the emergence of these problematic behaviors. The authors discuss the neurobiological similarities between these latter disorders and ICDs, emphasizing similar pathophysiological processes and discussing treatment options that have potential for translation to PD patients. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Esposito, Maria; Gimigliano, Francesca; Barillari, Maria R; Precenzano, Francesco; Ruberto, Maria; Sepe, Joseph; Barillari, Umberto; Gimigliano, Raffaele; Militerni, Roberto; Messina, Giovanni; Carotenuto, Marco
Selective mutism (SM) is a rare disease in children coded by DSM-5 as an anxiety disorder. Despite the disabling nature of the disease, there is still no specific treatment. The aims of this study were to verify the efficacy of six-month standard psychomotor treatment and the positive changes in lifestyle, in a population of children affected by SM. Randomized controlled trial registered in the European Clinical Trials Registry (EuDract 2015-001161-36). University third level Centre (Child and Adolescent Neuropsychiatry Clinic). Study population was composed by 67 children in group A (psychomotricity treatment) (35 M, mean age 7.84±1.15) and 71 children in group B (behavioral and educational counseling) (37 M, mean age 7.75±1.36). Psychomotor treatment was administered by trained child therapists in residential settings three times per week. Each child was treated for the whole period by the same therapist and all the therapists shared the same protocol. The standard psychomotor session length is of 45 minutes. At T0 and after 6 months (T1) of treatments, patients underwent a behavioral and SM severity assessment. To verify the effects of the psychomotor management, the Child Behavior Checklist questionnaire (CBCL) and Selective Mutism Questionnaire (SMQ) were administered to the parents. After 6 months of psychomotor treatment SM children showed a significant reduction among CBCL scores such as in social relations, anxious/depressed, social problems and total problems (Ppsychomotricity a safe and efficacy therapy for pediatric selective mutism.
Lønborg, C.; Middelboe, M.; Brussaard, C.P.D.
The viral mediated transformation of phytoplankton organic carbon to dissolved forms (“viral shunt”) has been suggested as a major source of dissolved organic carbon (DOC) in marine systems. Despite the potential implications of viral activity on the global carbon fluxes, studies investigating
The synthesis of pyridinium cationic lipids, their counter-ion exchange, and the transfection of lipoplexes consisting of these lipids with firefly luciferase plasmid DNA (6.7 KDa), into lung, prostate and breast cancer cell lines was investigated. The transfection ability of these newly synthesized compounds was found to be twice as high as DOTAP/cholesterol and Lipofectamine TM (two commercially available successful transfection agents). The compaction of the DNA onto silica (SiO2) nanoparticles was also investigated. For this purpose, it was necessary to study the stability and fusion studies of colloidal systems composed of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine), a zwitterionic lipid, and mixtures of DMPC with cationic DMTAP (1,2-dimyristoyl-3-trimethylammonium-propane).
Craane, B.; Dijkstra, P. U.; Stappaerts, K.; De Laat, A.
This study evaluated the one-year effect of physical therapy on pain and mandibular dysfunction associated with anterior disc displacement without reduction of the temporomandibular joint (closed lock). Forty-nine individuals were randomly assigned to either a physical therapy group [n = 23, mean
Dengler, Ellen C; Alberti, Lauren A; Bowman, Brandi N; Kerwin, Audra A; Wilkerson, Jenny L; Moezzi, Daniel R; Limanovich, Eugene; Wallace, James A; Milligan, Erin D
Peri-spinal subarachnoid (intrathecal; i.t.) injection of non-viral naked plasmid DNA encoding the anti-inflammatory cytokine, IL-10 (pDNA-IL-10) suppresses chronic neuropathic pain in animal models. However, two sequential i.t. pDNA injections are required within a discrete 5 to 72-hour period for prolonged efficacy. Previous reports identified phagocytic immune cells present in the peri-spinal milieu surrounding the i.t injection site that may play a role in transgene uptake resulting in subsequent IL-10 transgene expression. In the present study, we aimed to examine whether factors known to induce pro-phagocytic anti-inflammatory properties of immune cells improve i.t. IL-10 transgene uptake using reduced naked pDNA-IL-10 doses previously determined ineffective. Both the synthetic glucocorticoid, dexamethasone, and the hexose sugar, D-mannose, were factors examined that could optimize i.t. pDNA-IL-10 uptake leading to enduring suppression of neuropathic pain as assessed by light touch sensitivity of the rat hindpaw (allodynia). Compared to dexamethasone, i.t. mannose pretreatment significantly and dose-dependently prolonged pDNA-IL-10 pain suppressive effects, reduced spinal IL-1β and enhanced spinal and dorsal root ganglia IL-10 immunoreactivity. Macrophages exposed to D-mannose revealed reduced proinflammatory TNF-α, IL-1β, and nitric oxide, and increased IL-10 protein release, while IL-4 revealed no improvement in transgene uptake. Separately, D-mannose dramatically increased pDNA-derived IL-10 protein release in culture supernatants. Lastly, a single i.t. co-injection of mannose with a 25-fold lower pDNA-IL-10 dose produced prolonged pain suppression in neuropathic rats. Peri-spinal treatment with D-mannose may optimize naked pDNA-IL-10 transgene uptake for suppression of allodynia, and is a novel approach to tune spinal immune cells toward pro-phagocytic phenotype for improved non-viral gene therapy.
McDonald, Scott A; Innes, Hamish A; Hayes, Peter C; Dillon, John F; Mills, Peter R; Goldberg, David J; Barclay, Stephen; Allen, Sam; Fox, Ray; Fraser, Andrew; Kennedy, Nicholas; Bhattacharyya, Diptendu; Hutchinson, Sharon J
The global burden associated with hepatitis C virus (HCV) infection has prompted a scale-up of antiviral therapy. Hitherto, no data exist on the impact of scaling-up, on the characteristics of treated populations, or on sustained viral response (SVR) rates. We assessed the country-wide scale-up of antiviral therapy in Scotland, a country which nationally monitors uptake of and response to HCV treatment. Data for patients, initiated on combined pegylated interferon and ribavirin therapy at 13 specialist HCV clinics in 2001-2010, were extracted from the Scottish HCV Clinical Database (n=3895). Patient characteristics included age, genotype, PWID (people who inject drugs) status, prison referral, and diagnosed cirrhosis. Temporal trends in covariates and adjusted effects on a SVR were examined via mixed-effects regression. The number of patients starting treatment increased from 237 in 2001-2002 to 1560 in 2009-2010, with an increasing trend in SVR from 44% to 57% over this period. For a given clinic, between 2001/2 and 2010 there was a decrease in the odds of those treated being diagnosed with cirrhosis (odds ratio [OR]=0.84 per year), and increasing temporal trends for those treated being PWID (OR=1.08) and prison referrals (OR=1.06). Adjusting for covariates, the proportion of a given clinic's patients achieving SVR was positively associated with the percentage of PWID (OR=1.01 per percent increase; 95% confidence interval [CI]: 1.00-1.02) and genotype 2/3 (OR=1.03; 95% CI: 1.02-1.04). Despite changes in patient characteristics, a country-wide scale-up of antiviral therapy did not compromise SVR rates. Results are highly relevant to countries planning on scaling-up treatment, given the forthcoming availability of new interferon-free therapies. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
The work studies the viral marketing. These are past viral campaigns, viral campaigns today, and evaluates their actuality. The work tries to predict the development of viral marketing on the basis of the research done by the author.
Mintken, Paul E; McDevitt, Amy W; Cleland, Joshua A; Boyles, Robert E; Beardslee, Amber R; Burns, Scott A; Haberl, Matthew D; Hinrichs, Lauren A; Michener, Lori A
Study Design Multicenter randomized controlled trial. Background Cervicothoracic manual therapy has been shown to improve pain and disability in individuals with shoulder pain, but the incremental effects of manual therapy in addition to exercise therapy have not been investigated in a randomized controlled trial. Objectives To compare the effects of cervicothoracic manual therapy and exercise therapy to those of exercise therapy alone in individuals with shoulder pain. Methods Individuals (n = 140) with shoulder pain were randomly assigned to receive 2 sessions of cervicothoracic range-of-motion exercises plus 6 sessions of exercise therapy, or 2 sessions of high-dose cervicothoracic manual therapy and range-of-motion exercises plus 6 sessions of exercise therapy (manual therapy plus exercise). Pain and disability were assessed at baseline, 1 week, 4 weeks, and 6 months. The primary aim (treatment group by time) was examined using linear mixed-model analyses and the repeated measure of time for the Shoulder Pain and Disability Index (SPADI), the numeric pain-rating scale, and the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH). Patient-perceived success was assessed and analyzed using the global rating of change (GROC) and the Patient Acceptable Symptom State (PASS), using chi-square tests of independence. Results There were no significant 2-way interactions of group by time or main effects by group for pain or disability. Both groups improved significantly on the SPADI, numeric pain-rating scale, and QuickDASH. Secondary outcomes of success on the GROC and PASS significantly favored the manual therapy-plus-exercise group at 4 weeks (P = .03 and Pmanual therapy to an exercise program did not improve pain or disability in patients with shoulder pain, but did improve patient-perceived success at 4 weeks and 6 months and acceptability of symptoms at 4 weeks. More research is needed on the use of cervicothoracic manual
Melissa Karina Pupin; Adriana Gut Lopes Riccetto; José Dirceu Ribeiro; Emílio Carlos Elias Baracat
OBJETIVO: Comparar os efeitos das técnicas de aumento do fluxo expiratório (AFE) e vibração associada à drenagem postural (DP) nos parâmetros cardiorrespiratórios de frequência cardíaca (FC), frequência respiratória (FR) e SpO2 de lactentes com bronquiolite viral aguda (BVA). MÉTODOS: Foram analisados lactentes com diagnóstico clínico e radiológico de BVA. A FC, FR e SpO2 foram registradas em quatro tempos: antes do procedimento e após 10, 30 e 60 min do término do procedimento. Os pacientes ...
Maclachlan, N James; Mayo, Christie E
Bluetongue (BT) is a non-zoonotic arboviral disease of certain wild and domestic species of cloven-hoofed ungulates. The causative agent, bluetongue virus (BTV), is spread through temperate and tropical regions of the world by biting Culicoides midges. Control of BTV infection is complicated by the plurality of virus serotypes and the ubiquity and opportunistic feeding behavior of its midge vector. The global distribution of BTV infection has recently altered, perhaps driven in part by climatic influences on midge species resident in different regions. The goal of this review is to evaluate realistic strategies that might be utilized to control or prevent future outbreaks of BT and other Culicoides-transmitted diseases. Importantly, optimal control of emerging, rapidly evolving arbovirus diseases such as BT will require integrated countermeasures that mitigate all aspects of the virus's transmission cycle. This will best be accomplished using preventative, rather than purely reactive strategies. Copyright © 2013 Elsevier B.V. All rights reserved.
Lebbink, Robert Jan; de Jong, Dorien C M; Wolters, Femke; Kruse, Elisabeth M; van Ham, Petra M; Wiertz, Emmanuel J H J; Nijhuis, Monique
HIV presents one of the highest evolutionary rates ever detected and combination antiretroviral therapy is needed to overcome the plasticity of the virus population and control viral replication. Conventional treatments lack the ability to clear the latent reservoir, which remains the major obstacle
Soo Jeong Choi
Conclusion: FIR therapy improved needling pain. Although FIR therapy improved Qa, the unassisted patency was not different compared with the control. A larger and multicenter study is needed to evaluate the effect of FIR therapy.
Jørgensen, K T; Wiik, A; Pedersen, M
To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA).......To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA)....
Burdette, E. Clif; Lichtenstiger, Carol; Rund, Laurie; Keralapura, Mallika; Gossett, Chad; Stahlhut, Randy; Neubauer, Paul; Komadina, Bruce; Williams, Emery; Alix, Chris; Jensen, Tor; Schook, Lawrence; Diederich, Chris J.
Heat therapy has long been used for treatments in dermatology and sports medicine. The use of laser, RF, microwave, and more recently, ultrasound treatment, for psoriasis, collagen reformation, and skin tightening has gained considerable interest over the past several years. Numerous studies and commercial devices have demonstrated the efficacy of these methods for treatment of skin disorders. Despite these promising results, current systems remain highly dependent on operator skill, and cannot effectively treat effectively because there is little or no control of the size, shape, and depth of the target zone. These limitations make it extremely difficult to obtain consistent treatment results. The purpose of this study was to determine the feasibility for using acoustic energy for controlled dose delivery sufficient to produce collagen modification for the treatment of skin tissue in the dermal and sub-dermal layers. We designed and evaluated a curvilinear focused ultrasound device for treating skin disorders such as psoriasis, stimulation of wound healing, tightening of skin through shrinkage of existing collagen and stimulation of new collagen formation, and skin cancer. Design parameters were examined using acoustic pattern simulations and thermal modeling. Acute studies were performed in 201 freshly-excised samples of young porcine underbelly skin tissue and 56 in-vivo treatment areas in 60- 80 kg pigs. These were treated with ultrasound (9-11MHz) focused in the deep dermis. Dose distribution was analyzed and gross pathology assessed. Tissue shrinkage was measured based on fiducial markers and video image registration and analyzed using NIH Image-J software. Comparisons were made between RF and focused ultrasound for five energy ranges. In each experimental series, therapeutic dose levels (60degC) were attained at 2-5mm depth. Localized collagen changes ranged from 1-3% for RF versus 8-15% for focused ultrasound. Therapeutic ultrasound applied at high
Virologic response to tipranavir-ritonavir or darunavir-ritonavir based regimens in antiretroviral therapy experienced HIV-1 patients: a meta-analysis and meta-regression of randomized controlled clinical trials.
Full Text Available The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative, Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI for viral loads of <50 copies and <400 copies HIV RNA/ml at the end of the intervention were determined by the random effects model. Meta-regression, sensitivity analysis and funnel plots were done. The number of HIV-1 patients who were on either a tipranavir-ritonavir or darunavir-ritonavir based regimen and achieved viral load less than 50 copies HIV RNA/ml was significantly higher (overall OR = 3.4; 95% CI, 2.61-4.52 than the number of HIV-1 patients who were on investigator selected boosted comparator HIV-1 protease inhibitors (CPIs-ritonavir. Similarly, the number of patients with viral load less than 400 copies HIV RNA/ml was significantly higher in either the tipranavir-ritonavir or darunavir-ritonavir based regimen treated group (overall OR = 3.0; 95% CI, 2.15-4.11. Meta-regression showed that the viral load reduction was independent of baseline viral load, baseline CD4 count and duration of tipranavir-ritonavir or darunavir-ritonavir based regimen.Tipranavir and darunavir based regimens were more effective in patients who were ART experienced and had poor viral load control. Further studies are required to determine their consistent
Erkkilä, Jaakko; Punkanen, Marko; Fachner, Jörg; Ala-Ruona, Esa; Pöntiö, Inga; Tervaniemi, Mari; Vanhala, Mauno; Gold, Christian
Music therapy has previously been found to be effective in the treatment of depression but the studies have been methodologically insufficient and lacking in clarity about the clinical model employed...
randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional. Therapy Group. N Engl J Med 1990; 323: 295-301. 14. Ncayiyana DJ. Coming to grips with the future of health care - the ANC National. Health Plan. 5 Air Med J 1994; ...
Zhao, Yuan; Stepto, Hannah; Schneider, Christian K
Gene therapy is a rapidly evolving field. So far, there have been >2,400 gene therapy products in clinical trials and four products on the market. A prerequisite for producing gene therapy products is ensuring their quality and safety. This requires appropriately controlled and standardized production and testing procedures that result in consistent safety and efficacy. Assuring the quality and safety of lentivirus-based gene therapy products in particular presents a great challenge because they are cell-based multigene products that include viral and therapeutic proteins as well as modified cells. In addition to the continuous refinement of a product, changes in production sites and manufacturing processes have become more and more common, posing challenges to developers regarding reproducibility and comparability of results. This paper discusses the concept of developing a first World Health Organization International Standard, suitable for the standardization of assays and enabling comparison of cross-trial and cross-manufacturing results for this important vector platform. The standard will be expected to optimize the development of gene therapy medicinal products, which is especially important, given the usually orphan nature of the diseases to be treated, naturally hampering reproducibility and comparability of results. PMID:28747142
Guy, Rebecca; Lambert, Stephen; Kelly, Heath
To estimate influenza vaccine effectiveness (VE) from an outbreak of influenza A in an aged care facility in which neuraminidase inhibitors were used as part of outbreak control measures. The outbreak occurred between 25 December 2001 and 21 January 2002. Neuraminidase inhibitors were used to control the outbreak. Residents and staff with respiratory symptoms were tested for influenza using RT-PCR and/or serology. Vaccine effectiveness (VE) was estimated for the prevention of laboratory-confirmed influenza. Nineteen of 42 (45%) residents and four of 29 (14%) staff were laboratory-confirmed as cases. The outbreak was caused by an influenza A (H3N2) strain, antigenically matched to that season's vaccine. The VE for preventing laboratory-confirmed influenza infection was 61% (95% CI 41-73) among residents and 100% (95% CI 63-100) among staff. The VE estimates calculated from this outbreak were consistent with other published results. Outbreaks of influenza in institutions provide a good opportunity to review influenza VE, but use of antiviral medications as control measures may affect interpretation of findings.
Swati P Ahir
Full Text Available Background & objectives: Mother-to-child transmission (MTCT is the most significant route of HIV transmission in children below the age of 15 yr. In India, perinatal HIV transmission, even after treatment, accounts for 5.4 per cent of HIV cases. The present study was conducted to evaluate the efficacy of anti-retro viral therapy (ART or prophylactic treatment (PT to control maternal viral load in HIV positive women, and its effect on vertical HIV transmission to their infants. Methods: A total of 58 HIV positive women were enrolled at the time of delivery and their plasma samples were obtained within 24 h of delivery for estimation of viral load. Viral load analysis was completed in 38 women. Infants received single dose nevirapine within 2 h of birth and zidovudine for 6 wk. At the end of 18 month follow up, HIV positive or negative status was available in 28 infants. Results: Results revealed undetectable levels of viral load in 58.3 per cent of women with ART compared to 30.7 per cent of women with PT. No women on ART had viral load more than 10,000 copies/ml, whereas seven (26.9%, P=0.07 women receiving PT had this viral load. Median CD4 count of women on PT (483 cells/μl was high compared to the women on ART (289 cells/ μl. At the end of 18 months follow up, only two children were HIV positive, whose mothers were on PT. One had in utero transmission; infection detected within 48 h of delivery, while the other child was infected post partum as HIV was detected at six months follow up. Interpretation & conclusions: Women who received a single dose of nevirapine during delivery had higher levels of viral load than women on ART. Combination drug therapy for pregnant women is now a standard of care in most of the western countries; use of nevirapine monotherapy at the time of delivery in our settings is not effective in controlling viral load. This highlights initiation of ART in pregnant women to control their viral load and thus to inhibit
HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition.
Miura, Toshiyuki; Brockman, Mark A; Schneidewind, Arne; Lobritz, Michael; Pereyra, Florencia; Rathod, Almas; Block, Brian L; Brumme, Zabrina L; Brumme, Chanson J; Baker, Brett; Rothchild, Alissa C; Li, Bin; Trocha, Alicja; Cutrell, Emily; Frahm, Nicole; Brander, Christian; Toth, Ildiko; Arts, Eric J; Allen, Todd M; Walker, Bruce D
Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag(240-249) TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.
Flexman, Jennifer A.; Cross, Donna J.; Lewellen, Barbara L.; Miyoshi, Sosuke; Kim, Yongmin
Gene and drug therapy for organ-specific diseases in part depends on the efficient delivery to a particular region of the body. We examined the biodistribution of a viral envelope commonly used as a nanoscale gene delivery vehicle using positron emission tomography (PET) and investigated the magnetic alteration of its biodistribution. Iron oxide nanoparticles and 18 F-fluoride were encapsulated by hemagglutinating virus of Japan envelopes (HVJ-Es). HVJ-Es were then injected intravenously in the rat and imaged dynamically using high-resolution PET. Control subjects received injections of encapsulated materials alone. For magnetic targeting, permanent magnets were fixed on the head during the scan. Based on the quantitative analysis of PET images, HVJ-Es accumulated in the liver and spleen and activity remained higher than control subjects for 2 h. Histological sections of the liver confirmed imaging findings. Pixel-wise activity patterns on coregistered PET images of the head showed a significantly different pattern for the subjects receiving magnetic targeting as compared to all control groups. Imaging demonstrated the initial biodistribution of a viral envelope within the rodent by providing quantitative behavior over time and in specific anatomical regions. Magnetic force altered the biodistribution of the viral envelope to a target structure, and could enable region-specific delivery of therapeutic vehicles noninvasively. PMID:18779103
Karagülle, Mine; Kardeş, Sinan; Dişçi, Rian; Karagülle, Müfit Zeki
This study aims to investigate whether 2-week spa therapy, as an adjunct to usual pharmacological therapy, has any beneficial effect in patients with rheumatoid arthritis (RA). In this single-blind crossover study, 50 patients were randomly assigned in a 1:1 manner to receive usual pharmacological therapy plus 2-week spa therapy or usual pharmacological therapy alone (period 1.6 months); after a 9-month washout, patients were crossed over to the opposite assignment (period 2.6 months). Spa therapy program included a daily saline balneotherapy session at 36-37 °C for 20 min except Sundays. The clinical outcomes were evaluated at baseline, after spa therapy (2 weeks) and 3 and 6 months after the spa therapy in both period and were pain (Visual Analogue Scale (VAS)), patient and physician global assessments (VAS), Health Assessment Questionnaire (HAQ), and Disease Activity Score (DAS28). Spa therapy was superior to control therapy in improving all the assessed clinical outcomes at the end of the spa therapy. This superiority persisted significantly in physician global assessment (p = 0.010) and with a trend in favor of spa group in patient global assessment (p = 0.058), function (p = 0.092), and disease activity (p = 0.098) at 3 months. Statistically significant improvements were found in spa therapy compared to control in disease activity (p = 0.006) and patient (p = 0.020) and physician global (p = 0.011) assessments, and a trend toward improvements in pain (p = 0.069) and swollen joints (p = 0.070) at 6 months. A 2-week spa therapy adjunct to usual pharmacological therapy provided beneficial clinical effects compared to usual pharmacological therapy alone, in RA patients treated with traditional disease-modifying antirheumatic drugs. These beneficial effects may last for 6 months.
Erkkilä, Jaakko; Punkanen, Marko; Fachner, Jörg; Ala-Ruona, Esa; Pöntiö, Inga; Tervaniemi, Mari; Vanhala, Mauno; Gold, Christian
Music therapy has previously been found to be effective in the treatment of depression but the studies have been methodologically insufficient and lacking in clarity about the clinical model employed. Aims To determine the efficacy of music therapy added to standard care compared with standard care only in the treatment of depression among working-age people. Participants (n = 79) with an ICD-10 diagnosis of depression were randomised to receive individual music therapy plus standard care (20 bi-weekly sessions) or standard care only, and followed up at baseline, at 3 months (after intervention) and at 6 months. Clinical measures included depression, anxiety, general functioning, quality of life and alexithymia. ISRCTN84185937. Participants receiving music therapy plus standard care showed greater improvement than those receiving standard care only in depression symptoms (mean difference 4.65, 95% CI 0.59 to 8.70), anxiety symptoms (1.82, 95% CI 0.09 to 3.55) and general functioning (-4.58, 95% CI -8.93 to -0.24) at 3-month follow-up. The response rate was significantly higher for the music therapy plus standard care group than for the standard care only group (odds ratio 2.96, 95% CI 1.01 to 9.02). Individual music therapy combined with standard care is effective for depression among working-age people with depression. The results of this study along with the previous research indicate that music therapy with its specific qualities is a valuable enhancement to established treatment practices.
Cohorte Agence Nationale de Recherches sur le SIDA EP 11 study. J Infect Dis 186: 710–714. 8. Hermankova M, Ray SC, Ruff C, Powell-Davis M, Ingersoll R, et...malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine
Waldenström, Jesper; Westin, Johan; Nyström, Kristina
In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naïve patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-α (pegIFN-α), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-α, or (iii) standard-of-care (...
Hermanides, J; Nørgaard, K; Bruttomesso, D
To investigate the efficacy of sensor-augmented pump therapy vs. multiple daily injection therapy in patients with suboptimally controlled Type 1 diabetes.......To investigate the efficacy of sensor-augmented pump therapy vs. multiple daily injection therapy in patients with suboptimally controlled Type 1 diabetes....
Malbos, Eric; Rapee, Ronald M; Kavakli, Manolya
Past controlled clinical trials centred on virtual reality exposure therapy (VRET) for agoraphobia mostly used multicomponent therapy with success. However, the present paper aimed to evaluate the independent effect of VRET for agoraphobia. A controlled study involving 18 agoraphobic participants assigned to two groups: VRET only and VRET with cognitive therapy. Nine specific virtual environments were developed using an affordable game level editor. Questionnaires, behavioural tests and physiological measures indicated a positive effect of VRET. Correlations supported the predictive value of presence towards treatment outcome. The addition of cognitive therapy did not provide significant additional benefit. Overall, the isolated effects of VRET did not seem to be significantly less than the effects of VRET combined with cognitive therapy. Future research should explore the use of other components in addition to cognitive therapy and VRET for agoraphobia as well as its possible use in patients' homes.
Batista, G; Buvé, A; Ngom Gueye, N F; Manga, N M; Diop, M N; Ndiaye, K; Thiam, A; Ly, F; Diallo, A; Ndour, C T; Seydi, M
We determined the risk factors and incidence of clinical events associated with suboptimal immune reconstitution (SIR) defined by an increase in CD4 inferior to 50 cells/μL, from inclusion up to six months of antiretroviral treatment (ARVT), in patients with an undetectable viral load ( 40 years (aOR = 1.74, 95% CI = 1.10-2.75), baseline CD4 ≥ 100 cells/μL (aOR = 2.06, 95% CI = 1.24-3.42), ARVT including AZT (aOR = 4.57, 95% CI=1.06-19.76), and the occurrence of a severe opportunistic infection during the first semester of ARVT (aOR = 2.38 95% CI= 1.49-3.80) were associated with SIR. After six months of ARVT and up to seven years of follow-up, 39 patients with SIR had presented with an opportunistic infection or death (rate= 9.78/100 person-years) compared to 168 with a normal recovery (rate = 7.75/100 person-years) but the difference was not statistically significant (aHR = 1.22, 95% CI = 0.85 to 1.74). SIR is less common in our country and is not associated with increased mortality or a greater incidence of opportunistic infections after six months of ARVT. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
D'Orsogna, Maria R.
Successful viral infection of a healthy cell requires complex host-pathogen interactions. In this talk we focus on the dynamics specific to the HIV virus entering a eucaryotic cell. We model viral entry as a stochastic engagement of receptors and coreceptors on the cell surface. We also consider the transport of virus material to the cell nucleus by coupling microtubular motion to the concurrent biochemical transformations that render the viral material competent for nuclear entry. We discuss both mathematical and biological consequences of our model, such as the formulation of an effective integrodifferential boundary condition embodying a memory kernel and optimal timing in maximizing viral probabilities.
Bossak, Brian H; Welford, Mark R
Recent research into the world's greatest recorded epidemic, the Medieval Black Death (MBD), has cast doubt on Bubonic Plague as the etiologic agent. Prior research has recently culminated in outstanding advances in our understanding of the spatio-temporal pattern of MBD mortality, and a characterization of the incubation, latent, infectious, and symptomatic periods of the MBD. However, until now, several mysteries remained unexplained, including perhaps the biggest quandary of all: why did the MBD exhibit inverse seasonal peaks in mortality from diseases recorded in modern times, such as seasonal Influenza or the Indian Plague Epidemics of the early 1900 s? Although some have argued that climate changes likely explain the observed differences between modern clinical Bubonic Plague seasonality and MBD mortality accounts, we believe that another factor explains these dissimilarities. Here, we provide a synthetic hypothesis which builds upon previous theories developed in the last ten years or so. Our all-encompassing theory explains the causation, dissemination, and lethality of the MBD. We theorize that the MBD was a human-to-human transmitted virus, originating in East-Central Asia and not Africa (as some recent work has proposed), and that its areal extent during the first great epidemic wave of 1347-1350 was controlled hierarchically by proximity to trade routes. We also propose that the seasonality of medieval trade controlled the warm-weather mortality peaks witnessed during 1347-1350; during the time of greatest market activity, traders, fairgoers, and religious pilgrims served as unintentional vectors of a lethal virus with an incubation period of approximately 32 days, including a largely asymptomatic yet infectious period of roughly three weeks. We include a description of the rigorous research agenda that we have proposed in order to subject our theory to scientific scrutiny and a description of our plans to generate the first publicly available
Sharma, Bhagwan S; Gupta, Mukesh K; Rafik, Shaikh P
To compare the length of hospital stay (primary) and improvement in clinical severity scores (secondary) among children with bronchiolitis nebulized with 3 % hypertonic saline or 0.9% saline. Randomized double blind controlled trial. Tertiary care teaching hospital. Hospitalized children (1-24 months) with acute bronchiolitis of moderate severity. Nebulization of 4 ml of 3% hypertonic saline or 4 mL of 0.9% saline, along with 2.5 mg salbutamol, at 4-hourly intervals till the patient was ready for discharge. Baseline characteristics were similar in two groups. Median clinical severity score at admission was 6 (IQR-1) in both the groups. Clinical severity scores monitored afterwards 12-hourly till discharge (132 h) did not show statistically significant differences in 3% and 0.9% saline groups. Mean length of hospital stay (time to reach predefined clinical severity scoresaline group and 63.51 ± 21.27 h in 0.9% saline group (P=0.878). No adverse events were reported by the parents, caregivers or treating medical attendants in both groups. Nebulized 3 % saline is not superior to 0.9% saline in infants with clinically diagnosed acute bronchiolitis.
Baxter G David
Full Text Available Abstract Background Non-pharmacological, non-surgical interventions are recommended as the first line of treatment for osteoarthritis (OA of the hip and knee. There is evidence that exercise therapy is effective for reducing pain and improving function in patients with knee OA, some evidence that exercise therapy is effective for hip OA, and early indications that manual therapy may be efficacious for hip and knee OA. There is little evidence as to which approach is more effective, if benefits endure, or if providing these therapies is cost-effective for the management of this disorder. The MOA Trial (Management of OsteoArthritis aims to test the effectiveness of two physiotherapy interventions for improving disability and pain in adults with hip or knee OA in New Zealand. Specifically, our primary objectives are to investigate whether: 1. Exercise therapy versus no exercise therapy improves disability at 12 months; 2. Manual physiotherapy versus no manual therapy improves disability at 12 months; 3. Providing physiotherapy programmes in addition to usual care is more cost-effective than usual care alone in the management of osteoarthritis at 24 months. Methods This is a 2 × 2 factorial randomised controlled trial. We plan to recruit 224 participants with hip or knee OA. Eligible participants will be randomly allocated to receive either: (a a supervised multi-modal exercise therapy programme; (b an individualised manual therapy programme; (c both exercise therapy and manual therapy; or, (d no trial physiotherapy. All participants will continue to receive usual medical care. The outcome assessors, orthopaedic surgeons, general medical practitioners, and statistician will be blind to group allocation until the statistical analysis is completed. The trial is funded by Health Research Council of New Zealand Project Grants (Project numbers 07/199, 07/200. Discussion The MOA Trial will be the first to investigate the effectiveness and cost
Evans, ME; Jordan, CT; Chang, SMW; Conrad, C; Gerberding, JL; Kaufman, HL; Mayhall, CG; Nolta, JA; Pilaro, AM; Sullivan, S; Weber, DJ; Wivel, NA
Gene therapy is being studied for the treatment of a variety of acquired and inherited disorders. Retroviruses, adenoviruses, poxviruses, adeno-associated viruses, herpesviruses, and others are being engineered to transfer genes into humans. Treatment protocols using recombinant viruses are being
Despite the lack of English literature about Traditional Chinese Medicine (TCM) food therapy, there is abundant Chinese literature about the application of food therapy for hypertension control. This paper summarizes basic concepts of TCM, the principles of food therapy and its application for hypertension control according to Chinese literature. In TCM, food is conceptualized according to both nutritional and functional aspects, and can be used to treat illnesses. Four principles of TCM food therapy including light eating, balancing the "hot" and "cold" nature of food, the harmony of the five flavors of food, and consistency between dietary intake and different health conditions, can be used to facilitate hypertension control. Based on a statistical analysis of antihypertensive foods recommended in 20 books on the application of food therapy for hypertension control, the 38 most frequently recommended are celery, tomato, banana, hawthorn, garlic, onion, seaweed, apple, corn, green beans, persimmon, laver, kiwi, watermelon, eggplant, carrots, mushroom, peanut, soy products, sea cucumber, buckwheat, garland chrysanthemum, spinach, honey, dairy products, vinegar, black fungus, jellyfish, green onion, shepherd's purse, soybean, potato, pear, winter melon, bitter melon, oat, pea, and tea. Food therapy emphasizes the therapeutic effects of food, considering its nature, taste, and function on human balanced health, which leads to optimal blood pressure control. Current literature suggests that food therapy is effective in blood pressure control and can be incorporated into blood pressure self-management in the Chinese population.
Full Text Available El Perú está catalogado como un país de mediana endemicidad para la infección por la hepatitis B (HBV, sin embargo, esta enfermedad se está dispersando en el país por la intensa migración de áreas de alta endemicidad a zonas de baja que endemicidad. Además de los mecanismos clásicos de transmisión de la infección como la vía parenteral y la vía sexual, debe destacarse la transmisión horizontal sobre todo en población infantil de áreas hiperendémicas y la limitada ocurrencia de transmisión vertical a diferencia de Asia. Desde que se cuenta con una vacuna segura y eficaz contra la HBV, se ha desarrollado programas de vacunación piloto en el país, luego de lo cual se ha generalizado la inmunización de la población infantil primero de áreas endémicas y luego a todo el país, según la prioridad y disponibilidad de vacunas. Dada la dispersión de la infección, y para lograr un efectivo control del problema en personas susceptibles, en un menor tiempo, es necesaria la inmunización contra HBV de adolescentes, jóvenes y grupos de riesgo, intervención que es una de las más costo-efectivas en salud pública, mereciendo en el mediano y largo plazo la evaluación de su real impacto. Estos temas son los que se desarrollan en la presente revisión.
Full Text Available The macroautophagy machinery has been implicated in MHC class II restricted antigen presentation. Here, we report that this machinery assists in the internalization of MHC class I molecules. In the absence of the autophagy factors Atg5 and Atg7, MHC class I surface levels are elevated due to decreased endocytosis and degradation. Internalization of MHC class I molecules occurs less efficiently if AAK1 cannot be recruited via Atg8/LC3B. In the absence of Atg-dependent MHC class I internalization, dendritic cells stimulate CD8+ T cell responses more efficiently in vitro and in vivo. During viral infections, lack of Atg5 results in enhanced influenza- and LCMV-specific CD8+ T cell responses in vivo. Elevated influenza-specific CD8+ T cell responses are associated with better immune control of this infection. Thus, the macroautophagy machinery orchestrates T cell immunity by supporting MHC class II but compromises MHC class I restricted antigen presentation.
de Betue, Carlijn T; van Waardenburg, Dick A; Deutz, Nicolaas E; van Eijk, Hans M; van Goudoever, Johannes B; Luiking, Yvette C; Zimmermann, Luc J; Joosten, Koen F
Objective The preservation of nutritional status and growth is an important aim in critically ill infants, but difficult to achieve due to the metabolic stress response and inadequate nutritional intake, leading to negative protein balance. This study investigated whether increasing protein and energy intakes can promote anabolism. The primary outcome was whole body protein balance, and the secondary outcome was first pass splanchnic phenylalanine extraction (SPEPhe). Design This was a double-blind randomised controlled trial. Infants (n=18) admitted to the paediatric intensive care unit with respiratory failure due to viral bronchiolitis were randomised to continuous enteral feeding with protein and energy enriched formula (PE-formula) (n=8; 3.1±0.3 g protein/kg/24 h, 119±25 kcal/kg/24 h) or standard formula (S-formula) (n=10; 1.7±0.2 g protein/kg/24 h, 84±15 kcal/kg/24 h; equivalent to recommended intakes for healthy infants anabolism in critically ill infants in the first days after admission. Since this is an important target of nutritional support, increased protein and energy intakes should be preferred above standard intakes in these infants. Dutch Trial Register number: NTR 515. PMID:21673183
de Betue, Carlijn T; van Waardenburg, Dick A; Deutz, Nicolaas E; van Eijk, Hans M; van Goudoever, Johannes B; Luiking, Yvette C; Zimmermann, Luc J; Joosten, Koen F
The preservation of nutritional status and growth is an important aim in critically ill infants, but difficult to achieve due to the metabolic stress response and inadequate nutritional intake, leading to negative protein balance. This study investigated whether increasing protein and energy intakes can promote anabolism. The primary outcome was whole body protein balance, and the secondary outcome was first pass splanchnic phenylalanine extraction (SPE(Phe)). This was a double-blind randomised controlled trial. Infants (n=18) admitted to the paediatric intensive care unit with respiratory failure due to viral bronchiolitis were randomised to continuous enteral feeding with protein and energy enriched formula (PE-formula) (n=8; 3.1 ± 0.3 g protein/kg/24 h, 119 ± 25 kcal/kg/24 h) or standard formula (S-formula) (n=10; 1.7 ± 0.2 g protein/kg/24 h, 84 ± 15 kcal/kg/24 h; equivalent to recommended intakes for healthy infants anabolism in critically ill infants in the first days after admission. Since this is an important target of nutritional support, increased protein and energy intakes should be preferred above standard intakes in these infants. Dutch Trial Register number: NTR 515.
Pierce, Lindsey R; Willey, James C; Crawford, Erin L; Palsule, Vrushalee V; Leaman, Douglas W; Faisal, Mohamed; Kim, Robert K; Shepherd, Brian S; Stanoszek, Lauren M; Stepien, Carol A
Viral Hemorrhagic Septicemia virus (VHSv) causes one of the world's most important finfish diseases, killing >80 species across Eurasia and North America. A new and especially virulent strain (IVb) emerged in the North American Great Lakes in 2003, threatening fisheries, baitfish, and aquaculture industries. Weeks-long and costly cell culture is the OIE and USDA-APHIS approved diagnostic. A new Standardized Reverse Transcriptase Polymerase Chain Reaction (StaRT-PCR) assay that uniquely incorporates internal standards to improve accuracy and prevent false negatives was developed and evaluated for its ability to detect and quantify VHSv. Results from StaRT-PCR, SYBR(®) green real time qRT-PCR, and cell culture were compared, as well as the effects of potential PCR inhibitors (EDTA and high RNA). Findings show that StaRT-PCR is sensitive, detecting a single molecule, with 100% accuracy at six molecules, and had no false negatives. In comparison, false negatives ranged from 14 to 47% in SYBR(®) green real time qRT-PCR tests, and 47-70% with cell culture. StaRT-PCR uniquely controlled for EDTA and RNA interference. Range of VHSv quantitation by StaRT-PCR was 1.0×10(0)-1.2×10(5) VHSv/10(6)actb1 molecules in wild caught fishes and 1.0×10(0)-8.4×10(5) molecules in laboratory challenged specimens. In the latter experiments, muskellunge with skin lesions had significantly more viral molecules (mean=1.9×10(4)) than those without (1.1×10(3)) (p<0.04). VHSv infection was detected earlier in injection than in immersion challenged yellow perch (two versus three days), with molecule numbers in both being comparable and relatively consistent over the remaining course of the experiment. Our results show that the StaRT-PCR test accurately and reliably detects and quantifies VHSv. Copyright © 2013 Elsevier B.V. All rights reserved.
Voigt-Radloff, S; Ruf, G.; Vogel, A.; van Nes, F.; Hüll, M.
OBJECTIVE: Previous systematic reviews on occupational therapy for elderly included studies until 2003. The present evidence mapping summarizes recent evidence for the efficacy of occupational therapy with older persons based on randomised controlled trials from 2004-2012. METHOD: An electronic
Kaufmann, Daniel; Burri, Christian; Arnold, Patrik; Koch, Volker M.; Meier, Christoph; Považay, Boris; Justiz, Joern
Selective retina therapy and optical coherence tomography have been combined to monitor laser-tissue interaction in real-time. An ex-vivo study of porcine eyes unveils mechanisms that enable automated and accurate dose-control during laser-therapy.
Mosepele, Mosepele; Hemphill, Linda C.; Moloi, Walter; Moyo, Sikhulile; Nkele, Isaac; Makhema, Joseph; Bennett, Kara,; Triant, Virginia A.; Lockman, Shahin
Objectives Human immune deficiency virus (HIV) is associated with increased cardiovascular disease (CVD) risk, yet the relationship between HIV and carotid atherosclerosis / monocyte activation among virally suppressed HIV-infected patients in sub-Saharan Africa is not well understood. Methods We measured traditional CVD risk factors, bilateral distal common carotid intima media thickness (cIMT), presence of carotid plaque and plasma sCD163 levels among virally suppressed HIV-infected adults ...
Parry, Ingrid; Painting, Lynda; Bagley, Anita; Kawada, Jason; Molitor, Fred; Sen, Soman; Greenhalgh, David G; Palmieri, Tina L
Commercially available, interactive videogames that use body movements for interaction are used clinically in burn rehabilitation and have been shown to facilitate functional range of motion (ROM) but their efficacy with burn patients has not yet been proven. The purpose of this pilot randomized control study was to prospectively compare planar and functional ROM, compliance, pain, enjoyment, and exertion in pediatric burn patients receiving two types of rehabilitation therapy. Seventeen school-aged children with 31 affected limbs who demonstrated limited shoulder ROM from burn injury were randomized to receive exercises using either standard therapy ROM activities (ST) or interactive videogame therapy (VGT). Patients received 3 weeks of the designated therapy intervention twice daily. They were then given a corresponding home program of the same type of therapy to perform regularly for 6 months. Standard goniometry and three-dimensional motion analysis during functional tasks were used to assess ROM. Measures were taken at baseline, 3 weeks, 3 months, and 6 months. Pain was measured before and after each treatment session during the 3-week intervention. There was no difference in compliance, enjoyment, or exertion between the groups. Patients in both the ST and VGT groups showed significant improvement in shoulder flexion (P videogames were equally effective as traditional therapy for overall ROM gains and resulted in quicker recovery of motion with less pain experienced. Such videogames are a useful adjunct to therapy and should be considered as part of a holistic approach to rehabilitation within the hospital and at home after discharge in pediatric patients recovering from burn injury.
Hvenegaard, Morten; Watkins, Ed R; Poulsen, Stig; Rosenberg, Nicole K; Gondan, Matthias; Grafton, Ben; Austin, Stephen F; Howard, Henriette; Moeller, Stine B
Cognitive behavioural therapy is an effective treatment for depression. However, one third of the patients do not respond satisfactorily, and relapse rates of around 30 % within the first post-treatment year were reported in a recent meta-analysis. In total, 30-50 % of remitted patients present with residual symptoms by the end of treatment. A common residual symptom is rumination, a process of recurrent negative thinking and dwelling on negative affect. Rumination has been demonstrated as a major factor in vulnerability to depression, predicting the onset, severity, and duration of future depression. Rumination-focused cognitive behavioural therapy is a psychotherapeutic treatment targeting rumination. Because rumination plays a major role in the initiation and maintenance of depression, targeting rumination with rumination-focused cognitive behavioural therapy may be more effective in treating depression and reducing relapse than standard cognitive behavioural therapy. This study is a two-arm pragmatic randomised controlled superiority trial comparing the effectiveness of group-based rumination-focused cognitive behaviour therapy with the effectiveness of group-based cognitive behavioural therapy for treatment of depression. One hundred twenty-eight patients with depression will be recruited from and given treatment in an outpatient service at a psychiatric hospital in Denmark. Our primary outcome will be severity of depressive symptoms (Hamilton Rating Scale for Depression) at completion of treatment. Secondary outcomes will be level of rumination, worry, anxiety, quality of life, behavioural activation, experimental measures of cognitive flexibility, and emotional attentional bias. A 6-month follow-up is planned and will include the primary outcome measure and assessment of relapse. The clinical outcome of this trial may guide clinicians to decide on the merits of including rumination-focused cognitive behavioural therapy in the treatment of depression in
Harvey, Allison G; Bélanger, Lynda; Talbot, Lisa; Eidelman, Polina; Beaulieu-Bonneau, Simon; Fortier-Brochu, Émilie; Ivers, Hans; Lamy, Manon; Hein, Kerrie; Soehner, Adriane M; Mérette, Chantal; Morin, Charles M
To examine the unique contribution of behavior therapy (BT) and cognitive therapy (CT) relative to the full cognitive behavior therapy (CBT) for persistent insomnia. Participants were 188 adults (117 women; M age = 47.4 years, SD = 12.6) with persistent insomnia (average of 14.5 years duration). They were randomized to 8 weekly, individual sessions consisting of BT (n = 63), CT (n = 65), or CBT (n = 60). Full CBT was associated with greatest improvements, the improvements associated with BT were faster but not as sustained and the improvements associated with CT were slower and sustained. The proportion of treatment responders was significantly higher in the CBT (67.3%) and BT (67.4%) relative to CT (42.4%) groups at post treatment, while 6 months later CT made significant further gains (62.3%), BT had significant loss (44.4%), and CBT retained its initial response (67.6%). Remission rates followed a similar trajectory, with higher remission rates at post treatment in CBT (57.3%) relative to CT (30.8%), with BT falling in between (39.4%); CT made further gains from post treatment to follow up (30.9% to 51.6%). All 3 therapies produced improvements of daytime functioning at both post treatment and follow up, with few differential changes across groups. Full CBT is the treatment of choice. Both BT and CT are effective, with a more rapid effect for BT and a delayed action for CT. These different trajectories of changes provide unique insights into the process of behavior change via behavioral versus cognitive routes. PsycINFO Database Record (c) 2014 APA, all rights reserved.
Prince, Jessica; Lundgren, Alyssa; Stadnisky, Michael D; Nash, William T; Beeber, Amira; Turner, Stephen D; Brown, Michael G
MHC class I D(k) and Ly49G2 (G2) inhibitory receptor-expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D(k), G2(+) NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G2, D(k) licenses G2(+) NK cells for effector activity. These data suggested that D(k)-licensed G2(+) NK cells might recognize and control MCMV infection. However, a role for licensed NK cells in viral immunity is uncertain. We combined classical genetics with flow cytometry to visualize the host response to MCMV. Immune cells collected from individuals of a diverse cohort of MA/My × C57L offspring segregating D(k) were examined before infection and postinfection, including Ly49(+) NK subsets, receptor expression features, and other phenotypic traits. To identify critical NK cell features, automated analysis of 110 traits was performed in R using the Pearson correlation, followed with a Bonferroni correction for multiple tests. Hierarchical clustering of trait associations and principal component analyses were used to discern shared immune response and genetic relationships. The results demonstrate that G2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G2(+) NK cell expansion following viral exposure occurred selectively in D(k) offspring; this response was more highly correlated with MCMV control than all other immune cell features. We infer that D(k)-licensed G2(+) NK cells efficiently detected missing-self MHC cues on viral targets, which elicited cellular expansion and target cell killing. Therefore, MHC polymorphism regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control.
Conget, Ignacio; Battelino, Tadej; Giménez, Marga
studies investigating the effect of real-time continuous glucose monitoring (CGM) combined with pump therapy on glycemic outcomes in type 1 diabetes are increasing. Pump therapy is well established as a "gold standard" for insulin delivery, offering improvements over multiple daily insulin...... injections. However, there is still a proportion of subjects using continuous subcutaneous insulin infusion in whom goals for metabolic control are far from achieved or benefits of this type of insulin therapy are transient. The SWITCH (Sensing With Insulin pump Therapy to Control HbA(1c) [hemoglobin A1c......]) study is a multicenter, randomized, controlled, crossover study to evaluate if adding CGM to experienced pump patients with suboptimal metabolic control will provide additional insight enabling clinical and therapeutic benefit....
Kongtragul, Jaruwan; Tukhanon, Wanvara; Tudpudsa, Piyanuch; Suedee, Kanita; Tienchai, Supaporn; Leewansangtong, Sunai; Nualgyong, Chaiyong
.... One hundred thirty five patients were randomized into the intervention group that concentration therapy was added to Kegel exercise, and control group that was Kegel exercise only, using the stratified randomization...
Kerkhof, P.C.M. van de
Psoriasis is a chronic, incurable disease that frequently requires long-term treatment. Although many patients benefit from effective traditional systemic therapies, namely methotrexate, cyclosporin, retinoids and fumaric acid esters, and some patients achieve long-term disease control, unrestricted
Full Text Available Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as
Toth, Karoly; Lee, Sang R; Ying, Baoling; Spencer, Jacqueline F; Tollefson, Ann E; Sagartz, John E; Kong, Il-Keun; Wang, Zhongde; Wold, William S M
Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models.
Background: Pestiviruses in general, and Bovine Viral Diarrhea (BVD) in particular, present several potential targets for directed antiviral therapy. Material and Methods: The antiviral effect of Cynanchum paniculatum (Bge.) Kitag (Dog strangling vine: DS) extract on the bovine viral diarrhea (BVD) virus was tested. First ...
Holzbach, Thomas; Vlaskou, Dialekti; Neshkova, Iva; Konerding, Moritz A; Wörtler, Klaus; Mykhaylyk, Olga; Gänsbacher, Bernd; Machens, H-G; Plank, Christian; Giunta, Riccardo E
Abstract Adenoviral transduction of the VEGF gene in an oversized skin flap increases flap survival and perfusion. In this study, we investigated the potential of magnetofection of magnetic lipospheres containing VEGF165-cDNA on survival and perfusion of ischemic skin flaps and evaluated the method with respect to the significance of applied magnetic field and ultrasound. We prepared perfluoropropane-filled magnetic lipospheres (‘magnetobubbles’) from Tween60-coated magnetic nanoparticles, Metafectene, soybean-oil and cDNA and studied the effect in an oversized random-pattern-flap model in the rats (n= 46). VEGF-cDNA-magnetobubbles were administered under a magnetic field with simultaneously applied ultrasound, under magnetic field alone and with applied ultrasound alone. Therapy was conducted 7 days pre-operative. Flap survival and necrosis were measured 7 days post-operatively. Flap perfusion, VEGF-protein concentration in target and surrounding tissue, formation and appearance of new vessels were analysed additionally. Magnetofection with VEGF-cDNA-magnetobubbles presented an increased flap survival of 50% and increased flap perfusion (P < 0.05). Without ultrasound and without magnetic field, the effect is weakened. VEGF concentration in target tissue was elevated (P < 0.05), while underlying muscle was not affected. Our results demonstrate the successful VEGF gene therapy by means of magnetobubble magnetofection. Here, the method of magnetofection of magnetic lipospheres is equally efficient as adenoviral transduction, but has a presumable superior safety profile. PMID:19040418
Holzbach, Thomas; Vlaskou, Dialekti; Neshkova, Iva; Konerding, Moritz A; Wörtler, Klaus; Mykhaylyk, Olga; Gänsbacher, Bernd; Machens, H-G; Plank, Christian; Giunta, Riccardo E
Adenoviral transduction of the VEGF gene in an oversized skin flap increases flap survival and perfusion. In this study, we investigated the potential of magnetofection of magnetic lipospheres containing VEGF(165)-cDNA on survival and perfusion of ischemic skin flaps and evaluated the method with respect to the significance of applied magnetic field and ultrasound. We prepared perfluoropropane-filled magnetic lipospheres ('magnetobubbles') from Tween60-coated magnetic nanoparticles, Metafectene, soybean-oil and cDNA and studied the effect in an oversized random-pattern-flap model in the rats (n= 46). VEGF-cDNA-magnetobubbles were administered under a magnetic field with simultaneously applied ultrasound, under magnetic field alone and with applied ultrasound alone. Therapy was conducted 7 days pre-operative. Flap survival and necrosis were measured 7 days post-operatively. Flap perfusion, VEGF-protein concentration in target and surrounding tissue, formation and appearance of new vessels were analysed additionally. Magnetofection with VEGF-cDNA-magnetobubbles presented an increased flap survival of 50% and increased flap perfusion (P < 0.05). Without ultrasound and without magnetic field, the effect is weakened. VEGF concentration in target tissue was elevated (P < 0.05), while underlying muscle was not affected. Our results demonstrate the successful VEGF gene therapy by means of magnetobubble magnetofection. Here, the method of magnetofection of magnetic lipospheres is equally efficient as adenoviral transduction, but has a presumable superior safety profile.
Jones, Jennifer D
The use of a control group is fundamental to experimental research design, though the use with clinical populations must be carefully considered. The purpose of this research was to examine the use of control groups in research with clinical and nonclinical populations published in Journal of Musical Therapy from 1964 through 2004. Criteria for inclusion were music or music therapy as an independent variable applied to one or more groups and at least one control group that did not receive a music treatment. Control groups were qualified as alternative treatment, placebo, no contact, and treatment as usual. Of the 692 articles, 94 met these criteria, 62 clinical and 32 nonclinical, representing 13.5% of the publications. Results indicated that research with clinical populations involved a mean of 38.1 subjects typically divided into two groups, an experimental and a control group. The pretest-posttest design was the most common (55%) as was a treatment as usual control group (45%). These design methods maximized the impact of the experimental music treatment on outcome. Experimental music groups significantly improved over control groups in the vast majority of studies identified. Undoubtedly, the foundation for evidence-based clinical practice is firm.
Kongkasuwan, Ratcharin; Voraakhom, Kotchakorn; Pisolayabutra, Prim; Maneechai, Pichai; Boonin, Jiraporn; Kuptniratsaikul, Vilai
To examine the efficacy of creative art therapy plus conventional physical therapy, compared with physical therapy only, in increasing cognitive ability, physical functions, psychological status and quality of life of stroke patients. Randomized controlled trial with blinded assessor. An in-patient setting PARTICIPANTS: One hundred and eighteen stroke patients aged ⩾50 years who could communicate verbally. All participants received conventional physical therapy five days per week. An intervention group received additional creative art therapy, twice a week for four weeks, in a rehabilitation ward. Cognitive function, anxiety and depression, physical performance and quality of life were measured with the Abbreviated Mental Test, the Hospital Anxiety and Depression Scale, the modified Barthel Index scale and the pictorial Thai Quality of Life questionnaire, respectively. Mean differences for the intervention group were significantly greater than the control group for depression (-4.5, 95% CI -6.5, -2.5, part therapy and most reported improved concentration (68.5%), emotion (79.6%), self-confidence (72.2%) and motivation (74.1%). Creative art therapy combined with conventional physical therapy can significantly decrease depression, improve physical functions and increase quality of life compared with physical therapy alone. © The Author(s) 2015.
Tara L Kieffer
Full Text Available In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR in combination with peginterferon and ribavirin (PR significantly increased sustained virologic response (SVR rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm, 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms. NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.
Arif, M; Sadlier, M; Rajenderkumar, D; James, J; Tahir, T
Psychotherapeutic interventions have been adopted effectively in the management of tinnitus for a long time. This study compared mindfulness meditation and relaxation therapy for management of tinnitus. In this randomised controlled trial, patients were recruited for five sessions of mindfulness meditation or five sessions of relaxation therapy. Patients' responses were evaluated using the Tinnitus Reaction Questionnaire as a primary outcome measure, and the Hospital Anxiety and Depression Scale, visual analogue scale and a health status indicator as secondary outcome measures. A total of 86 patients were recruited. Thirty-four patients completed mindfulness meditation and 27 patients completed relaxation therapy. Statistically significant improvement was seen in all outcome measures except the health status indicator in both treatment groups. The change in treatment scores was greater in the mindfulness meditation group than in the relaxation therapy group. This study suggests that although both mindfulness meditation and relaxation therapy are effective in the management of tinnitus, mindfulness meditation is superior to relaxation therapy.
Acute viral bronchiolitis represents the most common lower respiratory tract infection in infants and young children and is associated with substantial morbidity and mortality. Respiratory syncytial virus is the most frequently identified virus, but many other viruses may also cause acute bronchiolitis. There is no common definition of acute viral bronchiolitis used internationally, and this may explain part of the confusion in the literature. Most children with bronchiolitis have a self limiting mild disease and can be safely managed at home with careful attention to feeding and respiratory status. Criteria for referral and admission vary between hospitals as do clinical practice in the management of acute viral bronchiolitis, and there is confusion and lack of evidence over the best treatment for this condition. Supportive care, including administration of oxygen and fluids, is the cornerstone of current treatment. The majority of infants and children with bronchiolitis do not require specific measures. Bronchodilators should not be routinely used in the management of acute viral bronchiolitis, but may be effective in some patients. Most of the commonly used management modalities have not been shown to have a clear beneficial effect on the course of the disease. For example, inhaled and systemic corticosteroids, leukotriene receptor antagonists, immunoglobulins and monoclonal antibodies, antibiotics, antiviral therapy, and chest physiotherapy should not be used routinely in the management of bronchiolitis. The potential effect of hypertonic saline on the course of the acute disease is promising, but further studies are required. In critically ill children with bronchiolitis, today there is little justification for the use of surfactant and heliox. Nasal continuous positive airway pressure may be beneficial in children with severe bronchiolitis but a large trial is needed to determine its value. Finally, very little is known on the effect of the various
Ellis, Deborah A.; Templin, Thomas; Naar-King, Sylvie; Frey, Maureen A.; Cunningham, Phillippe B.; Podolski, Cheryl-Lynn; Cakan, Nedim
The primary purpose of the present study was to determine whether multisystemic therapy (MST), an intensive, home-based psychotherapy, improved regimen adherence, metabolic control, and rates of hospitalization for diabetic ketoacidosis (DKA) among adolescents with chronically poorly controlled Type 1 diabetes 6 months after the completion of…
Dignam, Jade; Copland, David; McKinnon, Eril; Burfein, Penni; O'Brien, Kate; Farrell, Anna; Rodriguez, Amy D
Most studies comparing different levels of aphasia treatment intensity have not controlled the dosage of therapy provided. Consequently, the true effect of treatment intensity in aphasia rehabilitation remains unknown. Aphasia Language Impairment and Functioning Therapy is an intensive, comprehensive aphasia program. We investigated the efficacy of a dosage-controlled trial of Aphasia Language Impairment and Functioning Therapy, when delivered in an intensive versus distributed therapy schedule, on communication outcomes in participants with chronic aphasia. Thirty-four adults with chronic, poststroke aphasia were recruited to participate in an intensive (n=16; 16 hours per week; 3 weeks) versus distributed (n=18; 6 hours per week; 8 weeks) therapy program. Treatment included 48 hours of impairment, functional, computer, and group-based aphasia therapy. Distributed therapy resulted in significantly greater improvements on the Boston Naming Test when compared with intensive therapy immediately post therapy (P=0.04) and at 1-month follow-up (P=0.002). We found comparable gains on measures of participants' communicative effectiveness, communication confidence, and communication-related quality of life for the intensive and distributed treatment conditions at post-therapy and 1-month follow-up. Aphasia Language Impairment and Functioning Therapy resulted in superior clinical outcomes on measures of language impairment when delivered in a distributed versus intensive schedule. The therapy progam had a positive effect on participants' functional communication and communication-related quality of life, regardless of treatment intensity. These findings contribute to our understanding of the effect of treatment intensity in aphasia rehabilitation and have important clinical implications for service delivery models. © 2015 American Heart Association, Inc.
Feeney, Megan E; Rowe, Sandra L B; Mah, Nathan D; Barton, Cassie A; Ran, Ran
The objective of this study is to evaluate the difference in response to ventricular rate control with intravenous (IV) metoprolol compared to IV diltiazem in patients taking chronic beta-blocker therapy who present to the emergency department (ED) in atrial fibrillation (AF) with rapid ventricular rate (RVR). This was a single-center, retrospective study of adult patients taking chronic oral metoprolol. Chronic metoprolol therapy was defined as patients prescribed and taking oral metoprolol within 5days of study inclusion. Rate control was defined as either a decrease in ventricular ratebeta-blocker therapy, however the difference between groups was not statistically significant. Copyright © 2017 Elsevier Inc. All rights reserved.
Lentil (Lens culinaris Medik) is grown as a pulse crop in many parts of the world including Australasia, the Indian subcontinent, the Middle East, North African, southern Europe and parts of North, Central and South America. It is consumed either as a whole seed or after decortication. The milling w...
Seki, Sayuri; Matano, Tetsuro
Cytotoxic T lymphocyte (CTL) responses exert a suppressive effect on HIV and simian immunodeficiency virus (SIV) replication. Under the CTL pressure, viral CTL escape mutations are frequently selected with viral fitness costs. Viruses with such CTL escape mutations often need additional viral genome mutations for recovery of viral fitness. Persistent HIV/SIV infection sometimes shows replacement of a CTL escape mutation with an alternative escape mutation toward higher viral fitness. Thus, multiple viral genome changes under CTL pressure are observed in the chronic phase of HIV/SIV infection. HIV/SIV transmission to HLA/MHC-mismatched hosts drives further viral genome changes including additional CTL escape mutations and reversions under different CTL pressure. Understanding of viral structure/function and host CTL responses would contribute to prediction of HIV evolution and control of HIV prevalence.
Full Text Available Abstract Background: Lower respiratory tract infections like acute bronchitis, exacerbated chronic obstructive pulmonary disease and community-acquired pneumonia are often unnecessarily treated with antibiotics, mainly because of physicians' difficulties to distinguish viral from bacterial cause and to estimate disease-severity. The goal of this trial is to compare medical outcomes, use of antibiotics and hospital resources in a strategy based on enforced evidence-based guidelines versus procalcitonin guided antibiotic therapy in patients with lower respiratory tract infections. Methods and design: We describe a prospective randomized controlled non-inferiority trial with an open intervention. We aim to randomize over a fixed recruitment period of 18 months a minimal number of 1002 patients from 6 hospitals in Switzerland. Patients must be >18 years of age with a lower respiratory tract infections Discussion: Use of and prolonged exposure to antibiotics in lower respiratory tract infections is high. The proposed trial investigates whether procalcitonin-guidance may safely reduce antibiotic consumption along with reductions in hospitalization costs and antibiotic resistance. It will additionally generate insights for improved prognostic assessment of patients with lower respiratory tract infections. Trial registration: ISRCTN95122877
Rodríguez-Mansilla, Juan; González López-Arza, María Victoria; Varela-Donoso, Enrique; Montanero-Fernández, Jesús; González Sánchez, Blanca; Garrido-Ardila, Elisa María
To assess the effectiveness of ear acupressure and massage vs. control in the improvement of pain, anxiety and depression in persons diagnosed with dementia. A pilot randomized controlled trial. Residential homes in Extremadura (Spain). A total of 120 elders with dementia institutionalized in residential homes. The participants were randomly allocated, in three groups. Control group - they continued with their routine activities; ear acupressure intervention group - they received ear acupressure treatment (pressure was applied to acupressure points on the ear); and massage therapy intervention group - they received relaxing massage therapy. The variables pain, anxiety and depression were assessed with the Doloplus2, Cornell and Campbell scales. The study was carried out during five months; three months of experimental treatment and two months with no treatment. The assessments were done at baseline, each month during the treatment and at one and two months of follow-up. In the statistical analysis the three groups were compared with each other. A total of 111 participants completed the study. Their aged ranged from 67 to 91 years old and 86 of them (77.4%) were women. The ear acupressure intervention group showed better improvements than the massage therapy intervention group in relation to pain and depression during the treatment period and at one month of follow-up. The best improvement in pain was achieved in the last (3rd) month of ear acupressure treatment (p massage therapy showed better results than the control group in relation to pain, anxiety and depression. However, ear acupressure achieved more improvements. © The Author(s) 2014.
Full Text Available Judy WM ChengMassachusetts College of Pharmacy and Health Sciences, Brigham and Women's Hospital, Boston, MA, USABackground: Edarbyclor® is a combined angiotensin receptor blocker (ARB and thiazide-like diuretic (azilsartan and chlorthalidone, and was approved on December 20, 2011 by the US Food and Drug Administration (FDA for hypertension management.Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management.Methods: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive using search terms “azilsartan”, “chlorthalidone”, “pharmacology”, “pharmacokinetics”, “pharmacodynamics”, “pharmacoeconomics”, and “cost-effectiveness”. The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information.Results: Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure. Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure.Conclusions: Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or
English, Coralie; Bernhardt, Julie; Crotty, Maria; Esterman, Adrian; Segal, Leonie; Hillier, Susan
Increased therapy has been linked to improvements in functional ability of people with stroke. To determine the effectiveness of two alternative models of increased physiotherapy service delivery (seven-day week therapy or group circuit class therapy five days a week) to usual care. Three-armed randomized controlled trial with blinded assessment of outcome. People admitted with a diagnosis of stroke, previously independently ambulant and with a moderate level of disability were recruited. 'Usual care' was individual physiotherapy provided five-days a week. Seven-day week therapy was usual care physiotherapy provided seven-days a week. Participants in the circuit class therapy arm of the trial received physiotherapy in group circuit classes in two 90-min sessions, five-days a week. Primary outcome was distance walked on the six-minute walk test at four-weeks post-randomization. Two hundred eighty-three participants were randomized; primary outcome data were available for 259 (92%). In the seven-day arm participants received an additional three hours of physiotherapy and those in the circuit class arm an additional 22 h. There were no significant between-group differences at four-weeks in walking distance (P = 0.72). Length of stay was shorter for seven-day (mean difference -2.9 days, 95% confidence interval -17.9 to 12.0) and circuit class participants (mean difference -9.2 days, 95% confidence interval -24.2 to 5.8) compared to usual care, but this was not significant. Both seven-day therapy and group circuit class therapy increased physiotherapy time, but walking outcomes were equivalent to usual care. © 2015 World Stroke Organization.
Roseen, Eric J; Cornelio-Flores, Oscar; Lemaster, Chelsey; Hernandez, Maria; Fong, Calvin; Resnick, Kirsten; Wardle, Jon; Hanser, Suzanne; Saper, Robert
Little is known about the feasibility of providing massage or music therapy to medical inpatients at urban safety-net hospitals or the impact these treatments may have on patient experience. To determine the feasibility of providing massage and music therapy to medical inpatients and to assess the impact of these interventions on patient experience. Single-center 3-arm feasibility randomized controlled trial. Urban academic safety-net hospital. Adult inpatients on the Family Medicine ward. Massage therapy consisted of a standardized protocol adapted from a previous perioperative study. Music therapy involved a preference assessment, personalized compact disc, music-facilitated coping, singing/playing music, and/or songwriting. Credentialed therapists provided the interventions. Patient experience was measured with the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) within 7 days of discharge. We compared the proportion of patients in each study arm reporting "top box" scores for the following a priori HCAHPS domains: pain management, recommendation of hospital, and overall hospital rating. Responses to additional open-ended postdischarge questions were transcribed, coded independently, and analyzed for common themes. From July to December 2014, 90 medical inpatients were enrolled; postdischarge data were collected on 68 (76%) medical inpatients. Participants were 70% females, 43% non-Hispanic black, and 23% Hispanic. No differences between groups were observed on HCAHPS. The qualitative analysis found that massage and music therapy were associated with improved overall hospital experience, pain management, and connectedness to the massage or music therapist. Providing music and massage therapy in an urban safety-net inpatient setting was feasible. There was no quantitative impact on HCAHPS. Qualitative findings suggest benefits related to an improved hospital experience, pain management, and connectedness to the massage or music therapist.
Cornelio-Flores, Oscar; Lemaster, Chelsey; Hernandez, Maria; Fong, Calvin; Resnick, Kirsten; Wardle, Jon; Hanser, Suzanne; Saper, Robert
Background Little is known about the feasibility of providing massage or music therapy to medical inpatients at urban safety-net hospitals or the impact these treatments may have on patient experience. Objective To determine the feasibility of providing massage and music therapy to medical inpatients and to assess the impact of these interventions on patient experience. Design Single-center 3-arm feasibility randomized controlled trial. Setting Urban academic safety-net hospital. Patients Adult inpatients on the Family Medicine ward. Interventions Massage therapy consisted of a standardized protocol adapted from a previous perioperative study. Music therapy involved a preference assessment, personalized compact disc, music-facilitated coping, singing/playing music, and/or songwriting. Credentialed therapists provided the interventions. Measurements Patient experience was measured with the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) within 7 days of discharge. We compared the proportion of patients in each study arm reporting “top box” scores for the following a priori HCAHPS domains: pain management, recommendation of hospital, and overall hospital rating. Responses to additional open-ended postdischarge questions were transcribed, coded independently, and analyzed for common themes. Results From July to December 2014, 90 medical inpatients were enrolled; postdischarge data were collected on 68 (76%) medical inpatients. Participants were 70% females, 43% non-Hispanic black, and 23% Hispanic. No differences between groups were observed on HCAHPS. The qualitative analysis found that massage and music therapy were associated with improved overall hospital experience, pain management, and connectedness to the massage or music therapist. Conclusions Providing music and massage therapy in an urban safety-net inpatient setting was feasible. There was no quantitative impact on HCAHPS. Qualitative findings suggest benefits related to an
Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study.
Caniglia, Ellen C; Cain, Lauren E; Sabin, Caroline A; Robins, James M; Logan, Roger; Abgrall, Sophie; Mugavero, Michael J; Hernández-Díaz, Sonia; Meyer, Laurence; Seng, Remonie; Drozd, Daniel R; Seage, George R; Bonnet, Fabrice; Dabis, Francois; Moore, Richard D; Reiss, Peter; van Sighem, Ard; Mathews, William C; Del Amo, Julia; Moreno, Santiago; Deeks, Steven G; Muga, Roberto; Boswell, Stephen L; Ferrer, Elena; Eron, Joseph J; Napravnik, Sonia; Jose, Sophie; Phillips, Andrew; Justice, Amy C; Tate, Janet P; Gill, John; Pacheco, Antonio; Veloso, Valdilea G; Bucher, Heiner C; Egger, Matthias; Furrer, Hansjakob; Porter, Kholoud; Touloumi, Giota; Crane, Heidi; Miro, Jose M; Sterne, Jonathan A; Costagliola, Dominique; Saag, Michael; Hernán, Miguel A
Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per μL, 350 cells per μL, and 500 cells per μL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count. 47 635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86-1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95-1·22) for threshold 200 and 1·03 (0·96-1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of
Morinet, Frédéric, E-mail: email@example.com [Centre des Innovations Thérapeutiques en Oncologie et Hématologie (CITOH), CHU Saint-Louis, Paris (France); Université Denis Diderot, Sorbonne Paris Cité Paris, Paris (France); Casetti, Luana [Institut Cochin INSERM U1016, Paris (France); François, Jean-Hugues; Capron, Claude [Institut Cochin INSERM U1016, Paris (France); Laboratoire d' Hématologie, Hôpital Ambroise Paré, Boulogne (France); Université de Versailles Saint-Quentin en Yvelynes, Versailles (France); Pillet, Sylvie [Laboratoire de Bactériologie-Virologie-Hygiène, CHU de Saint-Etienne, Saint-Etienne (France); Université de Lyon et Université de Saint-Etienne, Jean Monnet, GIMAP EA3064, F-42023 Saint-Etienne, Lyon (France)
The role of oxygen tension level is a well-known phenomenon that has been studied in oncology and radiotherapy since about 60 years. Oxygen tension may inhibit or stimulate propagation of viruses in vitro as well as in vivo. In turn modulating oxygen metabolism may constitute a novel approach to treat viral infections as an adjuvant therapy. The major transcription factor which regulates oxygen tension level is hypoxia-inducible factor-1 alpha (HIF-1α). Down-regulating the expression of HIF-1α is a possible method in the treatment of chronic viral infection such as human immunodeficiency virus infection, chronic hepatitis B and C viral infections and Kaposi sarcoma in addition to classic chemotherapy. The aim of this review is to supply an updating concerning the influence of oxygen tension level in human viral infections and to evoke possible new therapeutic strategies regarding this environmental condition. - Highlights: • Oxygen tension level regulates viral replication in vitro and possibly in vivo. • Hypoxia-inducible factor 1 (HIF-1α) is the principal factor involved in Oxygen tension level. • HIF-1α upregulates gene expression for example of HIV, JC and Kaposi sarcoma viruses. • In addition to classical chemotherapy inhibition of HIF-1α may constitute a new track to treat human viral infections.
Stroppa, Fabio; Marcheschi, Simone; Mastronicola, Nicola; Loconsole, Claudio; Frisoli, Antonio
Repetitive and task specific robot-based rehabilitation has been proved to be effective for motor recovery over time. During a therapy, the task should improve subject's impaired movements, but also enhance their efforts for a more effective recovery. This requires an accurate tuning of the task difficulty, which should be tailored directly to the patient. In this work, we propose a system for real-time assistance adaptation based on online performance evaluation for post-stroke subjects. In particular, the aim of the system is to implement the "assist-as-needed" paradigm based on actual patients' motor skills during a therapy session with an active upper-limb robotic exoskeleton. The strength of the work is to propose a real-time algorithm for the assistance tuning based on an "assistance-performance" relationship. Such a relationship is based on experimental measurements, and allows the algorithm to compute a straightforward calculation of the assistance required. Finally, an assessment phase will show how the system provides assistance based on the difficulties experienced from the subjects, also facilitating their adaptation during the task.
Thesis provides an overview of viral marketing. It describes the process by which you can be inspired to implement viral campaign. The thesis includes analysis of specific viral Web project. The aim of this thesis is to create a breakdown of the various components of viral marketing, to establish conditions that should be satisfied for the viral marketing to success, suggesting how to use viral marketing on social network Facebook and evaluate the various components of this service for the pr...
Kapadia, Naaz M; Zivanovic, Vera; Furlan, Julio C; Craven, B Cathy; McGillivray, Colleen; Popovic, Milos R
The purpose of this single-site randomized control trial was to assess the short-term and long-term efficacy of functional electrical stimulation (FES) therapy over conventional occupational therapy in improving voluntary hand function in incomplete C4-C7 spinal cord injury individuals. All 22 participants recruited in this randomized control trial received treatment for both the left and right upper extremities. Every participant, irrespective of group allocation, received one dose (60 min per day, 5 days per week for the duration of 8 weeks) of conventional occupational therapy for hand function. Of the 22 participants, 12 individuals received an additional dose of conventional occupational therapy, while the remaining 10 participants received a dose of FES hand therapy. The primary outcome measure was Functional Independence Measure (FIM) self-care subscore. The secondary outcome measures were Spinal Cord Independence Measure (SCIM) self-care subscore and Toronto Rehabilitation Institute Hand Function Test (TRI-HFT). The participants who received FES therapy showed significantly greater improvements in hand function at discharge, and were able to maintain their gains at long-term follow-up as assessed using FIM self-care subscore, SCIM self-care subscore, and TRI-HFT. The FES therapy effectively increased independence and thereby improved quality of life of individuals with tetraplegia when compared with conventional occupational therapy. © 2011, Copyright the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
Evidence from randomized controlled trials (RCTs) plays a powerful role in today's healthcare industry. At the same time, it is important that multiple types of evidence contribute to music therapy's knowledge base and that the dialogue of clinical effectiveness in music therapy is not dominated by the biomedical hierarchical model of evidence-based practice. Whether or not one agrees with the hierarchical model of evidence in the current healthcare climate, RCTs can contribute important knowledge to our field. Therefore, it is important that music therapists are prepared to design trials that meet current methodological standards and, equally important, are able to respond appropriately to those design aspects that may not be feasible in music therapy research. To provide practical guidelines to music therapy researchers for the design and implementation of RCTs as well as to enable music therapists to be well-informed consumers of RCT evidence. This article reviews key design aspects of RCTs and discusses how to best implement these standards in music therapy trials. A systematic presentation of basic randomization methods, allocation concealment strategies, issues related to blinding in music therapy trials and strategies for implementation, the use of treatment manuals, types of control groups, outcome selection, and sample size computation is provided. Despite the challenges of meeting all key design demands typical of an RCT, it is possible to design rigorous music therapy RCTs that accurately estimate music therapy treatment benefits.
Lazarov, Amit; Pine, Daniel S; Bar-Haim, Yair
Patients with social anxiety disorder exhibit increased attentional dwelling on social threats, providing a viable target for therapeutics. This randomized controlled trial examined the efficacy of a novel gaze-contingent music reward therapy for social anxiety disorder designed to reduce attention dwelling on threats. Forty patients with social anxiety disorder were randomly assigned to eight sessions of either gaze-contingent music reward therapy, designed to divert patients' gaze toward neutral stimuli rather than threat stimuli, or to a control condition. Clinician and self-report measures of social anxiety were acquired pretreatment, posttreatment, and at 3-month follow-up. Dwell time on socially threatening faces was assessed during the training sessions and at pre- and posttreatment. Gaze-contingent music reward therapy yielded greater reductions of symptoms of social anxiety disorder than the control condition on both clinician-rated and self-reported measures. Therapeutic effects were maintained at follow-up. Gaze-contingent music reward therapy, but not the control condition, also reduced dwell time on threat, which partially mediated clinical effects. Finally, gaze-contingent music reward therapy, but not the control condition, also altered dwell time on socially threatening faces not used in training, reflecting near-transfer training generalization. This is the first randomized controlled trial to examine a gaze-contingent intervention in social anxiety disorder. The results demonstrate target engagement and clinical effects. This study sets the stage for larger randomized controlled trials and testing in other emotional disorders.
Simnikiwe H Mayaphi
Full Text Available BACKGROUND: Cytomegalovirus (CMV infection is associated with severe diseases in immunosuppressed patients; however, there is a lack of data for pre-emptive therapy in patients with HIV/AIDS. METHOD: This was a retrospective study, which enrolled patients diagnosed with HIV/AIDS (CD41,000 copies/ml at baseline testing had significantly higher mortality compared to those who had 5,100 copies/ml and did not receive ganciclovir had 100% mortality compared to 58% mortality in those who received ganciclovir at VLs of >5,100 copies/ml, 50% mortality in those who were not treated and had low VLs of <5,100 copies/ml, and 44% mortality in those who had ganciclovir treatment at VLs of <5,100 copies/ml (p = 0.084, 0.046, 0.037, respectively. CONCLUSION: This study showed a significantly increased mortality in patients with HIV/AIDS who had high CMV VLs, and suggests that a threshold value of 1,000 copies/ml may be appropriate for pre-emptive treatment in this group.
Full Text Available High rates of patient attrition from care between HIV testing and antiretroviral therapy (ART initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.RapIT (Rapid Initiation of Treatment was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC and a hospital-based HIV clinic. Adult (≥18 y old, non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study ("rapid arm" received a point-of-care (POC CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV dispensing. Patients in the standard-initiation arm of the study ("standard arm" followed standard clinic procedures (three to five additional clinic visits over 2-4 wk prior to ARV dispensing. Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition
de Bruin, Eduard J; Bögels, Susan M; Oort, Frans J; Meijer, Anne Marie
To investigate the efficacy of cognitive behavioral therapy for insomnia (CBTI) in adolescents. A randomized controlled trial of CBTI in group therapy (GT), guided internet therapy (IT), and a waiting list (WL), with assessments at baseline, directly after treatment (post-test), and at 2 months follow-up. Diagnostic interviews were held at the laboratory of the Research Institute of Child Development and Education at the University of Amsterdam. Treatment for GT occurred at the mental health care center UvAMinds in Amsterdam, the Netherlands. One hundred sixteen adolescents (mean age = 15.6 y, SD = 1.6 y, 25% males) meeting DSM-IV criteria for insomnia, were randomized to IT, GT, or WL. CBTI of 6 weekly sessions, consisted of psychoeducation, sleep hygiene, restriction of time in bed, stimulus control, cognitive therapy, and relaxation techniques. GT was conducted in groups of 6 to 8 adolescents, guided by 2 trained sleep therapists. IT was applied through an online guided self-help website with programmed instructions and written feedback from a trained sleep therapist. Sleep was measured with actigraphy and sleep logs for 7 consecutive days. Symptoms of insomnia and chronic sleep reduction were measured with questionnaires. Results showed that adolescents in both IT and GT, compared to WL, improved significantly on sleep efficiency, sleep onset latency, wake after sleep onset, and total sleep time at post-test, and improvements were maintained at follow-up. Most of these improvements were found in both objective and subjective measures. Furthermore, insomnia complaints and symptoms of chronic sleep reduction also decreased significantly in both treatment conditions compared to WL. Effect sizes for improvements ranged from medium to large. A greater proportion of participants from the treatment conditions showed high end-state functioning and clinically significant improvement after treatment and at follow-up compared to WL. This study is the first randomized
Knuschke, Torben; Rotan, Olga; Bayer, Wibke; Sokolova, Viktoriya; Hansen, Wiebke; Sparwasser, Tim; Dittmer, Ulf; Epple, Matthias; Buer, Jan; Westendorf, Astrid M
Regulatory T cells (Tregs) have been shown to limit anti-viral immunity during chronic retroviral infection and to restrict vaccine-induced T cell responses. The objective of the study was to assess whether a combinational therapy of nanoparticle-based therapeutic vaccination and concomitant transient ablation of Tregs augments anti-viral immunity and improves virus control in chronically retrovirus-infected mice. Therefore, chronically Friend retrovirus (FV)-infected mice were immunized with calcium phosphate (CaP) nanoparticles functionalized with TLR9 ligand CpG and CD8(+) or CD4(+) T cell epitope peptides (GagL85-93 or Env gp70123-141) of FV. In addition, Tregs were ablated during the immunization process. Reactivation of CD4(+) and CD8(+) effector T cells was analysed and the viral loads were determined. Therapeutic vaccination of chronically FV-infected mice with functionalized CaP nanoparticles transiently reactivated cytotoxic CD8(+) T cells and significantly reduced the viral loads. Transient ablation of Tregs during nanoparticle-based therapeutic vaccination strongly enhanced anti-viral immunity and further decreased viral burden. Our data illustrate a crucial role for CD4(+) Foxp3(+) Tregs in the suppression of anti-viral T cell responses during therapeutic vaccination against chronic retroviral infection. Thus, the combination of transient Treg ablation and therapeutic nanoparticle-based vaccination confers robust and sustained anti-viral immunity.
In this podcast, Dr. John Ward, Director of CDCâs Division of Viral Hepatitis, discusses the 2010 report, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C, from the Institute of Medicine. Created: 5/18/2010 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP). Date Released: 5/18/2010.
Sara Olivan Garcia
Full Text Available Spinal muscular atrophy (SMA is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC, which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons in vitro and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3 and p62 and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln, TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease.
Karagülle, Mine; Kardeş, Sinan; Dişçi, Rian; Karagülle, Müfit Zeki
This study aims to investigate whether 2-week spa therapy, as an adjunct to usual pharmacological therapy, has any beneficial effect in patients with rheumatoid arthritis (RA). In this single-blind crossover study, 50 patients were randomly assigned in a 1:1 manner to receive usual pharmacological therapy plus 2-week spa therapy or usual pharmacological therapy alone (period 1.6 months); after a 9-month washout, patients were crossed over to the opposite assignment (period 2.6 months). Spa therapy program included a daily saline balneotherapy session at 36-37 °C for 20 min except Sundays. The clinical outcomes were evaluated at baseline, after spa therapy (2 weeks) and 3 and 6 months after the spa therapy in both period and were pain (Visual Analogue Scale (VAS)), patient and physician global assessments (VAS), Health Assessment Questionnaire (HAQ), and Disease Activity Score (DAS28). Spa therapy was superior to control therapy in improving all the assessed clinical outcomes at the end of the spa therapy. This superiority persisted significantly in physician global assessment (p = 0.010) and with a trend in favor of spa group in patient global assessment (p = 0.058), function (p = 0.092), and disease activity (p = 0.098) at 3 months. Statistically significant improvements were found in spa therapy compared to control in disease activity (p = 0.006) and patient (p = 0.020) and physician global (p = 0.011) assessments, and a trend toward improvements in pain (p = 0.069) and swollen joints (p = 0.070) at 6 months. A 2-week spa therapy adjunct to usual pharmacological therapy provided beneficial clinical effects compared to usual pharmacological therapy alone, in RA patients treated with traditional disease-modifying antirheumatic drugs. These beneficial effects may last for 6 months.
Beidel, Deborah C; Frueh, B Christopher; Neer, Sandra M; Bowers, Clint A; Trachik, Benjamin; Uhde, Thomas W; Grubaugh, Anouk
Virtual reality exposure therapy (VRET) realistically incorporates traumatic cues into exposure therapy and holds promise in the treatment of combat-related posttraumatic stress disorder (PTSD). In a randomized controlled trial of 92 Iraq and Afghanistan veterans and active duty military personnel with combat-related PTSD, we compared the efficacy of Trauma Management Therapy (TMT; VRET plus a group treatment for anger, depression, and social isolation) to VRET plus a psychoeducation control condition. Efficacy was evaluated at mid- and post-treatment, and at 3- and 6-month follow-up. Consistent with our hypothesis, VRET resulted in significant decreases on the Clinician Administered PTSD Scale and the PTSD Checklist-Military version for both groups. Also consistent with our hypothesis, significant decreases in social isolation occurred only for those participants who received the TMT group component. There were significant decreases for depression and anger for both groups, although these occurred after VRET and before group treatment. All treatment gains were maintained six-months later. Although not part of the original hypotheses, sleep was not improved by either intervention and remained problematic. The results support the use of VRET as an efficacious treatment for combat-related PTSD, but suggest that VRET alone does not result in optimal treatment outcomes across domains associated with PTSD. Copyright © 2017 Elsevier Ltd. All rights reserved.
Tremblay, Michel; Berthiaume, Laurent; Ackermann, Hans-Wolfgang
.... The 268 diagrams in Viral Pathogenesis in Diagrams were selected from over 800 diagrams of English and French virological literature, including one derived from a famous drawing by Leonardo da Vinci...
... Viral gastroenteritis (stomach flu) Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...
Batts, William N.; Winton, James R.
Viral hemorrhagic septicemia (VHS) is one of the most important viral diseases of finfish worldwide. In the past, VHS was thought to affect mainly rainbow trout Oncorhynchus mykiss reared at freshwater facilities in Western Europe where it was known by various names including Egtved disease and infectious kidney swelling and liver degeneration (Wolf 1988). Today, VHS is known as an important source of mortality for cultured and wild fish in freshwater and marine environments in several regions of the northern hemisphere (Dixon 1999; Gagné et al. 2007; Kim and Faisal 2011; Lumsden et al. 2007; Marty et al. 1998, 2003; Meyers and Winton 1995; Skall et al. 2005b; Smail 1999; Takano et al. 2001). Viral hemorrhagic septicemia is caused by the fish rhabdovirus, viral hemorrhagic septicemia virus (VHSV), a member of the genus Novirhabdovirus of the family Rhabdoviridae
... Chains Sex Hormone Binding Globulin (SHBG) Shiga toxin-producing Escherichia coli Sickle Cell Tests Sirolimus Smooth Muscle ... used each time. Will exercise, nutrition, and other lifestyle modifications help decrease my HIV viral load? There ...
de Grauw, W J; van de Lisdonk, E H; van Gerwen, W H; van den Hoogen, H J; van Weel, C
Strict glycaemic control in type 2 diabetic patients is recommended in a number of treatment protocols. However, although better glycaemic control prevents or postpones chronic diabetic complications, it remains uncertain how this affects quality of life in the short and long term. To study the impact of insulin therapy on glycaemic control and quality of life in type 2 diabetic patients, with secondary failure on maximal oral medication. Two separate sets of analyses were performed: a longitudinal analysis of those patients converted to insulin therapy and a comparison of 12-week outcomes between the two randomisation groups. Ten general practices, participating in the Nijmegen Monitoring Project. Patients, poorly controlled on maximal oral therapy, were stratified with respect to age and sex, and randomly allocated to insulin therapy in two different schedules: (a) after a 12-week period with enhanced compliance to diet and oral therapy: or (b) as soon as secondary failure was established. Patients were referred to a diabetologist to start insulin therapy and were referred back to their general practitioner (GP) as soon as glycaemic control was stable. We assessed fasting blood glucose, HbA1c functional health, and quality of life (Sickness Impact Profile, COOP/WONCA charts, Diabetes Symptom Checklist) at baseline, after the patient was referred back to the GP, and nine months later. Of the 38 included patients, three patients dropped out and seven patients were not switched over to insulin therapy. In patients starting insulin therapy, mean HbA1c and fasting blood glucose level decreased from 9.5% to 7.6%, and from 12.0 mmol to 8.4 mmol, respectively (P < 0.001). The better control was accompanied by a decrease in hyperglycaemic complaints (P = 0.01). No increase in hypoglycaemic complaints was found. There were no statistically significant changes in quality-of-life parameters. After 12 weeks, patients directly referred to insulin therapy showed a statistically
Full Text Available While a typical way for diabetes therapy is discrete insulin infusion based on long-time interval measurement, in this paper, we design a closed-loop control system for continuous drug infusion to improve the traditional discrete methods and make diabetes therapy automatic in practice. By exploring the accumulative function of drug to insulin, a continuous injection model is proposed. Based on this model, proportional-integral-derivative (PID and fuzzy logic controllers are designed to tackle a control problem of the resulting highly nonlinear plant. Even with serious disturbance of glucose, such as nutrition absorption at meal time, the proposed scheme can perform well in simulation experiments.
Sturkenboom, I.H.W.M.; Graff, M.J.L.; Borm, G.F.; Veenhuizen, Y.; Bloem, B.R.; Munneke, M.; Nijhuis-Van der Sanden, M.W.G.
AIM: To evaluate the feasibility of a randomized controlled trial including process and potential impact of occupational therapy in Parkinson's disease. DESIGN: Process and outcome were quantitatively and qualitatively evaluated in an exploratory multicentre, two-armed randomized controlled trial at
Full Text Available Background and aims: The regression of liver fibrosis and portal hypertension (PH and their influence on the natural history of compensated hepatitis C virus (HCV-related cirrhosis has not been studied previously. Our objective was to evaluate the influence of sustained virologic response (SVR on the portal pressure gradient (HVPG and non-invasive parameters of PH and prognostic factors of response. Methods: Sixteen patients with compensated HCV genotype 1-related cirrhosis with PH (HVPG > 6 mmHg without beta-blocker therapy were considered as candidates for PEGα2a + RBV + BOC (48 weeks; lead-in and accepted stopping rules. A hemodynamic study and Fibroscan® were performed at baseline, at eight weeks and, in the case of SVR, 24 weeks after treatment. In each hemodynamic study, serum samples were analyzed for inflammatory biomarkers associated with PH. Results: In eight cases, SVR was obtained; five patients relapsed, and treatment was stopped early for non-response to lead in (one case and a decrease of < 3 log at week 8 (two patients. Compared to baseline, there was a significant decrease in HVPG and Fibroscan® at weeks 8 and 72 (10.31 ± 4.3 vs 9.4 ± 5.04 vs 6.1 ± 3.61 mmHg, p < 0.0001 and 21.3 ± 14.5 vs 16.2 ± 9.5 vs 6.4 ± 4.5 kPa, p < 0.0001, respectively. The average HVPG decrease in SVR was 40.8 ± 17.53%, achieving an HVPG < 6 mmHg in five patients (62.5% and a Fibroscan® < 7.1 kPa in three patients (37.5%. Conclusions: Complete hemodynamic response (HVPG < 6 mmHg and fibrosis regression (Fibroscan® < 7.1 kPa occur in more than half and one-third of patients achieving SVR, respectively, and must be another target in cirrhotic patients with SVR.
Puente, Ángela; Cabezas, Joaquín; López Arias, María Jesús; Fortea, José Ignacio; Arias, María Teresa; Estébanez, Ángel; Casafont, Fernando; Fábrega, Emilio; Crespo, Javier
The regression of liver fibrosis and portal hypertension (PH) and their influence on the natural history of compensated hepatitis C virus (HCV)-related cirrhosis has not been studied previously. Our objective was to evaluate the influence of sustained virologic response (SVR) on the portal pressure gradient (HVPG) and non-invasive parameters of PH and prognostic factors of response. Sixteen patients with compensated HCV genotype 1-related cirrhosis with PH (HVPG > 6 mmHg) without beta-blocker therapy were considered as candidates for PEGα2a + RBV + BOC (48 weeks; lead-in and accepted stopping rules). A hemodynamic study and Fibroscan® were performed at baseline, at eight weeks and, in the case of SVR, 24 weeks after treatment. In each hemodynamic study, serum samples were analyzed for inflammatory biomarkers associated with PH. In eight cases, SVR was obtained; five patients relapsed, and treatment was stopped early for non-response to lead in (one case) and a decrease of < 3 log at week 8 (two patients). Compared to baseline, there was a significant decrease in HVPG and Fibroscan® at weeks 8 and 72 (10.31 ± 4.3 vs 9.4 ± 5.04 vs 6.1 ± 3.61 mmHg, p < 0.0001 and 21.3 ± 14.5 vs 16.2 ± 9.5 vs 6.4 ± 4.5 kPa, p < 0.0001, respectively). The average HVPG decrease in SVR was 40.8 ± 17.53%, achieving an HVPG < 6 mmHg in five patients (62.5%) and a Fibroscan® < 7.1 kPa in three patients (37.5%). Complete hemodynamic response (HVPG < 6 mmHg) and fibrosis regression (Fibroscan® < 7.1 kPa) occur in more than half and one-third of patients achieving SVR, respectively, and must be another target in cirrhotic patients with SVR.
Sugg, Holly Victoria Rose; Richards, David A; Frost, Julia
Morita Therapy, a psychological therapy for common mental health problems, is in sharp contrast to established western psychotherapeutic approaches in teaching that undesired symptoms are natural features of human emotion rather than something to control or eliminate. The approach is widely practiced in Japan, but untested and little known in the UK. A clinical trial of Morita Therapy is required to establish the effectiveness of Morita Therapy for a UK population. However, a number of methodological, procedural and clinical uncertainties associated with such a trial first require addressing. The Morita Trial is a mixed methods study addressing the uncertainties associated with an evaluation of Morita Therapy compared with treatment as usual for depression and anxiety. We will undertake a pilot randomised controlled trial with embedded qualitative study. Sixty participants with major depressive disorder, with or without anxiety disorders, will be recruited predominantly from General Practice record searches and randomised to receive Morita Therapy plus treatment as usual or treatment as usual alone. Morita Therapy will be delivered by accredited psychological therapists. We will collect quantitative data on depressive symptoms, general anxiety, attitudes and quality of life at baseline and four month follow-up to inform future sample size calculations; and rates of recruitment, retention and treatment adherence to assess feasibility. We will undertake qualitative interviews in parallel with the trial, to explore people's views of Morita Therapy. We will conduct separate and integrated analyses on the quantitative and qualitative data. The outcomes of this study will prepare the ground for the design and conduct of a fully-powered evaluation of Morita Therapy plus treatment as usual versus treatment as usual alone, or inform a conclusion that such a trial is not feasible and/or appropriate. We will obtain a more comprehensive understanding of these issues than would
Orrell, Catherine; Cohen, Karen; Mauff, Katya; Bangsberg, David R; Maartens, Gary; Wood, Robin
There are conflicting findings about whether mobile phone text message reminders impact on antiretroviral adherence. We hypothesized that text reminders sent when dosing was late would improve adherence and HIV viral suppression. Antiretroviral therapy (ART)-naive participants, from a South African outpatient ART clinic, were randomized to standard of care (SoC, 3 pretreatment education sessions), or intervention (SoC and automated text reminders if dosing >30 minutes late). Dosing time was recorded by real-time electronic adherence monitoring devices, given to participants at ART start. CD4 cell count and HIV RNA were determined at baseline, 16 and 48 weeks. Primary outcome was cumulative adherence execution by electronic adherence monitoring device. HIV-1 viral suppression (TIs) >72 hours were secondary outcomes. Analysis was by intention to treat (missing = failure). Registration was with the Pan-African Clinical Trials Registry: PACTR201311000641402. A total of 230 participants were randomly assigned to control (n = 115) or intervention (n = 115) arms. Median adherence was 82.1% (interquartile range, 56.6%-94.6%) in the intervention arm, compared with 80.4% (interquartile range, 52.8%-93.8%) for SoC [adjusted odds ratio for adherence 1.08; 95% confidence interval (CI): 0.77 to 1.52]. Suppressed HIV RNA (TIs of >72 hours was reduced (adjusted incident rate ratio, 0.84; 95% CI: 0.75 to 0.94). Text message reminders linked to late doses detected by real-time adherence monitoring reduced the number of prolonged TIs, but did not significantly improve adherence or viral suppression.
Swain, Jessica; Hancock, Karen; Dixon, Angela; Koo, Siew; Bowman, Jenny
Anxiety disorders affect approximately 10% to 20% of young people, can be enduring if left untreated, and have been associated with psychopathology in later life. Despite this, there is a paucity of empirical research to assist clinicians in determining appropriate treatment options. We describe a protocol for a randomized controlled trial in which we will examine the effectiveness of a group-based acceptance and commitment therapy program for children and adolescents with a primary diagnosis of anxiety disorder. For the adolescent participants we will also evaluate the elements of the intervention that act as mechanisms for change. We will recruit 150 young people (90 children and 60 adolescents) diagnosed with an anxiety disorder and their parent or caregiver. After completion of baseline assessment, participants will be randomized to one of three conditions (acceptance and commitment therapy, cognitive behavior therapy or waitlist control). Those in the acceptance and commitment therapy and cognitive behavior therapy groups will receive 10 × 1.5 hour weekly group-therapy sessions using a manualized treatment program, in accordance with the relevant therapy, to be delivered by psychologists. Controls will receive the cognitive behavior therapy program after 10 weeks waitlisted. Repeated measures will be taken immediately post-therapy and at three months after therapy cessation. To the best of our knowledge, this study will be the largest trial of acceptance and commitment therapy in the treatment of children and young people to date. It will provide comprehensive data on the use of acceptance and commitment therapy for anxiety disorders and will offer evidence for mechanisms involved in the process of change. Furthermore, additional data will be obtained for the use of cognitive behavior therapy in this population and this research will illustrate the comparative effectiveness of these two interventions, which are currently implemented widely in contemporary
Full Text Available Myofascial pain syndrome (MPS has been defined as a regional pain syndrome characterized by muscle pain caused by myofascial trigger points (MTrPs clinically. MTrP is defined as the hyperirritable spot in a palpable taut band of skeletal muscle fibers. Appropriate treatment to MTrPs can effectively relieve the clinical pain of MPS. Needling therapies, such as MTrP injection, dry needling, or acupuncture (AcP can effectively eliminate pain immediately. AcP is probably the first reported technique in treating MPS patients with dry needling based on the Traditional Chinese Medicine (TCM theory. The possible mechanism of AcP analgesia were studied and published in recent decades. The analgesic effect of AcP is hypothesized to be related to immune, hormonal, and nervous systems. Compared to slow-acting hormonal system, nervous system acts in a faster manner. Given these complexities, AcP analgesia cannot be explained by any single mechanism. There are several principles for selection of acupoints based on the TCM principles: “Ah-Shi” point, proximal or remote acupoints on the meridian, and extra-meridian acupoints. Correlations between acupoints and MTrPs are discussed. Some clinical and animal studies of remote AcP for MTrPs and the possible mechanisms of remote effectiveness are reviewed and discussed.
Chou, Li-Wei; Kao, Mu-Jung; Lin, Jaung-Geng
Myofascial pain syndrome (MPS) has been defined as a regional pain syndrome characterized by muscle pain caused by myofascial trigger points (MTrPs) clinically. MTrP is defined as the hyperirritable spot in a palpable taut band of skeletal muscle fibers. Appropriate treatment to MTrPs can effectively relieve the clinical pain of MPS. Needling therapies, such as MTrP injection, dry needling, or acupuncture (AcP) can effectively eliminate pain immediately. AcP is probably the first reported technique in treating MPS patients with dry needling based on the Traditional Chinese Medicine (TCM) theory. The possible mechanism of AcP analgesia were studied and published in recent decades. The analgesic effect of AcP is hypothesized to be related to immune, hormonal, and nervous systems. Compared to slow-acting hormonal system, nervous system acts in a faster manner. Given these complexities, AcP analgesia cannot be explained by any single mechanism. There are several principles for selection of acupoints based on the TCM principles: “Ah-Shi” point, proximal or remote acupoints on the meridian, and extra-meridian acupoints. Correlations between acupoints and MTrPs are discussed. Some clinical and animal studies of remote AcP for MTrPs and the possible mechanisms of remote effectiveness are reviewed and discussed. PMID:23346211
van Bruggen-Rufi, Monique C H; Vink, Annemieke C; Wolterbeek, Ron; Achterberg, Wilco P; Roos, Raymund A C
Music therapy may have beneficial effects on improving communication and expressive skills in patients with Huntington's disease (HD). Most studies are, however, small observational studies and methodologically limited. Therefore we conducted a multi-center randomized controlled trial. To determine the efficacy of music therapy in comparison with recreational therapy in improving quality of life of patients with advanced Huntington's disease by means of improving communication. Sixty-three HD-patients with a Total Functional Capacity (TFC) score of ≤7, admitted to four long-term care facilities in The Netherlands, were randomized to receive either group music therapy or group recreational therapy in 16 weekly sessions. They were assessed at baseline, after 8, 16 and 28 weeks using the Behaviour Observation Scale for Huntington (BOSH) and the Problem Behaviour Assessment-short version (PBA-s). A linear mixed model with repeated measures was used to compare the scores between the two groups. Group music therapy offered once weekly for 16 weeks to patients with Huntington's disease had no additional beneficial effect on communication or behavior compared to group recreational therapy. This was the first study to assess the effect of group music therapy on HD patients in the advanced stages of the disease. The beneficial effects of music therapy, recorded in many, mainly qualitative case reports and studies, could not be confirmed with the design (i.e. group therapy vs individual therapy) and outcome measures that have been used in the present study. A comprehensive process-evaluation alongside the present effect evaluation is therefore performed.
Gaal, E.V.B. van; Oosting, R.S.; Hennink, W.E.; Crommelin, D.J.A.; Mastrobattista, E.
Gene therapy aims at delivering exogenous DNA into the nuclei of target cells to establish expression of a therapeutic protein. Non-viral gene delivery is examined as a safer alternative to viral approaches, but is presently characterized by a low efficiency. In the past years several non-viral
Ineke Van Der Meulen; Ineke Van Der Meulen; Mieke WE Van De Sandt-Koenderman; Mieke WE Van De Sandt-Koenderman; Majanka H Heijenbrok; Majanka H Heijenbrok; Evy Visch-brink; Gerard M Ribbers; Gerard M Ribbers
AbstractMelodic Intonation Therapy (MIT) is a language production therapy for severely non-fluent aphasic patients using melodic intoning and rhythm to restore language. Although many studies have reported its beneficial effects on language production, randomized controlled trials (RCT) examining the efficacy of MIT are rare. In an earlier publication, we presented the results of an RCT on MIT in subacute aphasia and found that MIT was effective on trained and untrained items. Further, we obs...
Anderson, Page L; Price, Matthew; Edwards, Shannan M; Obasaju, Mayowa A; Schmertz, Stefan K; Zimand, Elana; Calamaras, Martha R
This is the first randomized trial comparing virtual reality exposure therapy to in vivo exposure for social anxiety disorder. Participants with a principal diagnosis of social anxiety disorder who identified public speaking as their primary fear (N = 97) were recruited from the community, resulting in an ethnically diverse sample (M age = 39 years) of mostly women (62%). Participants were randomly assigned to and completed 8 sessions of manualized virtual reality exposure therapy, exposure group therapy, or wait list. Standardized self-report measures were collected at pretreatment, posttreatment, and 12-month follow-up, and process measures were collected during treatment. A standardized speech task was delivered at pre- and posttreatment, and diagnostic status was reassessed at 3-month follow-up. Analysis of covariance showed that, relative to wait list, people completing either active treatment significantly improved on all but one measure (length of speech for exposure group therapy and self-reported fear of negative evaluation for virtual reality exposure therapy). At 12-month follow-up, people showed significant improvement from pretreatment on all measures. There were no differences between the active treatments on any process or outcome measure at any time, nor differences on achieving partial or full remission. Virtual reality exposure therapy is effective for treating social fears, and improvement is maintained for 1 year. Virtual reality exposure therapy is equally effective as exposure group therapy; further research with a larger sample is needed, however, to better control and statistically test differences between the treatments.
Full Text Available The nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. Unraveling this specificity is the task of neuroanatomy. In this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the Golgi method to electron microscopy. An ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in these neurons. Fortuitously, nature has already partially developed such a method in the form of neurotropic viruses, which have evolved to deliver their genetic material between synaptically connected neurons while largely eluding glia and the immune system. While these characteristics make some of these viruses a threat to human health, simple modifications allow them to be used in controlled experimental settings, thus enabling neuroanatomists to trace multi-synaptic connections within and across brain regions. Wild-type neurotropic viruses, such as rabies and alpha-herpes virus, have already contributed greatly to our understanding of brain connectivity, and modern molecular techniques have enabled the construction of recombinant forms of these and other viruses. These newly engineered reagents are particularly useful, as they can target genetically defined populations of neurons, spread only one synapse to either inputs or outputs, and carry instructions by which the targeted neurons can be made to express exogenous proteins, such as calcium sensors or light-sensitive ion channels, that can be used to study neuronal function. In this review, we address these uniquely powerful features of the viruses already in the neuroanatomist's toolbox, as well as the aspects of their biology that currently limit their utility. Based on the latter, we consider strategies for improving viral tracing methods by reducing toxicity, improving control of transsynaptic
Ruiter, Jeroen; Bonnema, Gerrit Maarten; van der Voort, Mascha C.; Broeders, Ivo Adriaan Maria Johannes
In therapeutic flexible endoscopy a team of physician and assistant(s) is required to control all independent translations and rotations of the flexible endoscope and its instruments. As a consequence the physician lacks valuable force feedback information on tissue interaction, communication errors
The efficacy of ECT in the treatment of Schizophrenia was investigated in a double blind controlled trial. The ICD – 10 criteria for Schizophrenia were fulfilled by the 20 patients who entered the trial. Consecutive individuals who satisfied the inclusion criteria were randomly allocated to a course of (bilateral) six real or ...
Sánchez, María S.; Lloyd-Smith, James O.; Porco, Travis C.; Williams, Brian G.; Borgdorff, Martien W.; Mansoer, John; Salomon, Joshua A.; Getz, Wayne M.
OBJECTIVE AND DESIGN: The increased risk for tuberculosis in HIV-infected people has fueled a worldwide resurgence of tuberculosis. A major hindrance to controlling tuberculosis is the long treatment duration, leading to default, jeopardizing cure, and generating drug resistance. We investigated how
Gradisar, Michael; Dohnt, Hayley; Gardner, Greg; Paine, Sarah; Starkey, Karina; Menne, Annemarie; Slater, Amy; Wright, Helen; Hudson, Jennifer L.; Weaver, Edward; Trenowden, Sophie
Objective: To evaluate cognitive-behavior therapy plus bright light therapy (CBT plus BLT) for adolescents diagnosed with delayed sleep phase disorder (DSPD). Design: Randomized controlled trial of CBT plus BLT vs. waitlist (WL) control with comparisons at pre- and post-treatment. There was 6-month follow-up for the CBT plus BLT group only. Setting: Flinders University Child & Adolescent Sleep Clinic, Adelaide, South Australia. Patients: 49 adolescents (mean age 14.6 ± 1.0 y, 53% males) diagnosed with DSPD; mean chronicity 4 y 8 months; 16% not attending school. Eighteen percent of adolescents dropped out of the study (CBT plus BLT: N = 23 vs WL: N = 17). Interventions: CBT plus BLT consisted of 6 individual sessions, including morning bright light therapy to advance adolescents' circadian rhythms, and cognitive restructuring and sleep education to target associated insomnia and sleep hygiene. Measurements and Results: DSPD diagnosis was performed via a clinical interview and 7-day sleep diary. Measurements at each time-point included online sleep diaries and scales measuring sleepiness, fatigue, and depression symptoms. Compared to WL, moderate-to-large improvements (d = 0.65-1.24) were found at post-treatment for CBT plus BLT adolescents, including reduced sleep latency, earlier sleep onset and rise times, total sleep time (school nights), wake after sleep onset, sleepiness, and fatigue. At 6-month follow-up (N = 15), small-to-large improvements (d = 0.24-1.53) continued for CBT plus BLT adolescents, with effects found for all measures. Significantly fewer adolescents receiving CBT plus BLT met DPSD criteria at post-treatment (WL = 82% vs. CBT plus BLT = 13%, P sleep and daytime impairments in the immediate and long-term. Studies evaluating the treatment effectiveness of each treatment component are needed. Clinical Trial Information: Australia – New Zealand Trials Registry Number: ACTRN12610001041044. Citation: Gradisar M; Dohnt H; Gardner G; Paine S; Starkey
Chen, Weikeng; Liu, J; Gluud, C
The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness.......The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness....
During the last four years GSI has developed a new procedure for cancer treatment by means of the intensity controlled rasterscan-method. This method includes active variations of beam parameters during the treatment session and the integration of 'on-line' PET monitoring. Starting in 1997 several patients have been successfully treated within this GSI experimental cancer treatment program; within this program about 350 patients shall be treated in the next 5 years. The developments and experiences of this program accompanied by intensive discussions with the medical community led to a proposal for a hospital based light ion accelerator facility for the clinic in Heidelberg. An essential part for patients treatments is the measurement of the beam properties within acceptance and constancy tests and especially for the rasterscan method during the treatment sessions. The presented description of the accelerator controls and beam diagnostic devices mainly covers the requests for the active scanning method, which...
Dong, Shufang; Lu, Ke-Qian; Sun, J. Q.; Rudolph, Katherine
Resistance exercise has been widely reported to have positive rehabilitation effects for patients with neuromuscular and orthopaedic conditions. This paper presents an optimal design of magneto-rheological fluid dampers for variable resistance exercise devices. Adaptive controls for regulating the resistive force or torque of the device as well as the joint motion are presented. The device provides both isometric and isokinetic strength training for various human joints.
Full Text Available AIM: To evaluate retrospectively adult cases of viral encephalitis. METHOD: Fifteen patients described viral encephalitis hospitalized between the years 2006-2011 follow-up and treatment at the infectious diseases clinic were analyzed retrospectively. RESULTS: Most of the patients (%60 had applied in the spring. Fever (87%, confusion (73%, neck stiffness (73%, headache (73%, nausea-vomiting (33%, loss of consciousness (33%, amnesia (33%, agitation (20%, convulsion (%20, focal neurological signs (13%, Brudzinski-sign (13% were most frequently encountered findings. Electroencephalography test was applied to 13 of 14 patients, and pathological findings compatible with encephalitis have been found. Radiological imaging methods such as CT and MRI were performed in 9 of the 14 patients, and findings consistent with encephalitis were reported. All of initial cerebrospinal fluid (CSF samples were abnormal. The domination of the first examples was lymphocytes in 14 patients; only one patient had an increase in neutrophilic cells have been found. CSF protein level was high in nine patients, and low glucose level was detected in two patients. Herpes simplex virus polymerized chain reaction (PCR analyze was performed to fourteen patients CSF. Only two of them (14% were found positive. One of the patients sample selectively examined was found to be Parvovirus B19 (+, the other patient urine sample Jacobs-creutzfeld virus PCR was found to be positively. Empiric acyclovir therapy was given to all patients. Neuropsychiatric squeal developed at the one patient. CONCLUSION: The cases in the forefront of change in mental status viral meningoencephalitis should be considered and empirical treatment with acyclovir should be started. [TAF Prev Med Bull 2012; 11(4.000: 447-452
Takahashi, Koichi; Wang, Feng; Kantarjian, Hagop; Doss, Denaha; Khanna, Kanhav; Thompson, Erika; Zhao, Li; Patel, Keyur; Neelapu, Sattva; Gumbs, Curtis; Bueso-Ramos, Carlos; DiNardo, Courtney D; Colla, Simona; Ravandi, Farhad; Zhang, Jianhua; Huang, Xuelin; Wu, Xifeng; Samaniego, Felipe; Garcia-Manero, Guillermo; Futreal, P Andrew
Therapy-related myeloid neoplasms are secondary malignancies that are often fatal, but their risk factors are not well understood. Evidence suggests that individuals with clonal haemopoiesis have increased risk of developing haematological malignancies. We aimed to identify whether patients with cancer who have clonal haemopoiesis are at an increased risk of developing therapy-related myeloid neoplasms. We did this retrospective case-control study to compare the prevalence of clonal haemopoiesis between patients treated for cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). All patients in both case and control groups were treated at MD Anderson Cancer Center (Houston, TX, USA) from 1997 to 2015. We used the institutional medical database to locate these patients. Patients were included as cases if they were treated for a primary cancer, subsequently developed therapy-related myeloid neoplasms, and had available paired samples of bone marrow from the time of therapy-related myeloid neoplasm diagnosis and peripheral blood from the time of primary cancer diagnosis. Patients were eligible for inclusion as age-matched controls if they were treated for lymphoma, received combination chemotherapy, and did not develop therapy-related myeloid neoplasms after at least 5 years of follow-up. We used molecular barcode sequencing of 32 genes on the pretreatment peripheral blood samples to detect clonal haemopoiesis. For cases, we also used targeted gene sequencing on bone marrow samples and investigated clonal evolution from clonal haemopoiesis to the development of therapy-related myeloid neoplasms. To further clarify the association between clonal haemopoiesis and therapy-related myeloid neoplasm development, we also analysed the prevalence of clonal haemopoiesis in an external cohort of patients with lymphoma who were treated in a randomised trial of front-line chemotherapy with cyclophosphamide
Spitzyna, G A; Wise, R J S; McDonald, S A; Plant, G T; Kidd, D; Crewes, H; Leff, A P
An acquired right-sided homonymous hemianopia can result in slowed left-to-right text reading, called hemianopic alexia (HA). Patients with HA lack essential visual information to help guide ensuing reading fixations. We tested two hypotheses: first, that practice with a visual rehabilitation method that induced small-field optokinetic nystagmus (OKN) would improve reading speeds in patients with HA when compared to a sham visual rehabilitation therapy; second, that this therapy would preferentially affect reading saccades into the blind field. Nineteen patients with HA were entered into a two-armed study with two therapy blocks in each arm: one group practiced reading moving text (MT) that scrolled from right to left daily for two 4-week blocks (Group1), while the other had sham therapy (spot the difference) for the first block and then crossed over to MT for the second. Group 1 showed significant improvements in static text reading speed over both therapy blocks (18% improvement), while Group 2 did not significantly improve over the first block (5% improvement) but did when they crossed over to the MT block (23% improvement). MT therapy was associated with a direction-specific effect on saccadic amplitude for rightward but not leftward reading saccades. Optokinetic nystagmus inducing therapy preferentially affects reading saccades in the direction of the induced (involuntary) saccadic component. This is the first study to demonstrate the effectiveness of a specific eye movement based therapy in patients with hemianopic alexia (HA) in the context of a therapy-controlled trial. A free Web-based version of the therapy used in this study is available online to suitable patients with HA.
Harel, Shira; Yanai, Livia; Brooks, Ronit; Bar, Yakira; Bistritzer, Tzvy; Ivgi, Shosh; Rachmiel, Marianna
To evaluate the effect of intensive art therapy in youth with poorly controlled type 1 diabetes mellitus (T1DM). A retrospective report of the characteristics and outcomes of all patients who were offered to receive individual art therapy sessions because of behavioral difficulties. The study population included 29 participants. The main behavioral difficulties were needle phobia and lack of compliance with nutritional recommendations or with insulin administration. The intervention group included 16 patients, with a mean age of 9.3±2.5 years, average intervention length of 0.77±0.41 years, and long-term data of 2.27±1.13 years. The control group included 13 patients, with a mean age of 9.3±3.4 years. Improvement was observed in 56% of the case group and in 23% of the control group. Art therapy was associated with a decrease in hemoglobin A1c in the intervention group compared with a similar control group (-0.79%, ±0.24%; r=0.17, p=0.025). The addition of intensive art therapy for poorly controlled youth with T1DM may improve their glycemic control.
Ogasawara, Nobuhiko; Kobayashi, Masahiro; Akuta, Norio; Kominami, Yoko; Fujiyama, Shunichiro; Kawamura, Yusuke; Sezaki, Hitomi; Hosaka, Tetsuya; Suzuki, Fumitaka; Saitoh, Satoshi; Suzuki, Yoshiyuki; Arase, Yasuji; Ikeda, Kenji; Kobayashi, Mariko; Kumada, Hiromitsu
Little information is available on the impact of direct-acting antiviral (DAA) therapy on changes in liver fibrosis and steatosis. Liver stiffness (LS) and controlled attenuation parameter (CAP) values were evaluated using transient elastography. The study subjects were 214 elderly patients infected with HCV genotype 1b who received 24-week daclatasvir and asunaprevir dual therapy. All patients of this retrospective study had no hepatocellular carcinoma before and during DAA therapy. LS and CAP were assessed before treatment (baseline), at end of treatment (EOT), and at 24, 48, 72 weeks (W) after EOT. The rate of sustained viral response (SVR) by daclatasvir and asunaprevir therapy was 91%. LS values for the entire group correlated with Fib-4 index at baseline (r = 0.565, P < 0.001). LS in both chronic hepatitis group (Fib-4 index <3.25) and cirrhosis group (Fib-4 index ≥3.25) decreased significantly at each time point compared with baseline (P < 0.001). Especially, a larger decrease in LS from baseline to EOT was seen in the cirrhosis group than chronic hepatitis group (P < 0.001). LS was also significantly lower in the SVR group at EOT, 24W, 48W, 72W compared with baseline (P < 0.001). Even in the non-SVR group, LS tended to be lower at EOT (P = 0.039), 24W (P = 0.009), 48W (P = 0.475), 72W (P = 0.033) compared with baseline. CAP increased significantly following the treatment from baseline to 48W post-EOT (P = 0.018). Our results showed significant improvement in LS in response to daclatasvir and asunaprevir dual therapy. In the other hand, there was a tendency that CAP increased from baseline. © 2017 Wiley Periodicals, Inc.
Kinser, Patricia Anne; Robins, Jo Lynne
Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research about mind-body therapies, we suggest that researchers should consider 4 key questions: whether the study design matches the research question; whether the control group addresses performance, expectation, and detection bias; whether the control group is ethical, feasible, and attractive; and whether the control group is designed to adequately control for nonspecific intervention effects. Based on these questions, we provide specific recommendations about control group design with the goal of minimizing bias and maximizing validity in future research.
Ivančica Strunjak-Perović; Mato Hacmanjek; Rozelinda Čož-Rakovac; Emin Teskeredžić
Adequate knowledge on fish diseases caused by viruses is still lacking. Up until now, in fish which live their entire life cycle or part of it in the sea, some viral diseases have been determined (lymphoeytis, viral necrosis of crythrocytes, ciravosti cod syndrome, encephalitis, viral hemoragic septichemistry, viral hematopoetic necrosis, viral gusteraca necrosis, chum renviral infection, branchionephritis, rabdociral eel infection). Some of these diseases primarily occur in the freshwater ph...
Full Text Available Objective: Evaluate the impact of fixed-dose combination (FDC containing emtricitabine (FTC, tenofovir (TDF, and efavirenz (EFV versus a free-dose combination (FRC of the same three drugs on clinical outcomes, adherence and quality of life in Malaysian outpatients with HIV. Methods: HIV patients (n=120 on highly active antiretroviral therapy (HAART in the infectious disease clinic of Hospital Sungai Buloh were randomized to either FDC (n=60 or FRC (n=60. Morisky scores, health-related quality of life scores and clinical outcomes such as CD4 count and viral load were assessed in both groups at baseline and six months. Result: Patients on FDC (108 SD=1.1 had a significantly higher CD4 count increase compared to the FRC group (746.1 SD=36.3 vs 799.8 SD=33.8 (p <0.001. The viral load profile was unchanged and remained undetectable in both groups. The quality of life EQ-5D scores showed a positive correlation with CD4 counts in the FDC group (ρ=0.301, p=0.019 at six months. On the other hand, quality of life EQ-VAS scores was significantly associated with medication adherence in the FDC group at six months (ρ=0.749, p=0.05. However, no significant changes or associations were observed in the FRC group. Conclusion: Management of HAART using an FDC demonstrated a positive clinical outcome, adherence and quality of life within six months in local HIV patients.
Flaitz, C M; Hicks, M J
The vast majority of the human experience with viral infections is associated with acute symptoms, such as malaise, fever, chills, rhinitis and diarrhea. With this acute or lytic phase, the immune system mounts a response and eliminates the viral agent while acquiring antibodies to that specific viral subtype. With latent or chronic infections, the viral agent becomes incorporated into the human genome. Viral agents capable of integration into the host's genetic material are particularly dangerous and may commandeer the host's ability to regulate normal cell growth and proliferation. The oncogenic viruses may immortalize the host cell, and facilitate malignant transformation. Cell growth and proliferation may be enhanced by viral interference with tumor suppressor gene function (p53 and pRb). Viruses may act as vectors for mutated proto-oncogenes (oncogenes). Overexpression of these oncogenes in viral-infected cells interferes with normal cell function and allows unregulated cell growth and proliferation, which may lead to malignant transformation and tumour formation. Development of oral neoplasms, both benign and malignant, has been linked to several viruses. Epstein-Barr virus is associated with oral hairy leukoplakia, lymphoproliferative disease, lymphoepithelial carcinoma, B-cell lymphomas, and nasopharyngeal carcinoma. Human herpesvirus-8 has been implicated in all forms of Kaposi's sarcoma, primary effusion lymphomas, multiple myeloma, angioimmunoblastic lymphadenopathy, and Castleman's disease. Human herpesvirus-6 has been detected in lymphoproliferative disease, lymphomas, Hodgkin's disease, and oral squamous cell carcinoma. The role of human papillomavirus in benign (squamous papilloma, focal epithelial hyperplasia, condyloma acuminatum, verruca vulgaris), premalignant (oral epithelial dysplasia), and malignant (squamous cell carcinoma) neoplasms within the oral cavity is well recognized. Herpes simplex virus may participate as a cofactor in oral squamous
Full Text Available Abstract To date, almost one and a half million cases of cancer are diagnosed every year in the US and nearly 560,000 Americans are expected to die of cancer in the current year, more than 1,500 people a day (data from the American Cancer Society at http://www.cancer.org/. According to the World Health Organization (WHO, roughly 20% of all cancers worldwide results from chronic infections; in particular, up to 15% of human cancers is characterized by a viral aetiology with higher incidence in Developing Countries. The link between viruses and cancer was one of the pivotal discoveries in cancer research during the past Century. Indeed, the infectious nature of specific tumors has important implications in terms of their prevention, diagnosis, and therapy. In the 21st Century, the research on viral oncology field continues to be vigorous, with new significant and original studies on viral oncogenesis and translational research from basic virology to treatment of cancer. This review will cover different viral oncology aspects, starting from the history of viral oncology and moving to the peculiar features of oncogenic RNA and DNA viruses, with a special focus on human pathogens.
Michaëlsson, Karl; Baron, John A; Farahmand, Bahman Y; Johnell, Olof; Magnusson, Cecilia; Persson, Per-Gunnar; Persson, Ingemar; Ljunghall, Sverker
Objective: To determine the relative risk of hip fracture associated with postmenopausal hormone replacement therapy including the effect of duration and recency of treatment, the addition of progestins, route of administration, and dose. Design: Population based case-control study. Setting: Six counties in Sweden. Subjects: 1327 women aged 50-81 years with hip fracture and 3262 randomly selected controls. Main outcome measure: Use of hormone replacement therapy. Results: Compared with women who had never used hormone replacement therapy, current users had an odds ratio of 0.35 (95 % confidence interval 0.24 to 0.53) for hip fracture and former users had an odds ratio of 0.76 (0.57 to 1.01). For every year of therapy, the overall risk decreased by 6% (3% to 9%): 4% (1% to 8%) for regimens without progestin and 11% (6% to 16%) for those with progestin. Last use between one and five years previously, with a duration of use more than five years, was associated with an odds ratio of 0.27 (0.08 to 0.94). After five years without hormone replacement therapy the protective effect was substantially diminished (−7% to 48%). With current use, an initiation of therapy nine or more years after the menopause gave equally strong reduction in risk for hip fracture as an earlier start. Oestrogen treatment with skin patches gave similar risk estimates as oral regimens. Conclusions: Recent use of hormone replacement therapy is required for optimum fracture protection, but therapy can be started several years after the menopause. The protective effect increases with duration of use, and an oestrogen-sparing effect is achieved when progestins are included in the regimen. Key messages Hormone replacement therapy should be continued for long periods for optimal protection of hip fracture No overall substantial hip fracture protection remains after five years without hormone replacement therapy Therapy can be initiated several years after menopause without loss of fracture protection
Gradisar, Michael; Dohnt, Hayley; Gardner, Greg; Paine, Sarah; Starkey, Karina; Menne, Annemarie; Slater, Amy; Wright, Helen; Hudson, Jennifer L; Weaver, Edward; Trenowden, Sophie
To evaluate cognitive-behavior therapy plus bright light therapy (CBT plus BLT) for adolescents diagnosed with delayed sleep phase disorder (DSPD). Randomized controlled trial of CBT plus BLT vs. waitlist (WL) control with comparisons at pre- and post-treatment. There was 6-month follow-up for the CBT plus BLT group only. Flinders University Child & Adolescent Sleep Clinic, Adelaide, South Australia. 49 adolescents (mean age 14.6 ± 1.0 y, 53% males) diagnosed with DSPD; mean chronicity 4 y 8 months; 16% not attending school. Eighteen percent of adolescents dropped out of the study (CBT plus BLT: N = 23 vs. WL: N = 17). CBT plus BLT consisted of 6 individual sessions, including morning bright light therapy to advance adolescents' circadian rhythms, and cognitive restructuring and sleep education to target associated insomnia and sleep hygiene. DSPD diagnosis was performed via a clinical interview and 7-day sleep diary. Measurements at each time-point included online sleep diaries and scales measuring sleepiness, fatigue, and depression symptoms. Compared to WL, moderate-to-large improvements (d = 0.65-1.24) were found at post-treatment for CBT plus BLT adolescents, including reduced sleep latency, earlier sleep onset and rise times, total sleep time (school nights), wake after sleep onset, sleepiness, and fatigue. At 6-month follow-up (N = 15), small-to-large improvements (d = 0.24-1.53) continued for CBT plus BLT adolescents, with effects found for all measures. Significantly fewer adolescents receiving CBT plus BLT met DPSD criteria at post-treatment (WL = 82% vs. CBT plus BLT = 13%, P adolescent DSPD is effective for improving multiple sleep and daytime impairments in the immediate and long-term. Studies evaluating the treatment effectiveness of each treatment component are needed. Australia-New Zealand Trials Registry Number: ACTRN12610001041044.